David Fiorentino, MD, PhD

All Publications

• Clinical Characteristics of Anti-Synthetase Syndrome: Analysis from the CLASS project. Arthritis & rheumatology (Hoboken, N.J.) Faghihi-Kashani, S., Yoshida, A., Bozan, F., Zanframundo, G., Rozza, D., Loganathan, A., Dourado, E., Sambataro, G., Ventura, I. B., Bae, S. S., Lim, D., Gallegos, D. R., Yamano, Y., Selva-O'Callaghan, A., Mammen, A. L., Scirè, C. A., Montecucco, C., Oddis, C. V., Fiorentino, D., Bonella, F., Miller, F. W., Lundberg, I. E., Schmidt, J., Rojas-Serrano, J., Hudson, M., Kuwana, M., González-Gay, M. A., McHugh, N., Corte, T. J., Doyle, T. J., Werth, V. P., Gupta, L., Roman, D. I., Bianchessi, L. M., Devarasetti, P. K., Shinjo, S. K., Luppi, F., Cavazzana, I., Moghadam-Kia, S., Fornaro, M., Volkmann, E. R., Piga, M., Loarce-Martos, J., De Luca, G., Knitza, J., Wolff-Cecchi, V., Sebastiani, M., Schiffenbauer, A., Rider, L. G., Campanilho-Marques, R., Marts, L., Bravi, E., Gunawardena, H., Aggarwal, R., Cavagna, L. 2024

  Abstract

  Anti-synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data-driven classification criteria for ASSD.We utilized a large, international, multi-center "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both ASSD patients and controls with mimicking conditions, namely SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort.Our analysis included 948 ASSD cases and 1077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo-1 and non-Jo-1 anti-synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti-Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/MRI/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between ASSD and controls or were inversely associated with ASSD.We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data-driven classification criteria for ASSD.

  View details for DOI 10.1002/art.43038

  View details for PubMedID 39467037

• Lipodermatosclerosis and Pulmonary Hypertension in Systemic Sclerosis. JAMA dermatology Davuluri, S., Kapoor, P., Nandyala, S., Li, S., Simard, J., Lewis, M., Fiorentino, D., Chung, L. 2024

  Abstract

  Lipodermatosclerosis (LDS) stems from vascular dysfunction and dermal inflammation and thereby is mechanistically similar to systemic sclerosis (SSc). The association of LDS with SSc in the clinical setting has not been well characterized in the literature.To evaluate the prevalence of LDS in SSc and the association of LDS with vascular complications, particularly pulmonary hypertension, in patients with SSc.This retrospective cohort study used prospectively collected longitudinal data from a cohort of patients from the multidisciplinary rheumatology and dermatology clinic at a single tertiary care center from November 2004 to November 2022. Adult patients (aged ≥18 years at the time of cohort entry) with SSc were included.Clinical diagnosis of LDS based on expert opinion or histopathologic findings.The main outcomes included prevalence of LDS, the association of LDS with the macrovascular complications, including pulmonary hypertension, digital gangrene and/or scleroderma renal crisis. Disease complications, including cardiac arrhythmias and heart failure, were compared among patients with and without LDS.Among 567 patients with SSc (494 [87.1%] female; mean [SD] age, 53.4 [14.4] years), 25 (4.4%) had LDS and 542 (95.6%) did not have LDS. Skin ulceration occurred in 8 patients with LDS (32.0%). Patients with LDS had higher frequencies of cardiac arrhythmia (11 of 24 [45.8%] vs 145 of 539 [26.9%]), heart failure (7 [28.0%] vs 55 [10.1%]), and pulmonary hypertension (12 [48.0%] vs 137 of 541 [25.3%]) compared with patients without LDS. Frequency of scleroderma renal crisis and digital gangrene did not differ significantly between patients with and without LDS (0 vs 37 [6.8%] and 4 [16.0%] vs 69 of 538 [12.8%], respectively). Among patients with LDS, 9 (36.0%) were either discharged to hospice or died during follow-up compared with 115 patients without LDS (21.2%). Lipodermatosclerosis was associated with pulmonary hypertension (adjusted prevalence odds ratio, 3.10; 95% CI, 1.33-7.25).In this cohort study, LDS was a rare clinical manifestation in patients with SSc but was associated with pulmonary hypertension. Therefore, patients with LDS should be closely monitored and screened for pulmonary hypertension.

  View details for DOI 10.1001/jamadermatol.2024.3929

  View details for PubMedID 39412798

• Cutting-edge approaches to B-cell depletion in autoimmune diseases. Frontiers in immunology Robinson, W. H., Fiorentino, D., Chung, L., Moreland, L. W., Deodhar, M., Harler, M. B., Saulsbery, C., Kunder, R. 2024; 15: 1454747

  Abstract

  B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases.

  View details for DOI 10.3389/fimmu.2024.1454747

  View details for PubMedID 39445025

  View details for PubMedCentralID PMC11497632

• The Relationship Between Anti-Cell Division Cycle and Apoptosis Regulator 1 Autoantibodies, Anti-Sp4 Autoantibodies, and Cancer in Anti-Transcription Intermediary Factor 1γ-Positive Dermatomyositis. ACR open rheumatology Mecoli, C. A., Fiorentino, D., Albayda, J., Paik, J. J., Tiniakou, E., Adler, B., Mammen, A. L., Christopher-Stine, L., Rosen, A., Casciola-Rosen, L. 2024

  Abstract

  The objective of this study was to describe the frequency, co-occurrence, and cancer association of anti-cell division cycle and apoptosis regulator 1 (anti-CCAR1) and anti-Sp4 in two large independent adult dermatomyositis (DM) cohorts.Anti-transcription intermediary factor 1γ (anti-TIF1γ)-positive patients with DM from two independent cohorts were studied to determine the serologic overlap of anti-CCAR1 and anti-Sp4 autoantibodies measured by enzyme-linked immunosorbent assay. Associations between cancer-associated myositis (CAM) and antibody-defined subgroups within anti-TIF1γ-positive patients with DM were determined.A total of 305 anti-TIF1γ-positive patients with DM were studied: 169 patients from Johns Hopkins and 136 patients from Stanford. In each cohort, approximately one-third of anti-TIF1γ-positive patients with DM were anti-Sp4 positive, one-third were anti-CCAR1 positive, 20% were positive for both, and half of patients were negative for both. There was a strong association with CAM in patients lacking both these antibodies (Johns Hopkins, odds ratio [OR] 12.9 [95% confidence interval (CI) 3.6-89.5]; Stanford, OR 4.5 [95% CI 1.8-13.2]). The strongest negative association with CAM was found in patients with anti-Sp4 or anti-CCAR1 (Johns Hopkins, OR 0.07 [95% CI 0.01-0.27]; Stanford, OR 0.22 [95% CI 0.07-0.55]).Both anti-Sp4 and anti-CCAR1 autoantibody subgroups are negatively associated with CAM. Although the magnitude of this association is substantial, cancer occasionally occurs in patients positive for either specificity. Conversely, approximately half of anti-TIF1γ-positive patients with DM are negative for both antibodies (anti-Sp4/anti-CCAR1 negative), and thus this subgroup may warrant more intensive cancer surveillance.

  View details for DOI 10.1002/acr2.11750

  View details for PubMedID 39370373

• TLR7/8 Activation in Immune Cells and Muscle by RNA-Containing Immune Complexes: Role in Inflammation and the Pathogenesis of Myositis. Arthritis & rheumatology (Hoboken, N.J.) Wu, Y., Deshpande, A., Geraci, N., Budde, P., Sellers, V., Velisetty, P., Sun, C. C., Strand, F., Bhavsar, C., Niewold, T. B., Jensen, M. A., Kalatskaya, I., Sarin, K. Y., Fiorentino, D., Bender, A. T. 2024

  Abstract

  Activation of endosomal toll-like receptors (TLRs) is one possible driver of inflammation in idiopathic inflammatory myopathies (IIM). We investigated the potential contribution of TLR7 and TLR8 to IIM pathogenesis.Activation of TLR7/8 in healthy donor peripheral blood mononuclear cells (PBMCs) by immune complexes from patients with IIM and lupus was tested. Autoantibody profiling of patient IgG samples was performed using a 1581-antigen array. TLR7 and/or TLR8 activation by RNA molecules associated with autoantibodies was assessed. Gene expression in human myoblasts and satellite cells following treatment with supernatants from TLR7/8-activated PBMCs was evaluated by NanoString. C57BL/6 mice were dosed intramuscularly with the TLR7/8 agonist R848 and single-cell RNA-sequencing was performed on the muscle to ascertain the cell types responding to TLR7/8 activation and the downstream effects.Overall, 69 patients with IIM were included with representation of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) subsets. Immune complexes from patients with IIM, as well as autoantibody-associated RNAs His-tRNA, Y1, Y4 and U1, activated PBMCs to produce IFN-α and IL-6 via TLR7/8. Several canonical (Ro60, Ro52, HIST1H4A) and novel (IL-36RN) autoreactivities correlated highly with TLR7/8 activation. Supernatants from TLR7/8-activated PBMCs had a negative impact on human myoblasts and satellite cells. Endothelial cells were activated by R848 in mouse muscle in vivo, in addition to immune cells such as monocytes and macrophages.Our results suggest that patients with IIM have autoantibodies in their blood causing TLR7/8 activation, which leads to inflammation in muscles with potential deleterious effects.

  View details for DOI 10.1002/art.42989

  View details for PubMedID 39279150

• SOX-5 Transcription Factor: a Novel Psoriatic Autoantigen Preferentially Found in Women. ACR open rheumatology Orbai, A. M., Fiorentino, D., Perin, J., Darrah, E., Yang, Q., Gutierrez-Alamillo, L., Bingham, C. O., Petri, M., Rosen, A., Casciola-Rosen, L. 2024

  Abstract

  Adaptive immunity mediates psoriatic disease pathogenesis. We aimed to identify novel psoriatic autoantigens and their phenotypic associations in deeply characterized patient cohorts.Sera from psoriatic arthritis (PsA) patients were used for autoantibody discovery. Immunoprecipitations performed with cell lysates were on-bead digested, and autoantigens were identified by mass spectrometry. Prevalence and clinical features associated with anti-SRY-Box transcription factor-D (SOX-D) antibodies were determined by screening discovery cohorts of patients with PsA (n = 135), patients with psoriasis without PsA (n = 24), and healthy controls (n = 41). A PsA validation cohort (n = 325) and disease control samples of individuals with rheumatoid arthritis (RA; n = 66) and systemic lupus erythematosus (SLE, n = 66) were assayed for anti-SOX5 antibodies. Disease characteristics were compared by antibody status. Longitudinal data were analyzed using linear mixed-effects models with patient-specific intercept to ascertain associations. We also tested PsA sera for the recently described anti-ADAMTS-L5 autoantibody in PsA.The novel autoantigens identified were SOX-D transcription factors, with SOX-5 being the focus of this analysis. Anti-SOX5 antibodies were present in 8.9% (12 of 135) and 4.3% (14 of 323) of patients in the PsA discovery and validation cohorts, respectively, 12.5% of patients (3 of 24) in the psoriasis group, 2.4% (1 of 41) of healthy controls, and 7.6% (5 of 66) each of patients in the RA and SLE groups. Anti-SOX5 were associated with female sex in both PsA cohorts (discovery: 15.7% women, 2.6% men, P = 0.006; validation: 6.3% women, 1.4% men, P = 0.049). In a longitudinal analysis adjusted for sex, anti-SOX5 associated with biologic disease-modifying antirheumatic drug treatment (95% vs 61%; P = 0.001; n = 96) and with differences in estimated treatment effects by mechanism of action. Anti-ADAMTS-L5 autoantibodies were identified in 8 of 124 patients (6.5%) in the PsA group.SOX-D transcription factors are novel psoriatic autoantigens. Anti-SOX5 antibodies were preferentially found in women with PsA and associated with specific clinical and treatment characteristics, suggesting that anti-SOX5 antibodies may identify mechanistic subgroups. We independently validated anti-ADAMTS-L5 autoantibodies in PsA.

  View details for DOI 10.1002/acr2.11740

  View details for PubMedID 39218617

• Myositis and Its Mimics: Guideline Updates, MRI Characteristics, and New Horizons. AJR. American journal of roentgenology Zandee van Rilland, E. D., Yao, L., Stevens, K. J., Chung, L. S., Fiorentino, D. F., Boutin, R. D. 2024

  Abstract

  Myositis is defined as inflammation within skeletal muscle and is a subcategory of myopathy, which is more broadly defined as any disorder affecting skeletal muscle. Myositis may be encountered as a component of autoimmune and connective tissue disease, where it is described as idiopathic inflammatory myopathy. Myositis can also be caused by infections, as well as toxins and drugs, including newer classes of medications. MRI plays an important role in the diagnosis and evaluation of patients with suspected myositis, but many entities may have imaging features similar to myositis and can be considered myositis mimics. These include muscular dystrophies, denervation, deep venous thrombosis, diabetic myonecrosis, muscle injury, heterotopic ossification, and even neoplasms. In patients with suspected myositis, definitive diagnosis may require integrated analysis of imaging findings with clinical, laboratory, and pathology data. The objectives of this article are to review the fundamental features of myositis, including recent updates in terminology and consensus guidelines for idiopathic inflammatory myopathies, the most important MRI differential diagnostic considerations for myositis (i.e., myositis mimics), and new horizons, including the potential importance of artificial intelligence and multimodal integrated diagnostics in the evaluation of patients with muscle disorders.

  View details for DOI 10.2214/AJR.24.31359

  View details for PubMedID 38838235

• Filling the Prescription Gap: The Value of Community Support in Psoriasis Management. The British journal of dermatology Leeolou, M. C., Sarin, K. Y., Fiorentino, D. F. 2024

  View details for DOI 10.1093/bjd/ljae168

  View details for PubMedID 38635917

• Author Correction: International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening: an International Myositis Assessment and Clinical Studies Group (IMACS) initiative. Nature reviews. Rheumatology Oldroyd, A. G., Callen, J. P., Chinoy, H., Chung, L., Fiorentino, D., Gordon, P., Machado, P. M., McHugh, N., Selva-O'Callaghan, A., Schmidt, J., Tansley, S. L., Vleugels, R. A., Werth, V. P., Aggarwal, R. 2024

  View details for DOI 10.1038/s41584-024-01111-x

  View details for PubMedID 38548933

• International exchange on the clinical practice and research of rheumatic skin diseases: A report of the 5th International Conference of Cutaneous Lupus Erythematosus. The Journal of dermatology Hasegawa, M., Chasset, F., Chong, B. F., Fiorentino, D. F., Fujimoto, M., Nyberg, F., Sato, S., Wenzel, J., Werth, V. P. 2024

  Abstract

  The 5th International Conference of Cutaneous Lupus Erythematosus was held in Tokyo, Japan on May 9 and 10, 2023. The latest topics on the pathogenesis, diagnosis, assessment, and treatment of cutaneous lupus erythematosus, dermatomyositis, and scleroderma (systemic sclerosis, morphea) were presented by experts in each field and new developments discussed. In these rheumatic skin diseases, many clinical trials of novel therapies targeting cytokines, signaling molecules, plasmacytoid dendritic cells, B cells, and other molecules are currently underway, and standardization of outcome assessment was discussed. In addition, the selection of the therapeutic agents available for the diversity of each case is becoming more important, together with the ongoing pathophysiological analysis of the diseases. The achievements of this conference will further promote the development of clinical practice and research in rheumatic skin diseases through international exchange among researchers. We hope that by reporting a summary of the conference in this manuscript, we can share its contents with readers.

  View details for DOI 10.1111/1346-8138.17153

  View details for PubMedID 38450816

• Novel therapeutic targets in dermatomyositis. The Journal of dermatology Bax, C., Aghdasi, C., Fiorentino, D. 2024

  Abstract

  Dermatomyositis (DM) is a systemic autoimmune disease with variable clinical presentations, including inflammation in the skin, muscle, lungs, and/or joints. Current therapeutic strategies in DM typically include broad immunosuppression; however, the currently used modalities are not universally effective and are associated with various side effects, including risk of infection. There is currently a highly unmet need for more effective and well-tolerated therapies. Recent years have witnessed increased interest in pharmaceutical development of new therapeutic strategies for DM. This review aims to summarize the landscape of therapies that are currently being tested or planned in patients with DM. These therapies have a wide variety of immunological targets, including T cells, B cells, inflammatory signaling pathways, type I interferons, autoantibodies, and other targets.

  View details for DOI 10.1111/1346-8138.17170

  View details for PubMedID 38433369

• Performance of the 2017 EULAR/ACR Classification Criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a scoping review. Clinical and experimental rheumatology Saygin, D., Glaubitz, S., Zeng, R., Bottai, M., de Visser, M., Dimachkie, M. M., Fiorentino, D., Gerhardson, I., Kuwana, M., Miller, F. W., Needham, M., Rider, L. G., Salem, Y., Schlüter, S., Shinjo, S. K., Wang, G., Werth, V. P., Aggarwal, R., Lundberg, I. E. 2024

  Abstract

  The 2017 EULAR/ACR classification criteria for adult/juvenile idiopathic inflammatory myopathies (IIM) were established using a data-driven approach by an international group of myositis experts to allow classification of IIM and its major subtypes. Since their publication, the performance of the criteria has been tested in multiple cohorts worldwide and significant limitations have been identified. Moreover, the understanding and classification of IIM have evolved since 2017. This scoping review was undertaken as part of a large international project to revise the EULAR/ACR criteria and aims to i) summarise the evidence from the current literature on the performance characteristics of the 2017 EULAR/ACR classification criteria in various cohorts and IIM subtypes, and ii) delineate the factors that need to be considered in the revision of the classification criteria. A systematic search of Medline (via PubMed), Cumulative Index to Nursing and Allied Health Literature, and conference abstract archives was conducted independently by three investigators for studies on the EULAR/ACR criteria published between October 2017 and January 2023. This scoping review of 19 articles and 13 abstracts revealed overall good performance characteristics of the EULAR/ACR criteria for IIM, yet deficiencies in lack of inclusion of certain IIM subtypes, such as immune mediated necrotising myopathy, amyopathic dermatomyositis, antisynthetase syndrome and overlap myositis. Published modifications that may improve the performance characteristics of the criteria for classification of IIM subtypes were also summarised. The results of this review suggest that a revision of the EULAR/ACR criteria is warranted.

  View details for DOI 10.55563/clinexprheumatol/vuc5py

  View details for PubMedID 38436279

• Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell Dou, D. R., Zhao, Y., Belk, J. A., Zhao, Y., Casey, K. M., Chen, D. C., Li, R., Yu, B., Srinivasan, S., Abe, B. T., Kraft, K., Hellström, C., Sjöberg, R., Chang, S., Feng, A., Goldman, D. W., Shah, A. A., Petri, M., Chung, L. S., Fiorentino, D. F., Lundberg, E. K., Wutz, A., Utz, P. J., Chang, H. Y. 2024; 187 (3): 733-749.e16

  Abstract

  Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

  View details for DOI 10.1016/j.cell.2023.12.037

  View details for PubMedID 38306984

• Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank. Clinical and experimental rheumatology Loganathan, A., Zanframundo, G., Yoshida, A., Faghihi-Kashani, S., Bauer Ventura, I., Dourado, E., Bozan, F., Sambataro, G., Yamano, Y., Bae, S. S., Lim, D., Ceribelli, A., Isailovic, N., Selmi, C., Fertig, N., Bravi, E., Kaneko, Y., Saraiva, A. P., Jovani, V., Bachiller-Corral, J., Cifrian, J., Mera-Varela, A., Moghadam-Kia, S., Wolff, V., Campagne, J., Meyer, A., Giannini, M., Triantafyllias, K., Knitza, J., Gupta, L., Molad, Y., Iannone, F., Cavazzana, I., Piga, M., De Luca, G., Tansley, S., Bozzalla-Cassione, E., Bonella, F., Corte, T. J., Doyle, T. J., Fiorentino, D., Gonzalez-Gay, M. A., Hudson, M., Kuwana, M., Lundberg, I. E., Mammen, A. L., McHugh, N. J., Miller, F. W., Montecucco, C., Oddis, C. V., Rojas-Serrano, J., Schmidt, J., Scire, C. A., Selva-O'Callaghan, A., Werth, V. P., Alpini, C., Bozzini, S., Cavagna, L., Aggarwal, R., Classification Criteria of Anti-Synthetase Syndrome project biobank, Agarwal, V., Fornaro, M., Alberti, M. L., Needham, M., Houssiau, F., Shinjo, S., Basharat, P., Wang, Q., Quintana, G., Gallay, L., Ebstein, E., Fiehn, C., Feist, E., Schneider, M., Drott, U., Voll, R. E., Danko, K., Shobha, V., Rajasekhar, L., Danieli, M. G., Limonta, M., Matucci-Cerinic, M., Emmi, G., Parronchi, P., Bargagli, E., Maggi, L., Sebastiani, M., Pesci, A., Sainaghi, P. P., Bartolobi-Bocci, E., Barsotti, S., Nakashima, R., Pipitone, N., Riccieri, V., Sebastiani, G., Scarpato, S., Cantarini, L., Berti, A., Colombelli, P. L., Tomietto, P., Lomater, C., Quartuccio, L., Orsolini, G., Kondo, Y., Kimura, N., Vazquez-Del Mercado, M., Andersson, H., Cabral de Fonseca, J. E., Prieto-Gonzalez, S., Greco Merino, M. G., Castaneda, S., Barrio, J. M., Nuno, L., Pinto, I. R., Alen, J. C., Saez-Comet, L., Cagnotto, G., Alpsoy, E., Chinoy, H., Schiopu, E., Gandiga, P., Dimachkie, M., Charles-Schoeman, C., Wilfong, E., Marder, G., Gunawardena, H., Ghetie, D. 2024; 42 (2): 277-287

  Abstract

  OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity.METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted kappa co-efficient.RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods.CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

  View details for DOI 10.55563/clinexprheumatol/s14zq8

  View details for PubMedID 38488094

• International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening: an International Myositis Assessment and Clinical StudiesGroup (IMACS)initiative. Nature reviews. Rheumatology Oldroyd, A. G., Callen, J. P., Chinoy, H., Chung, L., Fiorentino, D., Gordon, P., Machado, P. M., McHugh, N., Selva-O'Callaghan, A., Schmidt, J., Tansley, S. L., Vleugels, R. A., Werth, V. P., International Myositis Assessment and Clinical Studies Group Cancer Screening Expert Group, Aggarwal, R., Amato, A. A., Andersson, H., Andrade-Ortega, L., Ascherman, D., Benveniste, O., Cavagna, L., Charles-Shoeman, C., Chong, B. F., Christopher-Stine, L., Clarke, J. T., Crosbie, E. J., Crosbie, P. A., Danoff, S., Dastmalchi, M., De Visser, M., Dellaripa, P. F., Diederichsen, L. P., Dimachkie, M. M., Ensrud, E., Ernste, F., Evans, D. G., Fujimoto, M., Garcia-De La Torre, I., Garcia-Kutzbach, A., Griger, Z., Gupta, L., Hudson, M., Iannone, F., Isenberg, D., Jorizzo, J., Kurtz, H., Kuwana, M., Limaye, V., Lundberg, I. E., Mammen, A. L., Mann, H., Mastaglia, F., McWilliams, L., Mecoli, C. A., Meloni, F., Miller, F. W., Moghadam-Kia, S., Moiseev, S., Muro, Y., Nagy-Vincze, M., Nayler, C., Needham, M., Nishino, I., Oddis, C. V., Paik, J. J., Raaphorst, J., Rider, L. G., Rojas-Serrano, J., Saketkoo, L. A., Schiffenbauer, A., Shinjo, S. K., Shobha, V., Song, Y., Tillett, T., Troyanov, Y., van der Kooi, A. J., Mercado, M. V., Vencovsky, J., Wang, Q., Ytterberg, S. 2023

  Abstract

  Adult-onset idiopathic inflammatory myopathy (IIM) is associated with an increased cancer risk within the 3 years preceding and following IIM onset. Evidence- and consensus-based recommendations for IIM-associated cancer screening can potentially improve outcomes. This International Guideline for IIM-Associated Cancer Screening provides recommendations addressing IIM-associated cancer risk stratification, cancer screening modalities and screening frequency. The international Expert Group formed a total of 18 recommendations via a modified Delphi approach using a series of online surveys. First, the recommendations enable an individual patient's IIM-associated cancer risk to be stratified into standard, moderate or high risk according to the IIM subtype, autoantibody status and clinical features. Second, the recommendations outline a 'basic' screening panel (including chest radiography and preliminary laboratory tests) and an 'enhanced' screening panel (including CT and tumour markers). Third, the recommendations advise on the timing and frequency of screening via basic and enhanced panels, according to risk status. The recommendations also advise consideration of upper or lower gastrointestinal endoscopy, nasoendoscopy and 18F-FDG PET-CT scanning in specific patient populations. These recommendations are aimed at facilitating earlier IIM-associated cancer detection, especially in those who are at a high risk, thus potentially improving outcomes, including survival.

  View details for DOI 10.1038/s41584-023-01045-w

  View details for PubMedID 37945774

• Xist Ribonucleoproteins Promote Female Sex-biased Autoimmunity Dou, D., Zhao, Y., Belk, J., Zhao, Y., Casey, K., Chen, D., Li, R., Yu, B., Srinivasan, S., Abe, B., Kraft, K., Hellstroem, C., Sjoeberg, R., Chang, S., Feng, A., Goldman, D., Shah, A., Petri, M., Chung, L., Fiorentino, D., Lundberg, E., Wutz, A., Utz, P., Chang, H. WILEY. 2023: 25-26

  View details for Web of Science ID 001190014300018

• Toll-Like Receptor 7/8 Activation of Immune and Non-Immune Cells in Muscle by RNA-Containing Immune Complexes Can Contribute to Inflammation and the Pathogenesis of Myositis Wu, Y., Deshpande, A., Geraci, N., Sellers, V., Velisetty, P., Fiorentino, D., Sarin, K. Y., Bender, A. WILEY. 2023: 3894-3896

  View details for Web of Science ID 001190014304016

• A Novel Association Between Lipodermatosclerosis and Key Vascular Outcomes in Systemic Sclerosis Davuluri, S., Kapoor, P., Nandyala, S., Fiorentino, D., Simard, J., Chung, L. WILEY. 2023: 1306-1309

  View details for Web of Science ID 001190014301148

• The type 1 interferon signature reflects multiple phenotypic and activity measures in dermatomyositis. Arthritis & rheumatology (Hoboken, N.J.) Tabata, M. M., Hodgkinson, L. M., Wu, T. T., Li, S., Huard, C., Zhao, S., Bennett, D., Johnson, J., Tierney, C., He, W., Buhlmann, J. E., Page, K. M., Johnson, K., Casciola-Rosen, L., Chung, L., Sarin, K. Y., Fiorentino, D. 2023

  Abstract

  The type 1 interferon (IFN1) pathway is upregulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic IFN1 activity in adult patients with DM.RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed during the course of their clinical care. A previously defined 13-gene IFN1 score was modeled as a function of demographic, serologic and clinical variables using both cross-sectional and longitudinal data.The pattern of IFN1-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to SLE. The median IFN1 score was higher or lower in patients with anti-MDA5 or anti-Mi2 antibodies, respectively, compared to patients without these antibodies. Absolute IFN1 score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA5 antibodies. Changes in the IFN1 score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation (ρ=0.84-0.95) between changes in the IFN1 score and skin disease activity.The IFN1 score independently associates with both skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA5 status reveals that the IFN1 score is strongly correlated with skin disease activity and provides support for IFN1 blockade as a therapeutic strategy for DM. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/art.42526

  View details for PubMedID 37096447

• Performance of the 2016 ACR-EULAR myositis response criteria in adult dermatomyositis/polymyositis therapeutic trials and consensus profiles. Rheumatology (Oxford, England) Saygin, D., Kim, H., Douglas, C., Erman, B., Wilkerson, J., McGrath, J. A., Oddis, C. V., Lundberg, I. E., Amato, A. A., García-De La Torre, I., Chinoy, H., Fiorentino, D., Chung, L., Song, Y. W., Miller, F. W., Ruperto, N., Vencovsky, J., Aggarwal, R., Rider, L. G. 2023

  Abstract

  The ACR-EULAR myositis response criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength versus extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening.Data from adult dermatomyositis/polymyositis patients in the rituximab (n = 147), etanercept (n = 14), and abatacept (n = 19) trials, and consensus patient profiles (n = 232) were evaluated. The Total Improvement Score (TIS), number of improving versus worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC.Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories.The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials.

  View details for DOI 10.1093/rheumatology/kead110

  View details for PubMedID 36929923

• Anti-CCAR1 autoantibodies are specific for anti-TIF1gamma-positive dermatomyositis and decrease cancer risk relative to the general population. Arthritis & rheumatology (Hoboken, N.J.) Fiorentino, D., Mecoli, C. A., Igusa, T., Albayda, J., Paik, J. J., Tiniakou, E., Adler, B., Mammen, A. L., Shah, A. A., Rosen, A., Christopher-Stine, L., Casciola-Rosen, L. 2023

  Abstract

  OBJECTIVES: To describe the disease specificity, clinical phenotype, and cancer associations of patients with autoantibodies against cell division cycle and apoptosis regulator 1 (CCAR1).METHODS: Dermatomyositis patients from two independent cohorts, as well as several rheumatic disease and healthy control cohorts, were studied to determine the frequency of anti-CCAR1 autoantibodies measured by ELISA. Clinical features of anti-CCAR1-positive dermatomyositis patients and cancer risk compared to the general population were determined.RESULTS: Anti-CCAR1 antibodies were significantly associated with anti-TIF1-gamma-positive compared to anti-TIF1-gamma-negative dermatomyositis patients (80/252 [32%] vs 14/186 [8%], p<0.001). These antibodies were not detected in the healthy control sera assayed (0/32) and were present at very low frequencies in other rheumatic diseases: 1/44 (2.3%) in anti-HMGCR-positive necrotizing myopathy sera, 1/44 (2.3%) in inclusion body myositis sera, and 3/46 (6.5%) in systemic lupus erythematosus patient sera. Upon examining data on cancer occurrence from dermatomyositis onset onwards, the observed number of cancers diagnosed in anti-TIF1-gamma-positive patients was significantly greater than expected in both cohorts, with standardized incidence ratios (SIRs) of 3.49 (95% CI 2.39-4.92), p<0.001 for Hopkins and 4.54 (95% CI 3.04-6.52), p<0.001 for Stanford. In patients who were anti-TIF1-gamma-positive/anti-CCAR1-positive, the SIRs decreased to 1.78 (95% CI 0.77-3.51), p=0.172 and 1.61 (95% CI 0.44-4.13), p=0.48 for Hopkins and Stanford, respectively.CONCLUSIONS: Anti-CCAR1 autoantibodies are specific for anti-TIF1-gamma-positive dermatomyositis. Their presence in anti-TIF1-gamma-positive patients attenuates the risk of cancer to a level comparable to that seen in the general population.

  View details for DOI 10.1002/art.42474

  View details for PubMedID 36762496

• Clinical Associations of Degos-Like Lesions in Patients With Systemic Sclerosis. JAMA dermatology Song, P., Li, S., Lewis, M. A., Fiorentino, D. F., Chung, L. 2023

  Abstract

  Importance: Degos-like lesions are cutaneous manifestations of a small-vessel vasculopathy that appear as atrophic, porcelain-white papules with red, telangiectatic borders. No study has adequately examined Degos-like lesions in patients with systemic sclerosis (SSc).Objective: To characterize the serologic, cutaneous, and internal organ manifestations associated with Degos-like lesions in a large cohort of patients with SSc.Design, Settings, and Participants: This retrospective cohort study involved adult patients with SSc who were seen at Stanford Rheumatologic Dermatology Clinic between January 1, 1998, and December 31, 2018. Participants fulfilled the 2013 classification criteria for SSc. Data analysis was conducted from February 1 to June 1, 2019.Main Outcomes and Measures: Data on demographic characteristics; autoantibody status; clinical characteristics, including cutaneous and systemic manifestations of SSc; and presence of Degos-like lesions were collected.Results: The cohort comprised 506 patients with SSc (447 females [88.3%]; mean [SD] age at first non-Raynaud disease symptoms, 46.1 [15.2] years). Twenty-seven patients (5.3%) had Degos-like lesions, of whom 24 (89.0%) had lesions affecting the fingers. Patients with Degos-like lesions were more likely to have diffuse cutaneous SSc compared with patients without lesions (15 [55.6%] vs 181 [37.8%]; P=.04). Degos-like lesions were also associated with acro-osteolysis (10 [37.0%] vs 62 [12.9%]; P<.01), digital ulcers (15 [55.6%] vs 173 [36.1%]; P=.04), and calcinosis (15 [55.6%] vs 115 [24.0%]; P<.01). While Degos-like lesions were not associated with internal organ manifestations, such as scleroderma renal crisis, interstitial lung disease, or pulmonary arterial hypertension, there was P<.10 for the association with gastric antral vascular ectasia.Conclusions and Relevance: Results of this study suggest an association of Degos-like lesions with diffuse cutaneous SSc and other cutaneous manifestations of vasculopathy, including acro-osteolysis, calcinosis, and digital ulcers. A prospective longitudinal study is warranted to examine the onset of Degos-like lesions and to elucidate whether these lesions play a role in SSc.

  View details for DOI 10.1001/jamadermatol.2022.6330

  View details for PubMedID 36753129

• DEVELOPING CLASSIFICATION CRITERIA FOR SKIN-PRE-DOMINANT DERMATOMYOSITIS: REVIEWING THE PROCESS FROM THE DELPHI METHOD TO INTERNAL VALIDATION Concha, J. S., Merola, J. F., Fiorentino, D., Dutz, J., Goodfield, M., Nyberg, F., Volc-Platzer, B., Fujimoto, M., Ang, C., Werth, V. P. CLINICAL & EXPER RHEUMATOLOGY. 2023: 472

  View details for Web of Science ID 000944146200128

• Current concepts and advances in dermatomyositis: a dermatological perspective CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Lim, D., Fiorentino, D., Werth, V. 2023; 41 (2): 359-369

  View details for Web of Science ID 000952863200023

• Trial of Intravenous Immune Globulin in Dermatomyositis. The New England journal of medicine Werth, V. P., Fiorentino, D. F., Vleugels, R. A. 2023; 388 (1): 94

  View details for DOI 10.1056/NEJMc2214285

  View details for PubMedID 36599069

• Current concepts and advances in dermatomyositis: a dermatological perspective. Clinical and experimental rheumatology Lim, D., Fiorentino, D., Werth, V. 2023

  Abstract

  Dermatomyositis (DM) is an autoimmune disorder in which clinically amyopathic DM, characterised by hallmark cutaneous findings in the absence of clinical weakness, represents 20% of patients. This review will highlight current concepts and recent advances made in DM from a dermatological perspective, with a discussion of skin-predominant DM and its distinct challenges regarding diagnosis and management as well as their implications in clinical trials. An update will be presented with respect to classification criteria, pathogenesis in cutaneous DM, myositis-specific autoantibodies and their associations with cutaneous findings, skin-specific outcome measures and new therapeutics with their efficacy in skin disease.

  View details for DOI 10.55563/clinexprheumatol/ue71ku

  View details for PubMedID 36622138

• Extreme Phenotype Approach Identifies Rare Variants in Systemic Sclerosis and Dermatomyositis Patients with Severe Calcinosis Davuluri, S., Kaundal, U., Lood, C., Kapoor, P., Kawano, Y., Dell'Orso, S., Deng, Z., McMahan, Z., Shah, A., Hummers, L., Kastner, D., Wigley, F., Fiorentino, D., Gourh, P., Chung, L. WILEY. 2022: 3297-3300

  View details for Web of Science ID 000877386504154

• Cutaneous Manifestations, Clinical Trials, Safety Efficacy and Safety of Lenabasum in the Phase 3 DeterMine Trial in Dermatomyositis Werth, V., White, B., Concha, J., Dan, J., Dgetluck, N., Hally, K., Constantine, S., Aggarwal, R., Fiorentino, D., Lundberg, I., Oddis, C. WILEY. 2022: 323-325

  View details for Web of Science ID 000877386500173

• Performance of the 2016 ACR/EULAR Myositis Response Criteria in Adult Dermatomyositis and Polymyositis Therapeutic Trials and Consensus Profiles Saygin, D., Kim, H., Douglas, C., Erman, B., Wilkerson, J., Mcgrath, J., Oddis, C., Lundberg, I., Amato, A., Garcia-De la Torre, I., Chinoy, H., Fiorentino, D., Chung, L., Song, Y., Danko, K., Miller, F., Ruperto, N., Vencovsky, J., Aggarwal, R., Rider, L. G. WILEY. 2022: 4446-4448

  View details for Web of Science ID 000877386506214

• Cancer Screening Recommendations for Patients with Idiopathic Inflammatory Myopathy Oldroyd, A., Callen, J., Chinoy, H., Chung, L., Fiorentino, D., Gordon, P., Machado, P., McHugh, N., O'Callaghan, A., Schmidt, J., Tansley, S., Vleugels, R., Werth, V., Aggarwal, R. WILEY. 2022: 2-5

  View details for Web of Science ID 000877386500003

• Cessation of immunomodulatory medication use in dermatomyositis: a single center cohort study. Arthritis care & research Cho, S. K., Casciola-Rosen, L., Kapoor, P., Chung, L., Fiorentino, D. 2022

  Abstract

  OBJECTIVE: To determine the frequency with which adults with dermatomyositis (DM) are able to discontinue systemic immunomodulatory therapy and factors associated with medication cessation.METHODS: We studied a cohort of adult DM patients seen in a rheumatology/dermatology clinic between 2013 to 2020. All patients had exposure to at least one systemic immunomodulatory medication for a minimum of 3 months and were followed until medications were discontinued for at least 12 months. Survival analysis was performed using Kaplan-Meier curves with log rank analyses and multivariate analysis was done using Cox proportional-hazards models.RESULTS: 246 DM patients were followed for a median time of approximately 7years (47-134 months). 47 patients (19%) discontinued all immunomodulatory medications with a median follow-up of approximately 3years (IQR=22-108 months) following DM onset. Log rank analysis demonstrated that those with anti-MDA5 autoantibodies discontinued medications faster compared to those without autoantibodies (p=0.03). Multivariate modeling showed that clinically amyopathic patients were 2.7-fold (CI 1.34-5.59) more likely to discontinue medications than those with muscle disease. Those with anti-MDA5, anti-NXP2, and anti-SAE1 antibodies had increased likelihood of medication cessation with hazard ratios of 9.83 (CI 2.00-48.2), 8.92 (CI 1.69-47.0), and 10.8 (CI 2.06-56.6) respectively when compared to the autoantibody-negative group.CONCLUSION: Approximately 20% of adult DM patients discontinued immunomodulatory medications over a median 7-year follow-up. Those with clinically amyopathic disease, anti-MDA5, anti-NXP2, and anti-SAE1 antibodies have a higher likelihood of medication cessation.

  View details for DOI 10.1002/acr.24980

  View details for PubMedID 35792485

• Autoantibodies and Cancer Association: the Case of Systemic Sclerosis and Dermatomyositis. Clinical reviews in allergy & immunology Fiorentino, D. F., Casciola-Rosen, L. 2022

  Abstract

  Several rheumatic diseases have a perplexing association with cancer. Unraveling this mysterious connection is likely to provide deeper understanding regarding mechanisms governing the onset of both autoimmunity and cancer immunity, in addition to providing clinicians much needed guidance around whom and when to screen for occult malignancy. Systemic sclerosis (scleroderma) and dermatomyositis are two diseases in which the association with internal malignancy is well-described and can be considered as models from which to gain important insights that likely have broader applicability. The past 15 years have witnessed a striking acceleration in understanding how these two diseases are related to cancer emergence-an important crack in this inscrutable armor has been the discovery and characterization of disease-specific autoantigens that are closely tied with risk of cancer emergence. The best-described examples of this are antibodies against anti-RNA polymerase III (anti-POL3) and transcription intermediary factor 1-gamma (anti-TIF1gamma). Patients with systemic sclerosis and cancer that are diagnosed within a short time interval of each other frequently have anti-POL3 antibodies. Antibodies against the minor spliceosome protein RNA-Binding Region Containing 3 (RNPC3) are also associated with increased cancer incidence in systemic sclerosis. Similarly, in the dermatomyositis spectrum, the majority of anti-TIF1gamma-associated cancers are detected around the time of DM onset (most often within 1 year). Antibodies against Nuclear Matrix Protein 2 are also potentially associated with increased cancer emergence in dermatomyositis. The systemic sclerosis/anti-POL3 connection with close cancer onset led to the first experiments directly supporting the concept that rheumatic disease may in fact be a manifestation of cancer. It is now clear that studying these diseases through the lens of autoantibodies can reveal relationships and insights that would otherwise remain obscured. Extending these studies, new findings show that antibodies against RNA polymerase I large subunit are associated with protection against short interval cancers in anti-POL3-positive systemic sclerosis patients. These insights highlight the fact that autoantigen discovery related to cancer emergence remains an important priority; such new tools will enable the testing of specific hypotheses regarding mechanisms governing disease emergence and development of effective anti-tumor responses. Autoantibody phenotype will likely play an important role in the development of cancer screening guidelines that are critically needed by clinicians taking care of these patients. In this review, we will summarize the current state of knowledge regarding the different ways in which autoantibodies are connected with systemic sclerosis/dermatomyositis and malignancy and highlight potential paths forward.

  View details for DOI 10.1007/s12016-022-08944-y

  View details for PubMedID 35593962

• Update on Cutaneous Signs to Assist in the Diagnosis of Dermatomyositis. Current rheumatology reports El-Banna, G., Fiorentino, D. 2022

  Abstract

  PURPOSE OF REVIEW: Dermatomyositis (DM) is a heterogeneous idiopathic inflammatory myopathy that can be challenging to diagnose. Learning about the cutaneous manifestations in DM can assist with prompt diagnosis as well as subgroup classification. This review highlights recent data regarding cutaneous signs in DM and their associations with myositis-specific antibodies (MSAs).RECENT FINDINGS: Several novel DM skin signs have recently been reported. Novel and confirmatory data have helped to define more clearly the associations between various cutaneous manifestations and MSAs. Awareness of the diverse cutaneous phenotypes can help with the timely diagnosis of DM. As some MSAs are associated with atypical skin features and/or characteristic patterns of clinical findings, knowledge of these associations can help clinicians to recognize DM patients. Understanding how the prevalence and presentation of various cutaneous signs differ among ethnically diverse patients is a high priority for further study.

  View details for DOI 10.1007/s11926-022-01070-w

  View details for PubMedID 35404005

• Gastrointestinal Perforation in a patient with Anti-nuclear Matrix Protein 2 Antibody Positive Dermatomyositis. Arthritis care & research Valenzuela, A., Rieger, K. E., Blish, C. A., Chung, L., Fiorentino, D. 2022

  View details for DOI 10.1002/acr.24879

  View details for PubMedID 35287251

• Change in calcinosis over 1 year using the scleroderma clinical trials consortium radiologic scoring system for calcinosis of the hands in patients with systemic sclerosis. Seminars in arthritis and rheumatism Valenzuela, A., Stevens, K., Chung, M. P., Rodriguez-Reyna, T. S., Proudman, S., Baron, M., Castelino, F. V., Hsu, V., Green, L., Galdo, F. D., Li, S., Fiorentino, D., Chung, L. 2022; 53: 151980

  Abstract

  INTRODUCTION: Calcinosis cutis is a debilitating complication of systemic sclerosis (SSc). We previously developed a radiographic scoring system to assess severity of calcinosis affecting the hands in patients with SSc. We sought to further validate our radiographic scoring system to assess for change over 1 year and to identify factors associated with improvement or progression.MATERIALS AND METHODS: Baseline and 1-year antero-posterior hand radiographs were obtained in 39 SSc patients with calcinosis prospectively enrolled at 6 centers within the US, Canada, Mexico and Australia. Two readers (one radiologist and one rheumatologist) scored all radiographs using the calcinosis scoring system and a 5-point Likert scale (1=A lot better, 2=A little better, 3=No change, 4=A little worse, 5=A lot worse) on follow-up. By maximizing the Kappa coefficient of agreement between grouped Likert scale (better/no change/worse) and the percentage of change of calcinosis in the radiographic scoring system, we defined progressive calcinosis as >25% increase in score from baseline at 1-year, stable calcinosis as change in score between -25% to 25%, and improvement of calcinosis as decrease in score by >25%. Nineteen SSc patients from an independent cohort were used for validation.RESULTS: Inter-rater reliability of the calcinosis scoring system was high with intra-class correlation coefficient of 0.93 (0.89-0.95). The median percentage of change from baseline to 1 year was 12.8% (range -89.3 to 290.2%). Sixteen patients (41%) experienced progression of calcinosis over 1 year; 18 (46%) remained stable; and 5 (13%) had improvement. Patients with progressive calcinosis had lower T-score on bone densitometry (-3.3vs -1.7, p=0.044) and higher prevalence of loss of digital pulp on physical exam (56% vs 22%, p=0.027), with a trend towards lower baseline modified Rodnan skin score (mRSS) (3.8vs. 5.9, p=0.057), than patients who did not progress. Patients who experienced improvement in calcinosis had lower prevalence of digital pitting scars (20% vs 71%, p=0.047) than patients whose calcinosis did not improve. In multivariable analysis, loss of digital pulp remained a predictor of calcinosis progression (OR 5.8, p=0.023, CI 1.27 - 26.36). In the validation cohort, 2 (11%) patients improved, 10 (53%) remained stable, and 7 (37%) progressed.CONCLUSIONS: We confirmed the excellent inter-rater reliability of our radiographic calcinosis scoring system and demonstrated its usefulness to detect change over time. Approximately 40% of patients experienced progression of calcinosis over 1 year. Loss of digital pulp was predictive of progressive calcinosis providing further evidence that digital ischemia contributes to the progression of calcinosis.

  View details for DOI 10.1016/j.semarthrit.2022.151980

  View details for PubMedID 35183935

• Defining anti-synthetase syndrome: a systematic literature review. Clinical and experimental rheumatology Zanframundo, G., Faghihi-Kashani, S., Scire, C. A., Bonella, F., Corte, T. J., Doyle, T. J., Fiorentino, D., Gonzalez-Gay, M. A., Hudson, M., Kuwana, M., Lundberg, I. E., Mammen, A., McHugh, N., Miller, F. W., Monteccucco, C., Oddis, C. V., Rojas-Serrano, J., Schmidt, J., Selva-O'Callaghan, A., Werth, V. P., Sakellariou, G., Aggarwal, R., Cavagna, L. 2022; 40 (2): 309-319

  Abstract

  OBJECTIVES: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We systematically reviewed the literature to analyse proposed ASSD criteria, characteristics, and diagnostic performance.METHODS: We searched PubMed and Embase databases (01/01/1984 to 06/11/2018) and the ACR and EULAR meeting abstracts (2017-2018). Sensitivities, specificities, positive, negative likelihood ratios and risk of bias were calculated for ASSD criteria and key variables reported in the literature. We performed meta-analysis when appropriate.RESULTS: We retrieved 4,358 studies. We found 85 proposed ASSD criteria from a total of 82 studies. All but one study included anti-synthetase autoantibody (ARS) positivity in the ASSD criteria. Most studies required only one ASSD feature plus anti-ARS to define ASSD (n=64, 78%), whereas 16 studies required more than one ASSD variable plus anti-ARS. The only criteria not including anti-ARS positivity required 5 ASSD clinical features. We found limited data and wide variability in the diagnostic performance of each variable and definition proposed in the literature. Given these limitations we only meta-analysed the performance of individual muscle biopsy and clinical variables in diagnosing ASSD, which performed poorly.CONCLUSIONS: The current ASSD criteria include a variety of serological, clinical, and histological features with wide variability amongst proposed definitions and the performance of these definitions has not been tested. This systematic literature review suggests the need for additional data and consensus-driven classification criteria for ASSD.

  View details for PubMedID 35225224

• Defining anti-synthetase syndrome: a systematic literature review CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Zanframundo, G., Faghihi-Kashani, S., Scire, C. A., Bonella, F., Corte, T. J., Doyle, T. J., Fiorentino, D., Gonzalez-Gay, M. A., Hudson, M., Kuwana, M., Lundberg, I. E., Mammen, A., McHugh, N., Miller, F. W., Montecucco, C., Oddis, C. V., Rojas-Serrano, J., Schmidt, J., Selva-O'Callaghan, A., Werth, V. P., Sakellariou, G., Aggarwal, R., Cavagna, L. 2022; 40 (2): 309-319

  View details for Web of Science ID 000762805800016

• Immune responses to CCAR1 and other dermatomyositis autoantigens are associated with attenuated cancer emergence. The Journal of clinical investigation Fiorentino, D. F., Mecoli, C. A., Rosen, M. C., Chung, L. S., Christopher-Stine, L., Rosen, A., Casciola-Rosen, L. 1800; 132 (2)

  Abstract

  BACKGROUNDThe temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-gamma (TIF1-gamma). Nevertheless, many patients with anti-TIF1-gamma antibodies never develop cancer. We investigated whether additional autoantibodies are found in anti-TIF1-gamma-positive patients without cancer.METHODSUsing a proteomic approach, we defined 10 previously undescribed autoantibody specificities in 5 index anti-TIF1-gamma-positive DM patients without cancer. These were subsequently examined in discovery (n = 110) and validation (n = 142) cohorts of DM patients with anti-TIF1-gamma autoantibodies.RESULTSWe identified 10 potentially novel autoantibodies in anti-TIF1-gamma-positive DM patients, 6 with frequencies ranging from 3% to 32% in 2 independent DM cohorts. Autoantibodies recognizing cell division cycle and apoptosis regulator protein 1 (CCAR1) were the most frequent, and were significantly negatively associated with contemporaneous cancer (discovery cohort OR 0.27 [95% CI 0.7-1.00], P = 0.050; validation cohort OR 0.13 [95% CI 0.03-0.59], P = 0.008). When cancer did emerge, it occurred significantly later in anti-CCAR1-positive compared with anti-CCAR1-negative patients (median time from DM onset 4.3 vs. 0.85 years, respectively; P = 0.006). Cancers that emerged were more likely to be localized (89% of anti-CCAR1-positive cancers presenting at stage 0 or 1 compared with 42% of patients without anti-CCAR1 antibodies, P = 0.02). As the number of additional autoantibody specificities increased in anti-TIF1-gamma-positive DM patients, the frequency of cancer decreased (P < 0.001).CONCLUSIONAs the diversity of immune responses in anti-TIF1-gamma DM patients increases, the likelihood of cancer emerging decreases. Our findings have important relevance for cancer risk stratification in DM patients and for understanding natural immune regulation of cancer in humans.TRIAL REGISTRATIONNot applicable.FUNDING SOURCESThe NIH, the Donald B. and Dorothy L. Stabler Foundation, and the Huayi and Siuling Zhang Discovery Fund.

  View details for DOI 10.1172/JCI150201

  View details for PubMedID 35040440

• Corrigendum to: A systematic review and meta-analysis to inform cancer screening guidelines in idiopathic inflammatory myopathies. Rheumatology (Oxford, England) Oldroyd, A. G., Allard, A. B., Callen, J. P., Chinoy, H., Chung, L., Fiorentino, D., George, M. D., Gordon, P., Kolstad, K., Kurtzman, D. J., Machado, P. M., McHugh, N. J., Postolova, A., Selva-O'Callaghan, A., Schmidt, J., Tansley, S., Vleugels, R. A., Werth, V. P., Aggarwal, R. 2021

  View details for DOI 10.1093/rheumatology/keab616

  View details for PubMedID 34689208

• Factors Impacting Likelihood of Discontinuing Immunosuppression in Adult Dermatomyositis: A Single-Center Study Cho, S., Chung, L., Fiorentino, D. WILEY. 2021: 2138-2140

  View details for Web of Science ID 000744545204066

• Peripheral blood leucocyte telomere length is associated with progression of interstitial lung disease in systemic sclerosis. Thorax Liu, S., Chung, M. P., Ley, B., French, S., Elicker, B. M., Fiorentino, D. F., Chung, L. S., Boin, F., Wolters, P. J. 2021

  Abstract

  BACKGROUND: Peripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown.METHODS: A retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database.RESULTS: Patients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671base pairs (bp) vs 6782±698bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000bp TL decrease, 95%CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647bp vs 6651±653bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67mL greater loss in per year for every 1000bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95%CI -104 mL to -33mL, p<0.001).CONCLUSIONS: These findings suggest that telomere dysfunction may be associated with SSc-ILD progression and that PBL-TL measurement may be useful for stratifying risk for SSc-ILD progression.

  View details for DOI 10.1136/thoraxjnl-2020-215918

  View details for PubMedID 34272332

• Distinct purpuric lesions in patients with dermatomyositis. JAAD case reports Cho, S. K., Messenger, E., Fiorentino, D. F. 2021; 13: 94-96

  View details for DOI 10.1016/j.jdcr.2021.05.006

  View details for PubMedID 34179326

• Why rheumatologic skin disease? ANNALS OF TRANSLATIONAL MEDICINE Sontheimer, R. D., Connolly, M., Fiorentino, D. F., Werth, V. P. 2021; 9 (5): 428

  View details for DOI 10.21037/atm-2020-rsd-14

  View details for Web of Science ID 000632038100008

  View details for PubMedID 33842649

  View details for PubMedCentralID PMC8033298

• A Systematic Review and Meta-Analysis to Inform Cancer Screening Guidelines in Idiopathic Inflammatory Myopathies. Rheumatology (Oxford, England) Oldroyd, A. G., Allard, A. B., Callen, J. P., Chinoy, H., Chung, L., Fiorentino, D., George, M. D., Gordon, P., Kolstad, K., Kurtzman, D. J., Machado, P. M., McHugh, N. J., Postolova, A., Selva-O'Callaghan, A., Schmidt, J., Tansley, S., Vleugels, R. A., Werth, V. P., Aggarwal, R. 2021

  Abstract

  OBJECTIVES: To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening.METHODS: A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared to the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesised via narrative review.RESULTS: Sixty nine studies were included in the meta-analysis. Dermatomyositis subtype (RR 2.21), older age (WMD 11.19), male gender (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73), and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. Polymyositis (RR 0.49) and clinically amyopathic dermatomyositis (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD -1189.96) or lactate dehydrogenase (WMD -336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. Computed tomography (CT) scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers.DISCUSSION: Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.

  View details for DOI 10.1093/rheumatology/keab166

  View details for PubMedID 33599244

• Dermatomyositis autoantibodies: how can we maximize utility? Annals of Translational Medicine Hodgkinson, L. M., Wu, T. T., Fiorentino, D. F. 2021: 433

  Abstract

  The past 15 years has seen significant advances in the characterization of myositis-specific autoantibodies (MSAs) and their associated phenotypes in patients with dermatomyositis (DM). As more careful studies are performed, it is clear that unique combinations of clinical and pathological phenotypes are associated with each MSA, despite the fact that there is considerable heterogeneity within antibody classes as well as overlap across the groups. Because risk for interstitial lung disease (ILD), internal malignancy, adverse disease trajectory, and, potentially response to therapy differ by DM MSA group, a deeper understanding of MSAs and validation and standardization of assays used for detection are critical for optimizing diagnosis and treatment. Like any test, the diagnostic sensitivity and specificity of assays for various MSAs is not perfect. Currently tests for MSAs are helpful at minimum for a clinician to assess relative risk or contribute to diagnosis and perhaps counsel the appropriate patient about what to expect. With international standardization and larger studies it is likely that more antibody tests will make their way into formal schemata for diagnosis and actionable risk assessment in DM. In this review, we summarize key considerations for interpreting the clinical and pathologic associations with MSA in DM and identify critical gaps in knowledge and practice that will maximize their clinical utility and utility for understanding disease pathogenesis.

  View details for DOI 10.21037/atm-20-5175

  View details for PubMedCentralID PMC8033377

• A Pilot Study to Evaluate the Safety and Efficacy of Treprostinil in the Treatment of Calcinosis in Systemic Sclerosis. Rheumatology (Oxford, England) Chung, M. P., Valenzuela, A., Li, S., Catanese, B., Stevens, K., Fiorentino, D., Strand, V., Chung, L. 2021

  Abstract

  We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis.This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of ≥ 1 calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year (<25% increase in Scleroderma Clinical Trials Consortium radiographic score). Secondary endpoints included 1-year changes in Scleroderma HAQ (SHAQ), Cochin Hand Functional Scale, Medical Outcomes Survey Short Form 36 (SF-36), Raynaud Condition Score, and patient/physician assessment of calcinosis severity.Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 (range 35-68) years. Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1), and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of 5 who completed treatment, calcinosis was stable in 4 (80%) with progression in 1. Based on SF-36 Physical (PCS) and Mental (MCS) Component and Domain scores, transition question, and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline.Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of 5 patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year.NCT02663895.

  View details for DOI 10.1093/rheumatology/keab810

  View details for PubMedID 34718447

• Author Correction: Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis. Nature communications Liu, Q., Zaba, L. C., Satpathy, A. T., Longmire, M., Zhang, W., Li, K., Granja, J., Guo, C., Lin, J., Li, R., Tolentino, K., Kania, G., Distler, O., Fiorentino, D., Chung, L., Qu, K., Chang, H. Y. 2020; 11 (1): 6416

  View details for DOI 10.1038/s41467-020-20411-w

  View details for PubMedID 33318485

• Preliminary Baseline Subject Demographics and Disease Characteristics in a Phase 3 Clinical Trial of the Safety and Efficacy of Lenabasum in Dermatomyositis (DETERMINE) Werth, V., Oddis, C., Fiorentino, D., Dgetluck, N., Quinn Dinh, Tillinger, M., White, B., Lundberg, I. WILEY. 2020

  View details for Web of Science ID 000587568505143

• Increased Mortality in Asians With Systemic Sclerosis in Northern California. ACR open rheumatology Chung, M. P., Dontsi, M., Postlethwaite, D., Kesh, S., Simard, J. F., Fiorentino, D., Zaba, L. C., Chung, L. 2020

  Abstract

  OBJECTIVE: The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients.METHODS: A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference.RESULTS: A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome.CONCLUSION: Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.

  View details for DOI 10.1002/acr2.11126

  View details for PubMedID 32198914

• Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis. Nature communications Liu, Q., Zaba, L., Satpathy, A. T., Longmire, M., Zhang, W., Li, K., Granja, J., Guo, C., Lin, J., Li, R., Tolentino, K., Kania, G., Distler, O., Fiorentino, D., Chung, L., Qu, K., Chang, H. Y. 2020; 11 (1): 5843

  Abstract

  Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.

  View details for DOI 10.1038/s41467-020-19702-z

  View details for PubMedID 33203843

• Gastric antral vascular ectasia in systemic sclerosis: Association with anti-RNA polymerase III and negative anti-nuclear antibodies. Seminars in arthritis and rheumatism Serling-Boyd, N. n., Chung, M. P., Li, S. n., Becker, L. n., Fernandez-Becker, N. n., Clarke, J. n., Fiorentino, D. n., Chung, L. n. 2020; 50 (5): 938–42

  Abstract

  Gastric antral vascular ectasia (GAVE) is a vascular manifestation of systemic sclerosis (SSc) that can lead to iron deficiency anemia or acute gastrointestinal (GI) bleeding. We aimed to identify clinical features associated with GAVE.We performed a cohort study of SSc patients who were seen at Stanford between 2004 and 2018 and had undergone esophagogastroduodenoscopy (EGD). We compared the clinical features of those with and without GAVE, and multivariable logistic regression was performed to identify clinical correlates with GAVE.A total of 225 patients with SSc who underwent EGD were included in this study and 19 (8.4%) had GAVE. Those with GAVE were more likely to have scleroderma renal crisis (SRC) (21% vs 3%; p < 0.01), positive anti-RNA polymerase III antibody (71% vs 19%; p < 0.01), nucleolar pattern of anti-nuclear antibody (ANA) (33% vs 11%; p=0.04), and negative ANA (<1:80 by immunofluorescence) (33% vs 11%; p=0.02). On multivariate analysis with multiple imputation, anti-RNA polymerase III positivity (OR 4.57; 95% CI (1.57 - 13.23), p < 0.01) and ANA negativity (OR 3.75; 95% CI (1.21 - 11.62), p=0.02) remained significantly associated with GAVE.Positive anti-RNA polymerase III antibody and ANA negativity were significantly associated with GAVE. Further studies are necessary to determine whether patients with these autoantibody profiles should undergo screening endoscopies for GAVE.

  View details for DOI 10.1016/j.semarthrit.2020.06.016

  View details for PubMedID 32906028

• A phase 2 double-blinded, placebo-controlled trial of toll-like receptor 7,8,9 antagonist, IMO-8400, in dermatomyositis. Journal of the American Academy of Dermatology Kim, Y. J., Schiopu, E. n., Dankó, K. n., Mozaffar, T. n., Chunduru, S. n., Lees, K. n., Goyal, N. n., Sarazin, J. n., Fiorentino, D. F., Sarin, K. Y. 2020

  View details for DOI 10.1016/j.jaad.2020.07.122

  View details for PubMedID 32781178

• A Mortality Risk Score Model for Clinically Amyopathic Dermatomyositis-Associated Interstitial Lung Disease: Will It Have the Necessary "FLAIR" to Improve Clinical Outcomes? Chest Baker, M. C., Chung, L. n., Fiorentino, D. F. 2020; 158 (4): 1307–9

  View details for DOI 10.1016/j.chest.2020.06.001

  View details for PubMedID 33036075

• Calcinosis is associated with ischemic manifestations and increased disability in patients with systemic sclerosis. Seminars in arthritis and rheumatism Valenzuela, A. n., Baron, M. n., Rodriguez-Reyna, T. S., Proudman, S. n., Khanna, D. n., Young, A. n., Hinchcliff, M. n., Steen, V. n., Gordon, J. n., Hsu, V. n., Castelino, F. V., Schoenfeld, S. n., Li, S. n., Wu, J. Y., Fiorentino, D. n., Chung, L. n. 2020; 50 (5): 891–96

  Abstract

  Calcinosis is a debilitating complication of systemic sclerosis (SSc) with no effective treatments. We sought to identify clinical correlations and to characterize complications and disability associated with calcinosis in a multi-center, international cohort of SSc patients.We established a cohort of 568 consecutive SSc patients who fulfill 2013 revised ACR/EULAR criteria at 10 centers within North America, Australia, and Mexico. Calcinosis was defined as subcutaneous calcium deposition by imaging and/or physical examination, or a clear history of extruded calcium. All patients completed the Scleroderma Health Assessment Questionnaire Disability Index and Cochin Hand Functional Scale.215 (38%) patients had calcinosis. In multivariable analysis, disease duration (OR=1.24, p = 0.029), digital ischemia (OR=1.8, p = 0.002) and Acro-osteolysis (OR=2.97, p = 0.008) were significantly associated with calcinosis. In the subset of patients with bone densitometry (n = 68), patients with calcinosis had significantly lower median T-scores than patients without (-2.2 vs. -1.7, p = 0.004). The most common location of calcinosis lesions was the hands (70%), particularly the thumbs (19%) with decreasing frequency moving to the fifth fingers (8%). The most common complications were tenderness (29% of patients) and spontaneous extrusion of calcinosis through the skin (20%), while infection was rare (2%). Disability and hand function were worse in patients with calcinosis, particularly if locations in addition to the fingers/thumbs were involved.We confirmed a strong association between calcinosis and digital ischemia. Calcinosis in SSc patients most commonly affects the hands and is associated with a high burden of disability and hand dysfunction.

  View details for DOI 10.1016/j.semarthrit.2020.06.007

  View details for PubMedID 32898758

• Distinct dermatomyositis populations are detected with different autoantibody assay platforms CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Fiorentino, D. F., Gutierrez-Alamillo, L., Hines, D., Yang, Q., Casciola-Rosen, L. 2019; 37 (6): 1048–51

  View details for Web of Science ID 000531365800021

• Prevalence and Clinical Associations of Degos Lesions in Systemic Sclerosis Song, P., Chung, M., Li, S., Fiorentino, D., Chung, L. WILEY. 2019

  View details for Web of Science ID 000507466904361

• Change in Calcinosis over 1 Year Using the SCTC Radiologic Scoring System for Calcinosis of the Hands in Patients with Systemic Sclerosis Valenzuela, A., Chung, M., Rodriguez-Reyna, T. S., Proudman, S., Baron, M., Castelino, F., Hsu, V., Li, S., Fiorentino, D., Stevens, K., Chung, L. WILEY. 2019

  View details for Web of Science ID 000507466902497

• A Double-Blind, Placebo-Controlled, Phase 2 Trial of a Novel Toll-Like Receptor 7/8/9 Antagonist (IMO-8400) in Dermatomyositis Kim, Y., Schiopu, E., Danko, K., Mozaffar, T., Chunduru, S., Lees, K., Goyal, N., Fiorentino, D., Sarin, K. WILEY. 2019

  View details for Web of Science ID 000507466905071

• Skin Disease Activity and Autoantibody Phenotype Are Major Determinants of Blood Interferon Signatures in Dermatomyositis Tabata, M., Sarin, K., Page, K., Huard, C., Zhao, S., Bennett, D., Johnson, J., Johnson, K., Fiorentino, D. WILEY. 2019

  View details for Web of Science ID 000507466904503

• DESIGN OF PHASE 3 STUDY OF LENABASUM FOR THE TREATMENT OF DERMATOMYOSITIS Werth, V., Oddis, C. V., Lundberg, I. E., Fiorentino, D., Cornwall, C., Dgetluck, N., Constantine, S., White, B. BMJ PUBLISHING GROUP. 2019: 1228

  View details for DOI 10.1136/annrheumdis-2019-eular.6094

  View details for Web of Science ID 000472207103487

• Clinical factors associated with cutaneous histopathologic findings in dermatomyositis JOURNAL OF CUTANEOUS PATHOLOGY Wolstencroft, P. W., Rieger, K. E., Leatham, H. W., Fiorentino, D. F. 2019; 46 (6): 401–10

  View details for DOI 10.1111/cup.13442

  View details for Web of Science ID 000466179800002

• Clinical factors associated with cutaneous histopathologic findings in dermatomyositis. Journal of cutaneous pathology Wolstencroft, P. W., Rieger, K. E., Leatham, H. W., Fiorentino, D. F. 2019

  Abstract

  BACKGROUND: Common histopathologic findings in cutaneous dermatomyositis include vacuolar interface with dyskeratosis, mucin, and perivascular inflammation. Data examining the relationships between these and other histologic abnormalities, or their dependence on biopsy site, and medications are limited.METHODS: Using 228 dermatomyositis skin biopsies and statistical analyses including Chi-squared analyses, calculations of relative risk, and adjusted generalized estimating equation regressions, we investigated relationships between 14 histopathologic findings and the impact of clinical factors on these findings.RESULTS: In biopsies taken from sites of visible rash, interface dermatitis was seen in 91%, and 95% had at least one of perivascular inflammation, mucin, or basal vacuolization. Vascular abnormalities were not closely associated with epidermal or inflammatory findings. Concomitant prednisone significantly decreased the odds of basal vacuolization (odds ratio [OR]=0.34, 95% confidence interval [CI]: 0.12-0.98, P-value=0.05), perivascular inflammation (OR=0.19, 95% CI: 0.07-0.53, P-value=0.002), and vessel damage (OR=0.81, 95% CI: 0.68-0.96, P-value=0.02).CONCLUSION: Vasculopathy and classic findings of interface dermatitis may be driven by unique pathways in dermatomyositis. Corticosteroid use may impact skin biopsy findings. There is a need for clinicopathologic correlation when diagnosing dermatomyositis.

  View details for PubMedID 30737826

• Advances in Cutaneous Lupus Erythematosus and Dermatomyositis: A Report from the 4th International Conference on Cutaneous Lupus Erythematosus-An Ongoing Need for International Consensus and Collaborations JOURNAL OF INVESTIGATIVE DERMATOLOGY Concha, J. S., Patsatsi, A., Marshak-Rothstein, A., Liu, M., Sinha, A. A., Lee, L. A., Merola, J. F., Jabbari, A., Gudjonsson, J. E., Chasset, F., Jarrett, P., Chong, B., Arkin, L., Fernandez, A. P., Caproni, M., Greenberg, S. A., Kim, H., Pearson, D. R., Femia, A., Vleugels, R., Fiorentino, D., Fujimoto, M., Wenzel, J., Werth, V. P. 2019; 139 (2): 270–76

  View details for PubMedID 30243657

• Supplementing Dermatology Physician Resident Education in Vasculitis and Autoimmune Connective Tissue Disease: A Prospective Study of an Online Curriculum. JAMA dermatology Haemel, A., Kahl, L., Callen, J., Werth, V. P., Fiorentino, D., Fett, N. 2019

  View details for PubMedID 30624565

• Distinct dermatomyositis populations are detected with different autoantibody assay platforms. Clinical and experimental rheumatology Fiorentino, D. F., Gutierrez-Alamillo, L. n., Hines, D. n., Yang, Q. n., Casciola-Rosen, L. n. 2019

  Abstract

  To compare autoantibody-defined dermatomyositis sub-populations using immunoprecipitation-based assays, a commercially available line immunoblot assay and alternate commercial ELISA assays.Banked plasma from 261 carefully phenotyped dermatomyositis patients was studied. Immunoprecipitation-based assays were used to detect antibodies against Mi2, TIF1-γ MDA5, NXP2, SAE1 and PM-Scl, while anti-Jo1 antibodies were assayed using ELISA. These data were compared with that obtained using a commercial line immunoblot, and, additionally, for Mi2, TIF1-γ, MDA5, commercially available ELISA kits. Test agreement was measured using Cohen's kappa statistic, and phenotypic differences between differentially identified groups are described.Line immunoblot, immunoprecipitation, and ELISA detected increasingly larger nested pools of anti-TIF1-γ samples, with increasing frequency of concurrent anti-Mi2 reactivity and decreasing incidence of malignancy. Line immunoblot and immunoprecipitation showed fair concordance for identifying anti-NXP2 antibodies (Cohen's kappa=0.71) but very good agreement for identifying antibodies against Mi2, MDA5, and SAE1 (Cohen's κ=0.9, 0.94, 0.88, respectively). Anti-PM-Scl results showed moderate agreement (Cohen's κ=0.48) between immunoblot and immunoprecipitation.Our results demonstrate that for some specificities, especially anti-TIF1-γ, antibody results obtained using different assay platforms vary, and identify significantly different patient populations. These findings highlight the need for standard adoption of carefully validated platforms to detect dermatomyositis autoantibodies.

  View details for PubMedID 31376258

• New validated diagnostic criteria for pyoderma gangrenosum. Journal of the American Academy of Dermatology Maverakis, E., Le, S. T., Callen, J., Wollina, U., Marzano, A. V., Wallach, D., Schadt, C., Martinez-Alvardao, Y. C., Cheng, M. Y., Ma, C., Merleev, A., Ormerod, A., Craig, F., Jockenhofer, F., Dissemond, J., Salva, K., Williams, H. C., Fiorentino, D. 2018

  View details for PubMedID 30557582

• Developing a Classification Criteria for Cutaneous Dermatomyositis Utilizing the Delphi Technique Concha, J., Werth, V. P., Merola, J. F., Fiorentino, D., Dutz, J., Fujimoto, M., Goodfield, M., Ang, C., Nyberg, F., Vbc-Platzer, B. WILEY. 2018

  View details for Web of Science ID 000447268904031

• Identification of Risk Factors for Gastric Antral Vascular Ectasia (GAVE) Among Systemic Sclerosis Patients Serling-Boyd, N., Li, S., Fiorentino, D., Becker, L., Fernandez-Becker, N., Clarke, J., Chung, L. WILEY. 2018

  View details for Web of Science ID 000447268901344

• Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems Mehta, B. K., Franks, J., Wang, Y., Cai, G., Toledo, D. M., Wood, T. A., Archambault, K. A., Kosarek, N., Kolstad, K. D., Stark, M., Valenzuela, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Clarke, J., Boin, F., Wolters, P., Chung, L., Whitfield, M. L. WILEY. 2018

  View details for Web of Science ID 000447268902203

• Association Between Autoantibody Phenotype and Cutaneous Adverse Reactions to Hydroxychloroquine in Dermatomyositis. JAMA dermatology Wolstencroft, P. W., Casciola-Rosen, L., Fiorentino, D. F. 2018

  Abstract

  Importance: Hydroxychloroquine sulfate is a commonly used medication for patients with dermatomyositis and has been associated with a uniquely elevated risk of adverse cutaneous reactions in this population. No studies to date have examined whether certain subsets of patients with dermatomyositis are at increased risk of experiencing a hydroxychloroquine-associated skin eruption.Objective: To identify disease features that increase the risk of hydroxychloroquine-associated skin eruption in adults with dermatomyositis.Design, Setting, and Participants: A retrospective cohort study was conducted in the outpatient dermatology clinic at a tertiary academic referral center. All adults with dermatomyositis (age >18 years) who started receiving hydroxychloroquine between July 1, 1990, and September 13, 2016, were eligible for the analysis. Patients were considered to have a hydroxychloroquine-associated skin eruption if a skin eruption had developed within their first 4 weeks of treatment and resolved with discontinuation of hydroxychloroquine therapy.Exposures: One or more doses of hydroxychloroquine.Main Outcomes and Measures: The associations between autoantibodies (against transcription intermediary factor 1gamma [TIF-1gamma], nucleosome-remodeling deacetylase complex [Mi-2], nuclear matrix protein [NXP-2], small ubiquitinlike modifier 1 activating enzyme [SAE-1/2], melanoma differentiation-associated gene 5 [MDA-5], histidyl-transfer RNA synthetase [Jo-1], Ku, and signal recognition particles) and cutaneous adverse reactions to hydroxychloroquine in patients with dermatomyositis.Results: A total of 111 patients met the inclusion criteria, and 23 (20.7%) developed a hydroxychloroquine-associated skin eruption (20 [87.0%] were women with a mean [SD] age of 49 [14] years at diagnosis). Skin eruptions were approximately 3 times more common in patients with anti-SAE-1/2 autoantibodies (7 of 14 [50.0%]) compared with those without the autoantibody (16 of 97 [16.5%]). In contrast, none of 15 patients with anti-MDA-5 autoantibodies had a skin eruption vs 23 of 96 (24.0%) of those without the autoantibody. In exact logistic regressions adjusted for age, race/ethnicity, sex, amyopathic status, anti-Ro52 status, and dermatomyositis-associated cancer, the presence of anti-SAE-1/2 autoantibodies was significantly associated with a hydroxychloroquine-associated skin eruption (odds ratio [OR], 8.43; 95% CI, 1.98-49.19; P=.003) and presence of anti-MDA-5 autoantibodies was significantly negatively associated with a hydroxychloroquine-associated skin eruption (OR, 0.06; 95% CI, 0.0004-0.52; P=.006). No other autoantibodies were significantly positively or negatively associated with a hydroxychloroquine-associated skin eruption.Conclusions and Relevance: Adverse skin reactions to hydroxychloroquine are relatively common in a US cohort of patients with dermatomyositis. Our data suggest that pathophysiologic differences exist between autoantibody subsets in dermatomyositis.

  View details for PubMedID 30140893

• Clinical significance of autoantibodies in dermatomyositis and systemic sclerosis CLINICS IN DERMATOLOGY Tartar, D. M., Chung, L., Fiorentino, D. F. 2018; 36 (4): 508–24

  Abstract

  Autoimmune connective tissue diseases, including dermatomyositis and systemic sclerosis, have a heterogeneous clinical presentation and prognosis; moreover, their clinical features are often incomplete and overlap with other rheumatic disorders, which can make diagnosis and prognostic stratification challenging. Specific autoantibodies have been associated with certain clinical findings as well as prognostic implications, and many new associations have been made over the last decade. Although patient populations manifest considerable heterogeneity, autoantibodies can be used to help predict clinical features, prognosis, and response to therapy. In this review, the clinical and prognostic implications associated with disease-specific autoantibodies in dermatomyositis and scleroderma are summarized with an emphasis on how the clinician can use this information for patient care.

  View details for PubMedID 30047434

• Dermatomyositis Clinical and Pathological Phenotypes Associated with Myositis-Specific Autoantibodies. Current rheumatology reports Wolstencroft, P. W., Fiorentino, D. F. 2018; 20 (5): 28

  Abstract

  PURPOSE OF REVIEW: Dermatomyositis is an idiopathic inflammatory myopathy with a variety of systemic and cutaneous manifestations. The myositis-specific autoantibodies (MSAs) are associated with phenotypic features and provide a tool for sub-classification of dermatomyositis patients. This review focuses on recent work characterizing the clinical features that accompany the MSAs in dermatomyositis.RECENT FINDINGS: There is increasing recognition of the distinct clinical and pathological phenotypes associated with each MSA. Most of these features display considerable overlap between MSA groups. Despite this, there are notable differences between the typical combinations of cutaneous and systemic manifestations, response to therapy, prognosis, and disease sequelae that define each dermatomyositis MSA group. The MSAs may ultimately improve diagnosis and sub-classification of dermatomyositis patients. However, more work is needed to understand the pathologic basis for much of the heterogeneity found within these subgroups.

  View details for PubMedID 29637414

• Re-examining mechanic's hands as a characteristic skin finding in dermatomyositis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Concha, J. S., Merola, J. F., Fiorentino, D., Werth, V. P. 2018; 78 (4): 769-+

  Abstract

  Mechanic's hands is a poorly defined clinical finding that has been reported in a variety of rheumatologic diseases. Morphologic descriptions include hyperkeratosis on the sides of the digits that sometimes extends to the distal tips, diffuse palmar scale, and (more recently observed) linear discrete scaly papules in a similar lateral distribution. The association of mechanic's hands with dermatomyositis, although recognized, is still debatable. In this review, most studies have shown that mechanic's hands is commonly associated with dermatomyositis and displays histopathologic findings of interface dermatitis, colloid bodies, and interstitial mucin, which are consistent with a cutaneous connective tissue disease. A more specific definition of this entity would help to determine its usefulness in classifying and clinically identifying patients with dermatomyositis, with implications related to subsequent screening for associated comorbidities in this setting.

  View details for PubMedID 29102487

• Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum A Delphi Consensus of International Experts JAMA DERMATOLOGY Maverakis, E., Ma, C., Shinkai, K., Fiorentino, D., Callen, J. P., Wollina, U., Marzano, A., Wallach, D., Kim, K., Schadt, C., Ormerod, A., Fung, M. A., Steel, A., Patel, F., Qin, R., Craig, F., Williams, H. C., Powell, F., Merleev, A., Cheng, M. Y. 2018; 154 (4): 461–66

  Abstract

  Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a "diagnosis of exclusion," a definition not compatible with clinical decision making or inclusion for clinical trials.To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum.Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation.Delphi exercise yielded 1 major criterion-biopsy of ulcer edge demonstrating neutrophilic infiltrate-and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or "wrinkled paper" scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively.This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.

  View details for PubMedID 29450466

• Nomenclature of Cutaneous Vasculitis Dermatologic Addendum to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides ARTHRITIS & RHEUMATOLOGY Sunderkoetter, C. H., Zelger, B., Chen, K., Requena, L., Piette, W., Carlson, J., Dutz, J., Lamprecht, P., Mahr, A., Aberer, E., Werth, V. P., Wetter, D. A., Kawana, S., Luqmani, R., Frances, C., Jorizzo, J., Watts, J., Metze, D., Caproni, M., Alpsoy, E., Callen, J. P., Fiorentino, D., Merkel, P. A., Falk, R. J., Jennette, J. 2018; 70 (2): 171–84

  Abstract

  To prepare a dermatologic addendum to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012) to address vasculitides affecting the skin (D-CHCC). The goal was to standardize the names and definitions for cutaneous vasculitis.A nominal group technique with a facilitator was used to reach consensus on the D-CHCC nomenclature, using multiple face-to-face meetings, e-mail discussions, and teleconferences.Standardized names, definitions, and descriptions were adopted for cutaneous components of systemic vasculitides (e.g., cutaneous IgA vasculitis as a component of systemic IgA vasculitis), skin-limited variants of systemic vasculitides (e.g., skin-limited IgA vasculitis, drug-induced skin-limited antineutrophil cytoplasmic antibody-associated vasculitis), and cutaneous single-organ vasculitides that have no systemic counterparts (e.g., nodular vasculitis). Cutaneous vasculitides that were not included in the CHCC2012 nomenclature were introduced.Standardized names and definitions are a prerequisite for developing validated classification and diagnostic criteria for cutaneous vasculitis. Accurate identification of specifically defined variants of systemic and skin-limited vasculitides requires knowledgeable integration of data from clinical, laboratory, and pathologic studies. This proposed nomenclature of vasculitides affecting the skin, the D-CHCC, provides a standard framework both for clinicians and for investigators.

  View details for PubMedID 29136340

• Evidence supports blind screening for internal malignancy in dermatomyositis Data from 2 large US dermatology cohorts MEDICINE Leatham, H., Schadt, C., Chisolm, S., Fretwell, D., Chung, L., Callen, J. P., Fiorentino, D. 2018; 97 (2): e9639

  Abstract

  The association between dermatomyositis and internal malignancy is well established, but there is little consensus about the methods of cancer screening that should be utilized.We wished to analyze the prevalence and yield of selected cancer screening modalities in patients with dermatomyositis.We performed a retrospective analysis of 2 large US dermatomyositis cohorts comprising 400 patients.We measured the frequency of selected screening tests used to search for malignancy. Patients with a biopsy-confirmed malignancy were identified. Prespecified clinical and laboratory factors were tested for association with malignancy. For each malignancy we identified the screening test(s) that led to diagnosis and classified these tests as either blind (not guided by suspicious sign/symptom) or triggered (by a suspicious sign or symptom).Forty-eight patients (12.0% of total cohort) with 53 cancers were identified with dermatomyositis-associated malignancy. Twenty-one of these 53 cancers (40%) were diagnosed within 1 year of dermatomyositis symptom onset. In multivariate analysis, older age (P = .0005) was the only significant risk factor for internal malignancy. There was no significant difference in cancer incidence between classic and clinically amyopathic patients. Twenty-seven patients (6.8% of the total cohort) harbored an undiagnosed malignancy at the time of dermatomyositis diagnosis. The majority (59%) of these cancers were asymptomatic and computed tomography (CT) scans were the most common studies to reveal a cancer.This is the largest US cohort studied to examine malignancy prevalence and screening practices in dermatomyositis patients. Our results demonstrate that, while undiagnosed malignancy is present in <10% of US patients at the time of dermatomyositis onset, it is often not associated with a suspicious sign or symptom. Our data suggest that effective malignancy screening of dermatomyositis patients often requires evaluation beyond a history, physical examination, and "age-appropriate" cancer screening-these data may help to inform future guidelines for malignancy screening in this population.

  View details for PubMedID 29480875

• Factors Associated With Clinical Remission of Skin Disease in Dermatomyositis JAMA DERMATOLOGY Wolstencroft, P. W., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. F. 2018; 154 (1): 44–51

  Abstract

  Cutaneous disease represents a significant burden for patients with dermatomyositis. However, quantitative estimates of the probability of skin disease remission and clinical factors associated with skin outcomes are lacking.To characterize cutaneous disease course in adult patients with dermatomyositis.Prospective cohort study conducted at a dermatology clinic at a tertiary academic referral center. All adult patients with dermatomyositis (age >18 years) seen between May 15, 2007, and October 28, 2016, were eligible. Patients were included in the current analysis if they had a baseline Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score of 12 or higher, and 2 or more CDASI scores separated by 3 months or more within their first 3 years of follow-up.The percentage of patients who achieved clinical remission of their cutaneous disease as measured by the CDASI over a 3-year follow-up.A total of 74 patients met our inclusion criteria (mean [SD] age at initial CDASI scoring, 54 [13] years; 58 women [78%]), and 28 (38%) achieved clinical remission during our 3-year follow-up period. Increased age (odds ratio [OR], 1.07; 95% CI, 1.02-1.12; P = .01), a dermatomyositis-associated malignancy (OR, 14.46; 95% CI, 2.18-96.07; P = .01), and treatment with mycophenolate mofetil (OR, 6.00; 95% CI, 1.66-21.78; P = .01) were significantly associated with clinical remission of skin disease in multivariable analysis. Patients with anti-melanoma differentiation-associated protein 5 antibodies had a significantly lower probability of meeting outcome criteria in our time-to-event analysis. Baseline cutaneous disease activity, disease duration at baseline, and disease duration before first systemic therapy were not significantly associated with clinical remission of skin disease.Clinical remission was relatively uncommon in our population despite aggressive systemic therapy, and patients with anti-melanoma differentiation-associated protein 5 antibodies were even less likely to enter clinical remission during a 3-year follow-up period. Although mycophenolate mofetil compared favorably with other treatment options, our data provide evidence that a substantial population of patients with dermatomyositis have skin disease that is not adequately managed with standard-of-care therapies.

  View details for PubMedID 29114741

  View details for PubMedCentralID PMC5833585

• Pregnancy outcomes in adult patients with dermatomyositis and polymyositis. Seminars in arthritis and rheumatism Kolstad, K. D., Fiorentino, D., Li, S., Chakravarty, E. F., Chung, L. 2017

  Abstract

  OBJECTIVE: The idiopathic inflammatory myopathies dermatomyositis (DM) and polymyositis (PM) are autoimmune diseases that can affect females of childbearing potential. We assessed pregnancy outcomes in DM and PM patients compared with the general obstetric population.METHODS: The Nationwide Inpatient Sample (NIS) (1993-2007) was used to identify delivery-associated hospitalizations in women with DM or PM (DM/PM, n = 853). Controls were from the general obstetric population delivery-associated hospitalizations matched to each case by year of delivery. Pregnancy outcomes included hospital length of stay (LOS), hypertensive disorders (HTN), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and cesarean delivery. Multivariate regression analyses were performed using maternal age, race/ethnicity, and diabetes mellitus as covariates.RESULTS: On multivariate analysis, patients with DM/PM had longer LOS compared to controls (p < 0.001). DM/PM was associated with an increased risk of hypertensive disorders compared to controls (OR = 2.90, 95% CI: 2.00-4.22). There were no differences in rates of PROM, IUGR, or cesarean section in patients with DM/PM compared with controls. Independent of a DM/PM diagnosis, African-American race, older age, and diagnosis of diabetes increased the hospital LOS (p < 0.001). African-American race and diabetes increased the risk of hypertensive disorders (OR = 1.38, 95% CI: 1.19-1.60; OR = 2.94, 95% CI: 2.04-4.23, respectively) compared to controls.CONCLUSION: These data suggest that patients with inflammatory myopathies are at increased risk of hypertensive disorders of pregnancy and longer length of hospitalization. Vigilant monitoring of blood pressure is advisable in pregnant patients with DM or PM.

  View details for PubMedID 29217291

• 2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects RHEUMATOLOGY Rider, L. G., Ruperto, N., Pistorio, A., Erman, B., Bayat, N., Lachenbruch, P. A., Rockette, H., Feldman, B. M., Huber, A. M., Hansen, P., Oddis, C. V., Lundberg, I. E., Amato, A. A., Chinoy, H., Cooper, R. G., Chung, L., Danko, K., Fiorentino, D., Garcia-De la Torre, I., Reed, A. M., Song, Y., Cimaz, R., Cuttica, R. J., Pilkington, C. A., Martini, A., van der Net, J., Maillard, S., Miller, F. W., Vencovsky, J., Aggarwal, R., Int Myositis Assessment Clinical, Paediat Rheumatology Int Trials 2017; 56 (11): 1884–93

  Abstract

  The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM.Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data.Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference.Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis.

  View details for PubMedID 28977549

  View details for PubMedCentralID PMC5850656

• Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D., Ho, V., Lebwohl, M. G., Leite, L., Hopkins, L., Galindo, C., Goyal, K., Langholff, W., Fakharzadeh, S., Srivastava, B., Langley, R. G. 2017; 77 (5): 845-+

  Abstract

  The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood.Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).Nested case-control analyses were performed among patients with no history of malignancy. Cases were defined as first malignancy (other than nonmelanoma skin cancer) in the Psoriasis Longitudinal Assessment and Registry, and controls were matched by age, sex, geographic region, and time on registry. Study therapies included methotrexate, ustekinumab, and tumor necrosis factor-α (TNF-α) inhibitors. Exposure was defined as 1 or more doses of study therapy within 12 months of malignancy onset and further stratified by duration of therapy. Multivariate conditional logistic regression, adjusted for potential confounders, was used to estimate odds ratios of malignancies associated with therapy.Among 12,090 patients, 252 malignancy cases were identified and 1008 controls were matched. Treatment with methotrexate or ustekinumab for more than 0 months to less than 3 months, 3 months to less than 12 months, or 12 months or longer was not associated with increased malignancy risk versus no exposure. Longer-term (≥12 months) (odds ratio, 1.54; 95% confidence interval, 1.10-2.15; P = .01), but not shorter-term treatment, with a TNF-α inhibitor was associated with increased malignancy risk.Cases and controls could belong to 1 or more therapy categories.Long-term (≥12 months) treatment with a TNF-α inhibitor, but not methotrexate and ustekinumab, may increase risk for malignancy in patients with psoriasis.

  View details for PubMedID 28893407

• Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems Mehta, B. K., Franks, J., Cai, G., Toledo, D., Wood, T. A., Archambault, K. A., Kosarek, N., Kolstad, K., Stark, M., Valenzuela, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Clarke, J., Boin, F., Wolters, P., Chung, L., Whitfield, M. L. WILEY. 2017

  View details for Web of Science ID 000411824106435

• Factors Associated with Clinical Remission of Skin Disease in Dermatomyositis Wolstencroft, P., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. WILEY. 2017

  View details for Web of Science ID 000411824104386

• Transcriptome Sequencing Reveals Genetic Polymorphisms Associated with Ssc Gene Expression Subtypes Cai, G., Mehta, B. K., Huang, M., Franks, J., Wood, T. A., Kolstad, K. D., Stark, M., Valenzuela, A., Fiorentino, D., Simms, R. W., Orzechowski, N., Chung, L., Whitfield, M. L. WILEY. 2017

  View details for Web of Science ID 000411824101058

• Risk of malignancy associated with biologic therapy and methotrexate (MTX) in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) Fiorentino, D., Ho, V., Lebwohl, M., Leite, L., Hopkins, L., Galindo, C., Langholff, W., Srivastava, B., Langley, R. MOSBY-ELSEVIER. 2017: AB221

  View details for Web of Science ID 000403369302096

• 2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative ARTHRITIS & RHEUMATOLOGY Aggarwal, R., Rider, L. G., Ruperto, N., Bayat, N., Erman, B., Feldman, B. M., Oddis, C. V., Amato, A. A., Chinoy, H., Cooper, R. G., Dastmalchi, M., Fiorentino, D., Isenberg, D., Katz, J. D., Mammen, A., de Visser, M., Ytterberg, S. R., Lundberg, I. E., Chung, L., Danko, K., Garcia-De La Torre, I., Song, Y. W., Villa, L., Rinaldi, M., Rockette, H., Lachenbruch, P. A., Miller, F. W., Vencovsky, J. 2017; 69 (5): 898-910

  Abstract

  To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM).Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus.Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001).The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

  View details for DOI 10.1002/art.40064

  View details for Web of Science ID 000400068300004

  View details for PubMedID 28382787

• Pharmacodynamics, Safety, and Clinical Efficacy of AMG 811, a Human Anti-Interferon-gamma Antibody, in Patients With Discoid Lupus Erythematosus ARTHRITIS & RHEUMATOLOGY Werth, V. P., Fiorentino, D., Sullivan, B. A., Boedigheimer, M. J., Chiu, K., Wang, C., Arnold, G. E., Damore, M. A., Bigler, J., Welcher, A. A., Russell, C. B., Martin, D. A., Chung, J. B. 2017; 69 (5): 1028-1034

  Abstract

  Interferon-γ (IFNγ) is implicated in the pathogenesis of discoid lupus erythematosus (DLE). This study sought to evaluate a single dose of AMG 811, an anti-IFNγ antibody, in patients with DLE.The study was designed as a phase I randomized, double-blind, placebo-controlled crossover study of the pharmacodynamics, safety, and clinical efficacy of AMG 811 in patients with DLE. Patients received a single subcutaneous dose of AMG 811 (180 mg) or placebo. The patients in sequence 1 received AMG 811 followed by placebo, while those in sequence 2 received placebo followed by AMG 811. Pharmacodynamic end points included global transcriptional analyses of lesional and nonlesional skin, IFNγ blockade signature (IGBS) transcriptional scores in the skin and blood, keratinocyte IFNγ RNA scores, and serum levels of CXCL10 protein. Additional end points were efficacy outcome measures, including the Cutaneous Lupus Erythematosus Disease Area and Severity Index, and safety outcome measures.Sixteen patients with DLE were enrolled in the study (9 in sequence 1 and 7 in sequence 2). AMG 811 treatment reduced the IGBS score (which was elevated in DLE patients at baseline) in both the blood and lesional skin. The keratinocyte IFNγ RNA score was not affected by administration of AMG 811. Serum CXCL10 protein levels (which were elevated in the blood of DLE patients) were reduced with AMG 811 treatment. The AMG 811 treatment was well tolerated but did not lead to statistically significant improvements in any of the efficacy outcome measures.AMG 811 treatment led to changes in IFNγ-associated biomarkers and was well tolerated, but no significant clinical benefit was observed in patients with DLE.

  View details for DOI 10.1002/art.40052

  View details for Web of Science ID 000400068300017

• 2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative ANNALS OF THE RHEUMATIC DISEASES Aggarwal, R., Rider, L. G., Ruperto, N., Bayat, N., Erman, B., Feldman, B. M., Oddis, C. V., Amato, A. A., Chinoy, H., Cooper, R. G., Dastmalchi, M., Fiorentino, D., Isenberg, D., Katz, J. D., Mammen, A., de Visser, M., Ytterberg, S. R., Lundberg, I. E., Chung, L., Danko, K., Garcia-De La Torre, I., Song, Y. W., Villa, L., Rinaldi, M., Rockette, H., Lachenbruch, P. A., Miller, F. W., Vencovsky, J. 2017; 76 (5)

  Abstract

  To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

  View details for DOI 10.1136/annrheumdis-2017-211400

  View details for Web of Science ID 000398387200006

  View details for PubMedID 28385805

• The cutaneous and systemic findings associated with nuclear matrix protein-2 antibodies in adult dermatomyositis patients. Arthritis care & research Rogers, A., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. F. 2017

  Abstract

  To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with anti-NXP-2 antibodies.We conducted a retrospective cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. Electronic chart review employing a keyword search strategy was performed to collect clinical and laboratory data. Anti-NXP-2 antibodies were assayed by immunoprecipitation using NXP-2 produced by in vitro transcription/translation.Antibodies to NXP-2 were detected in 20 (11%) of the 178 patients. Anti-NXP-2 antibodies were associated with male gender (50% vs. 25%, p=0.02), dysphagia (74% vs. 39%, p=0.006), myalgia (89% vs. 52%, p=0.002), peripheral edema (35% vs. 11%, p=0.016), and calcinosis (37% vs. 11%, p=0.007). These patients were less likely to be clinically amyopathic (5% vs 23%, p=0.08). Five of the 20 patients with NXP-2 antibodies (25%) had an associated internal malignancy. No other cutaneous characteristics were associated with anti-NXP-2 antibodies except a decreased frequency of Gottron's sign (44% vs. 75%, p=0.012) and the fact that these patients were more likely to have mild skin disease.Dermatomyositis patients with anti-NXP2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema and significant dysphagia despite having milder inflammatory skin disease. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/acr.23210

  View details for PubMedID 28129490

• Pharmacodynamics, Safety, and Clinical Efficacy of AMG 811, a Human Anti-Interferon-? Antibody, in Subjects with Discoid Lupus Erythematosus. Arthritis & rheumatology (Hoboken, N.J.) Werth, V. P., Fiorentino, D., Sullivan, B. A., Boedigheimer, M. J., Chiu, K., Wang, C., Arnold, G. E., Damore, M. A., Bigler, J., Welcher, A. A., Russell, C. B., Martin, D. A., Chung, J. B. 2017

  Abstract

  Interferon-γ (IFNγ) is implicated in the pathogenesis of discoid lupus erythematosus (DLE). This study sought to evaluate a single dose of AMG 811, an anti-IFNγ antibody, in patients with DLE.The study was designed as a phase I randomized, double-blind, placebo-controlled crossover study of the pharmacodynamics, safety, and clinical efficacy of AMG 811 in patients with DLE. Patients received a single subcutaneous dose of AMG 811 (180 mg) or placebo. The patients in sequence 1 received AMG 811 followed by placebo, while those in sequence 2 received placebo followed by AMG 811. Pharmacodynamic end points included global transcriptional analyses of lesional and nonlesional skin, IFNγ blockade signature (IGBS) transcriptional scores in the skin and blood, keratinocyte IFNγ RNA scores, and serum levels of CXCL10 protein. Additional end points were efficacy outcome measures, including the Cutaneous Lupus Erythematosus Disease Area and Severity Index, and safety outcome measures.Sixteen patients with DLE were enrolled in the study (9 in sequence 1 and 7 in sequence 2). AMG 811 treatment reduced the IGBS score (which was elevated in DLE patients at baseline) in both the blood and lesional skin. The keratinocyte IFNγ RNA score was not affected by administration of AMG 811. Serum CXCL10 protein levels (which were elevated in the blood of DLE patients) were reduced with AMG 811 treatment. The AMG 811 treatment was well tolerated but did not lead to statistically significant improvements in any of the efficacy outcome measures.AMG 811 treatment led to changes in IFNγ-associated biomarkers and was well tolerated, but no significant clinical benefit was observed in patients with DLE.

  View details for DOI 10.1002/art.40052

  View details for PubMedID 28118537

• Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity. JCI insight Lofgren, S., Hinchcliff, M., Carns, M., Wood, T., Aren, K., Arroyo, E., Cheung, P., Kuo, A., Valenzuela, A., Haemel, A., Wolters, P. J., Gordon, J., Spiera, R., Assassi, S., Boin, F., Chung, L., Fiorentino, D., Utz, P. J., Whitfield, M. L., Khatri, P. 2016; 1 (21)

  Abstract

  Systemic sclerosis (SSc) is a rare autoimmune disease with the highest case-fatality rate of all connective tissue diseases. Current efforts to determine patient response to a given treatment using the modified Rodnan skin score (mRSS) are complicated by interclinician variability, confounding, and the time required between sequential mRSS measurements to observe meaningful change. There is an unmet critical need for an objective metric of SSc disease severity. Here, we performed an integrated, multicohort analysis of SSc transcriptome data across 7 datasets from 6 centers composed of 515 samples. Using 158 skin samples from SSc patients and healthy controls recruited at 2 centers as a discovery cohort, we identified a 415-gene expression signature specific for SSc, and validated its ability to distinguish SSc patients from healthy controls in an additional 357 skin samples from 5 independent cohorts. Next, we defined the SSc skin severity score (4S). In every SSc cohort of skin biopsy samples analyzed in our study, 4S correlated significantly with mRSS, allowing objective quantification of SSc disease severity. Using transcriptome data from the largest longitudinal trial of SSc patients to date, we showed that 4S allowed us to objectively monitor individual SSc patients over time, as (a) the change in 4S of a patient is significantly correlated with change in the mRSS, and (b) the change in 4S at 12 months of treatment could predict the change in mRSS at 24 months. Our results suggest that 4S could be used to distinguish treatment responders from nonresponders prior to mRSS change. Our results demonstrate the potential clinical utility of a novel robust molecular signature and a computational approach to SSc disease severity quantification.

  View details for DOI 10.1172/jci.insight.89073

  View details for PubMedID 28018971

  View details for PubMedCentralID PMC5161207

• Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study SEMINARS IN ARTHRITIS AND RHEUMATISM Valenzuela, A., Baron, M., Herrick, A. L., Proudman, S., Stevens, W., Rodriguez-Reyna, T. S., Vacca, A., Medsger, T. A., Hinchcliff, M., Hsu, V., Wu, J. Y., Fiorentino, D., Chung, L. 2016; 46 (3): 344-349

  Abstract

  We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC).This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses.A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR = 3.9; 95% CI: 2.7-5.5; p < 0.0001) and osteoporosis (OR = 4.2; 95% CI: 2.3-7.9; p < 0.0001).One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis.

  View details for DOI 10.1016/j.semarthrit.2016.05.008

  View details for Web of Science ID 000390979200012

  View details for PubMedID 27371996

• Current status of observations of malignancies in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W. WILEY-BLACKWELL. 2016: 48–49

  View details for Web of Science ID 000385353900124

• Immunosignature Technology Differentiates Patients with Systemic Sclerosis and Internal Organ Involvement Chung, L., Fiorentino, D., Gerwien, R., Jia, K., Legutki, J., Vergara, A., Zhu, L., Tarasow, T. M., Sykes, K. WILEY. 2016

  View details for Web of Science ID 000417143403071

• Comprehensive Characterization of Calcinosis in a Multicenter International Cohort of Patients with Systemic Sclerosis Valenzuela, A., Gordon, J. K., Sofia Rodriguez-Reyna, T., Proudman, S., Baron, M., Hinchcliff, M., Khanna, D., Young, A., Castelino, F. V., Schoenfeld, S. R., Steen, V. D., Fiorentino, D., Chung, L. WILEY. 2016

  View details for Web of Science ID 000417143401240

• Multi-Organ RNA-Sequencing of Systemic Sclerosis (SSc) Patients Shows Reproducible Gene Expression Profiles Across Organ Systems Mehta, B. K., Johnson, M. E., Archambault, K. A., Wood, T. A., Valenzuela, A., Crawford, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Boin, F., Wolters, P., Chung, L., Whitfield, M. WILEY. 2016

  View details for Web of Science ID 000417143401207

• Ovoid Palatal Patch in Dermatomyositis: A Novel Finding Associated With Anti-TIF1? (p155) Antibodies. JAMA dermatology Bernet, L. L., Lewis, M. A., Rieger, K. E., Casciola-Rosen, L., Fiorentino, D. F. 2016; 152 (9): 1049-1051

  View details for DOI 10.1001/jamadermatol.2016.1429

  View details for PubMedID 27224238

• IL-10 INHIBITS CYTOKINE PRODUCTION BY ACTIVATED MACROPHAGES JOURNAL OF IMMUNOLOGY Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M., O'Garra, A. 2016; 197 (5): 1539-1546

  View details for Web of Science ID 000385002300003

• IL-10 ACTS ON THE ANTIGEN-PRESENTING CELL TO INHIBIT CYTOKINE PRODUCTION BY Th1 CELLS JOURNAL OF IMMUNOLOGY Fiorentino, D. F., Zlotnik, A., Vieira, P., Mosmann, T. R., Howard, M., Moore, K. W., O'Garra, A. 2016; 197 (5): 1531-1538

  View details for Web of Science ID 000385002300002

• Pillars Article: IL-10 Inhibits Cytokine Production by Activated Macrophages. J. Immunol. 1991. 147: 3815-3822. Journal of immunology Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M., O'Garra, A. 2016; 197 (5): 1539-1546

  View details for PubMedID 27543667

• Identification of Alpha-Adrenergic Agonists as Potential Therapeutic Agents for Dermatomyositis through Drug-Repurposing Using Public Expression Datasets. journal of investigative dermatology Cho, H. G., Fiorentino, D., Lewis, M., Sirota, M., Sarin, K. Y. 2016; 136 (7): 1517-1520

  View details for DOI 10.1016/j.jid.2016.03.001

  View details for PubMedID 26975725

  View details for PubMedCentralID PMC5399882

• Comparative effectiveness of biological therapy in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) Study Strober, B., Bissonnette, R., Fiorentino, D., Kimball, A. B., Lebwohl, M., Naldi, L., Shear, N., Goyal, K., Langholff, W., Lee, S., Calabro, S., Galindo, C., Fakharzadeh, S. WILEY-BLACKWELL. 2016: 72–73

  View details for Web of Science ID 000379650200137

• Practice and Educational Gaps in Lupus, Dermatomyositis, and Morphea DERMATOLOGIC CLINICS Fett, N. M., Fiorentino, D., Werth, V. P. 2016; 34 (3): 243-?

  Abstract

  Patients with skin-predominant lupus erythematosus, dermatomyositis, and morphea should be evaluated, treated, and followed by dermatologists who can take primary responsibility for their care. Many academic centers have specialized centers with dermatologists who care for these patients. Patients with skin-predominant lupus erythematosus should be followed regularly with laboratory tests to detect significant systemic disease. Antibody tests can help determine the risks for individual patients. Patients with morphea rarely progress to systemic disease, but therapies can be helpful in treating and preventing progression of disease.

  View details for DOI 10.1016/j.det.2016.02.006

  View details for PubMedID 27363879

• Current status of observations of malignancies in the psoriasis longitudinal assessment and registry (PSOLAR) study Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W. WILEY-BLACKWELL. 2016: 13–14

  View details for Web of Science ID 000379780600021

• Current status of observations of malignancies in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W. WILEY-BLACKWELL. 2016: 59

  View details for Web of Science ID 000379650200108

• Characterization of patients with clinical overlap of morphea and systemic sclerosis: A case series JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chen, J. K., Chung, L., Fiorentino, D. F. 2016; 74 (6): 1272–74

  View details for PubMedID 27185438

• DESIGN OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2 CLINICAL TRIAL OF THE TOLL-LIKE RECEPTOR ANTAGONIST IMO-8400 IN PATIENTS WITH DERMATOMYOSITIS Gordon, P., Cooper, R., Chinoy, H., Isenberg, D., Lundberg, I. E., Werth, V., Gruis, K., Hurtt, M., Brevard, J., Granlund, L., Fiorentino, D. BMJ PUBLISHING GROUP. 2016: 1119

  View details for DOI 10.1136/annrheumdis-2016-eular.5174

  View details for Web of Science ID 000401523105379

• PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjogren's syndrome ANNALS OF THE RHEUMATIC DISEASES Fiorentino, D. F., Presby, M., Baer, A. N., Petri, M., Rieger, K. E., Soloski, M., Rosen, A., Mammen, A. L., Christopher-Stine, L., Casciola-Rosen, L. 2016; 75 (6): 1145-1151

  Abstract

  Autoantibodies are used clinically to phenotype and subset patients with autoimmune rheumatic diseases. We detected a novel 60 kDa autoantibody specificity by immunoblotting using a dermatomyositis (DM) patient's serum. Our objective was to identify the targeted autoantigen and to evaluate disease specificity and clinical significance of this new autoantibody.A new 60 kDa specificity was detected by immunoblotting HeLa cell lysates. The targeted autoantigen was identified as poly(U)-binding-splicing factor 60 kDa (PUF60) using (i) a human protein array and (ii) two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing. Anti-PUF60 antibodies were assayed by ELISA using sera from patients with primary Sjögren's syndrome (SS; n=84), systemic lupus erythematosus (SLE; n=71), DM (n=267), polymyositis (n=45), inclusion body myositis (n=45) and healthy controls (n=38).PUF60 was identified as a new autoantigen. Anti-PUF60 antibodies were present in 25/84 (30%) patients with SS, 6/71 (8.5%) patients with SLE and 2/38 (5.0%) control subjects (SS vs controls, p=0.002; SLE vs controls, p=0.711). Anti-PUF60 antibodies were present in 48/267 (18.0%) patients with DM versus 4/45 (8.9%) and 5/45 (11.1%) patients with inclusion body myositis and polymyositis, respectively. The antibody was significantly associated with anti-Ro52 antibodies, rheumatoid factor and hyperglobulinemia in the patients with primary SS. In patients with DM, the antibody was associated with anti-transcription intermediary factor 1 gamma seropositivity and Caucasian race.PUF60 represents a novel autoantigen in patients with SS and DM. PUF60 antibodies are associated with distinct clinical features and different immune responses in different diseases.

  View details for DOI 10.1136/annrheumdis-2015-207509

  View details for Web of Science ID 000376440900033

  View details for PubMedID 26253095

• Identification of alpha-adrenergic agonists as potential therapeutic agents for dermatomyositis through drug-repurposing using public expression datasets Cho, H. G., Fiorentino, D., Lewis, M., Sirota, M., Sarin, K. ELSEVIER SCIENCE INC. 2016: S44

  View details for DOI 10.1016/j.jid.2016.02.280

  View details for Web of Science ID 000380028800251

• Current status of observations of malignancies in the psoriasis longitudinal assessment and registry (PSOLAR) study Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W. MOSBY-ELSEVIER. 2016: AB243

  View details for Web of Science ID 000412760201819

• Comparative effectiveness of biologic therapy in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) Study Strober, B., Bissonnette, R., Fiorentino, D., Kimball, A. B., Lebwohl, M., Naldi, L., Shear, N., Goyal, K., Wayne, L., Fakharzadeh, S. MOSBY-ELSEVIER. 2016: AB240

  View details for Web of Science ID 000412760201810

• Comparative effectiveness of biologic agents for the treatment of psoriasis in a real-world setting: Results from a large, prospective, observational study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Strober, B. E., Bissonnette, R., Fiorentino, D., Kimball, A. B., Naldi, L., Shear, N. H., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W., You, Y., Galindo, C., Lee, S., Lebwohl, M. G. 2016; 74 (5): 851-?

  Abstract

  Comparing effectiveness of biologics in real-world settings will help inform treatment decisions.We sought to compare therapeutic responses among patients initiating infliximab, adalimumab, or etanercept versus ustekinumab during the Psoriasis Longitudinal Assessment and Registry (PSOLAR).Proportions of patients achieving a Physician Global Assessment score of clear (0)/minimal (1) and mean decrease in percentage of body surface area with psoriasis were evaluated at 6 and 12 months. Adjusted logistic regression (Physician Global Assessment score 0/1) and analysis of covariance (percentage of body surface area with psoriasis) were performed to determine treatment factors associated with effectiveness.Of 2541 new users on registry, 2076 had efficacy data: ustekinumab (n = 1041), infliximab (n = 116), adalimumab (n = 662), and etanercept (n = 257). Patients receiving tumor necrosis factor-alpha(-α) inhibitors were significantly less likely to achieve Physician Global Assessment score 0/1 versus ustekinumab (infliximab [odds ratio {OR} 0.396, P < .0001], adalimumab [OR 0.686, P = .0012], etanercept [OR 0.554, P = .0003] at 6 months and infliximab [OR 0.449, P = .0040] at 12 months). Mean decrease in percentage of body surface area with psoriasis was significantly greater for ustekinumab versus adalimumab (point estimate 1.833, P = .0020) and etanercept (point estimate 3.419, P < .0001) at 6 months and versus infliximab (point estimate 3.945, P = .0005) and etanercept (point estimate 2.778, P = .0007) at 12 months.Treatment selection bias and limited data for doing adjustments are limitations.In PSOLAR, effectiveness of ustekinumab was significantly better versus all 3 tumor necrosis factor-α inhibitors studied for the majority of comparisons at 6 and 12 months.

  View details for DOI 10.1016/j.jaad.2015.12.017

  View details for PubMedID 26853180

• Ustekinumab improved health-related quality of life in patients with psoriasis in a real world setting: Results from PSOLAR Strober, B., Bissonnette, R., Fiorentino, D., Kimball, A. B., Lebwohl, M., Naldi, L., Shear, N., Langholff, W., Lee, S., Goyal, K. MOSBY-ELSEVIER. 2016: AB281

  View details for Web of Science ID 000412760202034

• Leukotriene B-4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension HYPERTENSION Qian, J., Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Shuffle, E. M., Tu, A. B., Valenzuela, A., Jiang, S., Zamanian, R. T., Fiorentino, D. F., Voelkel, N. F., Peters-Golden, M., Stenmark, K. R., Chung, L., Rabinovitch, M., Nicolls, M. R. 2015; 66 (6): 1227-1239

  Abstract

  A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

  View details for DOI 10.1161/HYPERTENSIONAHA.115.06370

  View details for PubMedID 26558820

• Dual mTOR Inhibition Is Required to Prevent TGF-beta-Mediated Fibrosis: Implications for Scleroderma JOURNAL OF INVESTIGATIVE DERMATOLOGY Mitra, A., Luna, J. I., Marusina, A. I., Merleev, A., Kundu-Raychaudhuri, S., Fiorentino, D., Raychaudhuri, S. P., Maverakis, E. 2015; 135 (11): 2873–76

  View details for PubMedID 26134944

  View details for PubMedCentralID PMC4640976

• Validation of the Cutaneous Dermatomyositis Disease Area and Severity Index: characterizing disease severity and assessing responsiveness to clinical change BRITISH JOURNAL OF DERMATOLOGY Anyanwu, C. O., Fiorentino, D. F., Chung, L., Dzuong, C., Wang, Y., Okawa, J., Carr, K., PROPERT, K. J., Werth, V. P. 2015; 173 (4): 969-974

  Abstract

  The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) was developed for use in clinical trials and longitudinal patient assessment.To characterize disease severity using the CDASI and assess the responsiveness of this instrument to clinically meaningful changes in disease activity.Patients with cutaneous dermatomyositis at the University of Pennsylvania (UPenn, n = 93) and Stanford University (Stanford, n = 106) were prospectively evaluated using the CDASI, physician global assessment (PGA) Likert scales and a visual analogue scale (VAS). Data was analysed using logistic regression models and receiver operating characteristic curves to select cut-offs.Baseline CDASI activity scores for the patients evaluated at UPenn ranged from 0 to 47 (median 17), and baseline PGA VAS scores ranged from 0 to 9·6 (median 1·1). At UPenn a CDASI activity score of 19 differentiated mild from moderate and severe disease. At Stanford baseline CDASI scores ranged from 0 to 48 (median 21), baseline PGA VAS scores ranged from 0 to 9·7 (median 4·2) and CDASI activity scores of 14 or less characterized mild disease. When a 2-cm change in the PGA VAS was regarded as a clinically significant improvement, a 4-point (UPenn) or 5-point (Stanford) change in CDASI reflected a minimal clinically significant response.The CDASI is a valid and responsive measure that can be used to characterize cutaneous dermatomyositis severity and detect improvement in disease activity. Variations in cut-offs may be due to differences in disease severity between the two populations or inter-rater variations in the use of the external gold measures.

  View details for DOI 10.1111/bjd.13915

  View details for Web of Science ID 000363896800020

  View details for PubMedID 25994337

  View details for PubMedCentralID PMC4878996

• Activity of Type I and Type II Interferons in Dermatomyositis Skin Is Correlated with Characteristic Pathologic Features Leatham, H. W., Rieger, K., Chung, L., Li, S., Higgs, B. W., Yao, Y., Sarin, K., Fiorentino, D. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860202208

• Calcinosis Is Associated with Digital Ulcers and Osteoporosis in Patients with Systemic Sclerosis Valenzuela, A., Baron, M., Herrick, A. L., Proudman, S., Stevens, W., Sofia Rodriguez-Reyna, T., Vacca, A., Medsger, T. A., Hinchcliff, M., Hsu, V., Fiorentino, D., Chung, L., Canadian Scleroderma Res Grp WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860202096

• Dermatomyositis Associated with Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: A Longitudinal Analysis Lewis, M., Li, S., Chung, L., Fiorentino, D. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860203770

• Surgical treatment of systemic sclerosis-is it justified to offer peripheral sympathectomy earlier in the disease process? Microsurgery Momeni, A., Sorice, S. C., Valenzuela, A., Fiorentino, D. F., Chung, L., Chang, J. 2015; 35 (6): 441-446

  Abstract

  Systemic sclerosis (SSc) is a rare connective tissue disease associated with significant digital vasculopathy. Peripheral sympathectomy is frequently offered late in the disease process after severe digital ischemia has already occurred with patients being symptomatic for numerous years. The purpose of the present study was to analyze the results of peripheral sympathectomy in patients with a confirmed diagnosis of SSc.A retrospective analysis of 17 patients (26 hands) who underwent peripheral sympathectomy between January 2003 and September 2013 was performed. Data regarding patient demographics, clinical features, and postoperative outcomes were retrieved. Of note, preoperative pain was present in all patients with a mean duration of 9.6 years prior to peripheral sympathectomy.Pain improvement/resolution was seen in 24 hands (92.3%). Digital ulcers healed in all patients with only two patients (two hands; 7.7%) requiring surgical intervention for ulcer recurrence 6 months and 4.5 years later. Minor complications were seen in seven hands (26.9%); including infection, wound opening, and stitch abscess, but none required surgical intervention. Seven of eight patients queried would have preferred surgical treatment at an earlier point in the disease process.Peripheral sympathectomy is a well-tolerated procedure in patients with SSc and is associated with predictable pain relief and ulcer healing in the majority of patients. In light of these findings it seems prudent to offer surgical treatment not as a last resort but rather earlier in the disease process to decrease the duration that patients suffer pain. © 2015 Wiley Periodicals, Inc. Microsurgery, 2015.

  View details for DOI 10.1002/micr.22379

  View details for PubMedID 25585522

• Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR) JAMA DERMATOLOGY Kalb, R. E., Fiorentino, D. F., Lebwohl, M. G., Toole, J., Poulin, Y., Cohen, A. D., Goyal, K., Fakharzadeh, S., Calabro, S., Chevrier, M., Langholff, W., You, Y., Leonardi, C. L. 2015; 151 (9): 961-969

  Abstract

  The efficacy of treatment for psoriasis must be balanced against potential adverse events.To determine the effect of treatment on the risk of serious infections in patients with psoriasis.A multicenter, longitudinal, disease-based registry (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) at dermatology centers. Participants were adult patients with psoriasis who were receiving or were eligible to receive conventional systemic or biologic agents. The registry opened on June 20, 2007, and data included herein were collected through August 23, 2013.Patients were prescribed psoriasis therapies as in standard clinical practice. Patients will be followed for up to 8 years. Data were collected and serious adverse events (including serious infections) were assessed at regular intervals.Cohort characteristics are described based on evaluation at entry into the registry. The cumulative incidence rates of serious infections are reported across treatment cohorts, including ustekinumab, infliximab, adalimumab, etanercept, and nonbiologics (with or without methotrexate). A multivariate analysis using a Cox proportional hazards regression model was used to identify predictors of the time to the first serious infection using the nonmethotrexate/nonbiologics cohort as the reference.Data were analyzed from 11,466 patients with psoriasis (22,311 patient-years). Differences in patient characteristics were found between the biologics and nonmethotrexate/nonbiologics cohorts (eg, age, sex, body mass index, and disease characteristics), as well as among the individual biologic groups (eg, a higher prevalence of psoriatic arthritis in the infliximab cohort). The cumulative incidence rate of serious infections was 1.45 per 100 patient-years (n = 323) across treatment cohorts, and the rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient-years in the ustekinumab, etanercept, adalimumab, and infliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient-years in the nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts, respectively. The most commonly reported types of serious infections across the registry were pneumonia and cellulitis. Increasing age, diabetes mellitus, smoking, significant infection history, infliximab exposure, and adalimumab exposure were each associated with an increased risk of serious infection.Results from PSOLAR suggest a higher risk of serious infections with adalimumab and infliximab compared with nonmethotrexate and nonbiologic therapies. No increased risk was observed with ustekinumab or etanercept.clinicaltrials.gov Identifier: NCT00508547.

  View details for DOI 10.1001/jamadermatol.2015.0718

  View details for Web of Science ID 000361371100009

  View details for PubMedID 25970800

• Modelled analysis of serious infection risk in the treatment of psoriasis with biologics and systemic treatments in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) Kalb, R., Fiorentino, D., Lebwohl, M., Leonardi, C., Toole, J., Poulin, Y., Cohen, A., Goyal, K., Calabro, S., Langholff, W., Fakharzadeh, S. WILEY-BLACKWELL. 2015: 63–64

  View details for Web of Science ID 000357729300129

• Evaluation of malignancies in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W. WILEY-BLACKWELL. 2015: 59

  View details for Web of Science ID 000357729300118

• Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis ARTHRITIS RESEARCH & THERAPY Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17

  Abstract

  Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

  View details for DOI 10.1186/s13075-015-0669-3

  View details for Web of Science ID 000357069900001

  View details for PubMedID 26071192

  View details for PubMedCentralID PMC4487200

• MALIGNANCIES IN THE PSORIASIS LONGITUDINAL ASSESSMENT AND REGISTRY (PSOLAR) STUDY: CURRENT STATUS OF OBSERVATIONS Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W., PSOLAR Steering Comm BMJ PUBLISHING GROUP. 2015: 862

  View details for DOI 10.1136/annrheumdis-2015-eular.2000

  View details for Web of Science ID 000215799102666

• SERIOUS INFECTION EVENTS IN THE PSORIASIS LONGITUDINAL ASSESSMENT AND REGISTRY STUDY: CURRENT STATUS OF OBSERVATIONS Kalb, R., Fiorentino, D., Lebwohl, M., Leonardi, C., Toole, J., Poulin, Y., Cohen, A., Goyal, K., Calabro, S., Langholff, W., Fakharzadeh, S., PSOLAR Steering Comm BMJ PUBLISHING GROUP. 2015: 862–63

  View details for DOI 10.1136/annrheumdis-2015-eular.3592

  View details for Web of Science ID 000215799102667

• Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease. Arthritis care & research Narang, N. S., Casciola-Rosen, L., Li, S., Chung, L., Fiorentino, D. F. 2015; 67 (5): 667-672

  Abstract

  To identify clinical and serologic correlates of cutaneous ulcers in dermatomyositis (DM).We retrospectively examined a cohort of 152 DM patients. We compared the features of patients with ulcers to those without ulcers using chi-square or Fisher's exact tests and used univariate and multivariate logistic regression models to assess the association between ulcers and clinical features such as malignancy, interstitial lung disease (ILD), and amyopathic disease.Forty-three patients (28%) had cutaneous ulcers. Nearly half the patients had ulcers present in more than 1 location: 24 (56%) had ulcers over the extensor surfaces of joints, 18 (42%) at the digital pulp or periungual areas, and 25 (58%) had ulcers located elsewhere. In univariate analysis ulcers were associated with Asian race, but not with other clinical and demographic features, including malignancy or ILD. In multivariate analysis ulcers were significantly associated with anti-melanoma differentiation gene 5 (anti-MDA5) antibodies (odds ratio 10.14, 95% confidence interval 1.95-52.78; P = 0.0059) and this was greatest for ulcers located at the digital pulp. In patients with cutaneous ulcers, ILD risk was specifically increased only in patients with anti-MDA5-positive antibodies.We confirmed the strong association between anti-MDA5 antibodies and cutaneous ulcers, with the novel finding that the association of cutaneous ulcers with ILD depends upon the presence of anti-MDA5 antibodies. DM patients who display this cutaneous phenotype should undergo appropriate evaluation for ILD.

  View details for DOI 10.1002/acr.22498

  View details for PubMedID 25331610

  View details for PubMedCentralID PMC4404195

• Malignancies in the psoriasis longitudinal assessment and registry (PSOLAR) study: Current status of observations Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W. MOSBY-ELSEVIER. 2015: AB240

  View details for Web of Science ID 000360942902089

• Serious infection events in the Psoriasis Longitudinal Assessment and Registry Study (PSOLAR): Current status of observations Kalb, R. E., Fiorentino, D., Lebwohl, M., Leonardi, C., Toole, J., Poulin, Y., Cohen, A., Goyal, K., Calabro, S., Langholff, W., Fakharzadeh, S. MOSBY-ELSEVIER. 2015: AB252

  View details for Web of Science ID 000360942902131

• Drug repurposing for dermatomyositis using public expression datasets Cho, H. G., Fiorentino, D. F., Sirota, M., Sarin, K. NATURE PUBLISHING GROUP. 2015: S70

  View details for Web of Science ID 000352783200410

• Validation of the ICD-9-CM code for systemic sclerosis using updated ACR/EULAR classification criteria SCANDINAVIAN JOURNAL OF RHEUMATOLOGY VALENZUELA, A., Yaqub, A., Fiorentino, D., Krishnan, E., Chung, L. 2015; 44 (3): 253-255

  View details for DOI 10.3109/03009742.2015.1008038

  View details for Web of Science ID 000354392800013

  View details for PubMedID 25744697

• Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis research & therapy Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17: 159-?

  Abstract

  Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

  View details for DOI 10.1186/s13075-015-0669-3

  View details for PubMedID 26071192

  View details for PubMedCentralID PMC4487200

• Serious infection events in the Psoriasis Longitudinal Assessment and Registry Study: current status of observations Kalb, R., Fiorentino, D., Lebwohl, M., Leonardi, C., Toole, J., Goyal, K., Calabro, S., Langholff, W., Fakharzadeh, S. WILEY-BLACKWELL. 2014: E165–E166

  View details for Web of Science ID 000347236100134

• Malignancies in the psoriasis longitudinal assessment and registry (PSOLAR) study: current status of observations Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Lanholff, W. WILEY-BLACKWELL. 2014: 4

  View details for Web of Science ID 000349963100027

• Muscle Disease in Systemic Sclerosis Is Associated with an Increased Risk for Cardiac Involvement Hong, J., Valenzuela, A., Fiorentino, D., Chung, L. WILEY-BLACKWELL. 2014: S314–S315

  View details for Web of Science ID 000344384901265

• A Consensus Hybrid Definition Using a Conjoint Analysis Is the Proposed As Response Criteria for Minimal and Moderate Improvement for Adult Polymyositis and Dermatomyositis Clincal Trials. Aggarwal, R., Rider, L. G., Ruperto, N., Bayat, N., Erman, B., Feldman, B. M., Huber, A. M., Oddis, C. V., Lundberg, I. E., Amato, A. A., Cooper, R. G., Chinoy, H., Dastmalchi, M., Fiorentino, D., Isenberg, D., Katz, J. D., Mammen, A. L., de Visser, M., Ytterberg, S. R., Danko, K., Villa, L., Rinaldi, M., Rockette, H., Lachenbruch, P. A., Miller, F. W., Vencovsky, J. WILEY-BLACKWELL. 2014: S404–S405

  View details for Web of Science ID 000344384902019

• Malignancies in the Psoriasis Longitudinal Assessment and Registry Study: Cumulative Experience Fiorentino, D., Lebwohl, M., Ho, V., Langley, R., Goyal, K., Fakharzadeh, S., Calabro, S., Langholff, W. WILEY-BLACKWELL. 2014: S690

  View details for Web of Science ID 000344384903187

• Antibodies to Human Interferon-Inducible Protein-16 Are Present in Primary Sjogren's Syndrome and Systemic Lupus, but Are Rare in Dermatomyositis. Baer, A. N., Petri, M., Fiorentino, D., Wang, T., Sohn, J., Rosen, A., Casciola-Rosen, L. WILEY-BLACKWELL. 2014: S1110

  View details for Web of Science ID 000344384905216

• Serious Infection Events in the Psoriasis Longitudinal Assessment and Registry Study: Cumulative Experience. Kalb, R., Fiorentino, D., Lebwohl, M., Leonardi, C., Toole, J., Goyal, K., Calabro, S., Langholff, W., Fakharzadeh, S. WILEY-BLACKWELL. 2014: S814

  View details for Web of Science ID 000344384904002

• Effect of the endothelin type A-selective endothelin receptor antagonist ambrisentan on digital ulcers in patients with systemic sclerosis: Results of a prospective pilot study. Journal of the American Academy of Dermatology Chung, L., Ball, K., Yaqub, A., Lingala, B., Fiorentino, D. 2014; 71 (2): 400-401

  View details for DOI 10.1016/j.jaad.2014.04.028

  View details for PubMedID 25037794

• Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA dermatology Valenzuela, A., Chung, L., Casciola-Rosen, L., Fiorentino, D. 2014; 150 (7): 724-729

  Abstract

  Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied.To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM.A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (≥18 years of age) attending the Stanford University Medical Center clinic.Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination.Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4-18.1; vs median, 3.9 years; range, 0.2-19.2 years; P = .003) and more fingertip ulcers (50.0% vs 9.3%, P < .001). An association between calcinosis and both interstitial lung disease and anti-MDA-5 autoantibodies was identified, but this association did not persist in multivariate models that adjusted for fingertip ulcers. Fingertip ulcers and disease duration were strongly associated with calcinosis in all multivariate models, independent of the underlying autoantibody present. Autoantibodies to NXP-2 were associated with calcinosis (odds ratio, 15.52; 95% CI, 2.01-119.90), whereas anti-transcriptional intermediary factor 1-γ antibodies were protective (odds ratio, 0.2; 95% CI, 0.01-0.99) in multivariate analyses that adjusted for fingertip ulcers and other covariates.Calcinosis was a relatively uncommon clinical feature in our cohort of adults with DM. Our data suggest that calcinosis is positively associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies and negatively associated with transcriptional intermediary factor 1-γ antibodies. A common vascular mechanism may underlie the development of both calcinosis and fingertip ulcers in patients with DM.

  View details for DOI 10.1001/jamadermatol.2013.10416

  View details for PubMedID 24869801

• Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA dermatology Valenzuela, A., Chung, L., Casciola-Rosen, L., Fiorentino, D. 2014; 150 (7): 724-729

  Abstract

  Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied.To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM.A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (≥18 years of age) attending the Stanford University Medical Center clinic.Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination.Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4-18.1; vs median, 3.9 years; range, 0.2-19.2 years; P = .003) and more fingertip ulcers (50.0% vs 9.3%, P < .001). An association between calcinosis and both interstitial lung disease and anti-MDA-5 autoantibodies was identified, but this association did not persist in multivariate models that adjusted for fingertip ulcers. Fingertip ulcers and disease duration were strongly associated with calcinosis in all multivariate models, independent of the underlying autoantibody present. Autoantibodies to NXP-2 were associated with calcinosis (odds ratio, 15.52; 95% CI, 2.01-119.90), whereas anti-transcriptional intermediary factor 1-γ antibodies were protective (odds ratio, 0.2; 95% CI, 0.01-0.99) in multivariate analyses that adjusted for fingertip ulcers and other covariates.Calcinosis was a relatively uncommon clinical feature in our cohort of adults with DM. Our data suggest that calcinosis is positively associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies and negatively associated with transcriptional intermediary factor 1-γ antibodies. A common vascular mechanism may underlie the development of both calcinosis and fingertip ulcers in patients with DM.

  View details for DOI 10.1001/jamadermatol.2013.10416

  View details for PubMedID 24869801

• Malignancy events in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study: Current status of observations Fiorentino, D., Langley, R., Fakharzadeh, S., Ho, V. MOSBY-ELSEVIER. 2014: AB175

  View details for Web of Science ID 000360583900691

• Abstract 46: surgical treatment of systemic sclerosis: re-thinking the role and timing of peripheral sympathectomy. Plastic and reconstructive surgery Momeni, A., Sorice, S. C., Valenzuela, A., Fiorentino, D. F., Chung, L., Chang, J. 2014; 133 (4): 1010-?

  View details for DOI 10.1097/01.prs.0000445829.40020.04

  View details for PubMedID 24675339

• IDENTIFICATION OF ICD-9 CODES ASSOCIATED WITH SCLERODERMA RENAL CRISIS Vergara, A., Yaqub, A., Fiorentino, D., Krishnan, E., Chung, L. CLINICAL & EXPER RHEUMATOLOGY. 2014: S115

  View details for Web of Science ID 000335936400307

• Atherosclerotic Cardiovascular Disease in Hospitalized Patients With Systemic Sclerosis: Higher Mortality Than Patients With Lupus and Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Dave, A. J., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2014; 66 (2): 323-327

  Abstract

  Systemic sclerosis (SSc; scleroderma) patients have an increased risk for atherosclerotic cardiovascular disease (ASCVD), possibly mediated through inflammatory and fibrotic mechanisms affecting the macrovasculature and microvasculature. We utilized the US Nationwide Inpatient Sample to assess the frequency of and mortality risk associated with ASCVD among hospitalized SSc patients.We examined the frequency and mortality associated with primary diagnoses and procedures related to ASCVD among adult SSc patients using data from 1993 to 2007. Using multivariate logistic regression (controlling for age, sex, nonelective admission, and modified Charlson Comorbidity Index), we compared the odds of death among hospitalized SSc patients with ASCVD to those with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), as well as to a control group that excluded patients with connective tissue diseases.A total of 308,452 hospitalizations of SSc patients were included, of which 5.4% were associated with a primary ASCVD diagnosis or procedure. ASCVD-related SSc hospitalizations were more likely to result in death compared with non-ASCVD SSc hospitalizations (odds ratio [OR] 1.3, 95% confidence interval [95% CI] 1.1-1.4). Multivariate analyses showed that ASCVD-related SSc hospitalizations were more likely to result in death than similar hospitalizations of SLE (OR 1.5, 95% CI 1.2-1.8), RA (OR 2.3, 95% CI 1.9-2.8), and control patients (OR 1.4, 95% CI 1.2-1.8) with ASCVD.SSc patients with ASCVD have higher in-hospital mortality than comparable groups of SLE and RA patients with ASCVD. Further research to elucidate the specific mechanisms underlying ASCVD in SSc is necessary.

  View details for DOI 10.1002/acr.22152

  View details for Web of Science ID 000330266100020

  View details for PubMedID 24022876

• Dermatomyositis EVIDENCE-BASED DERMATOLOGY, 3RD EDITION Vleugels, R., Fiorentino, D. F., Callen, J. P., Williams, H. C., Bigby, M., Herxheimer, A., Naldi, L., Rzany, B., Dellavalle, R. P., Ran, Y., Furue, M. 2014: 531–44

  View details for Web of Science ID 000351239700065

• The plasma cell signature in autoimmune disease. Arthritis & rheumatology (Hoboken, N.J.) Streicher, K., Morehouse, C. A., Groves, C. J., Rajan, B., Pilataxi, F., Lehmann, K. P., Brohawn, P. Z., Higgs, B. W., McKeever, K., Greenberg, S. A., Fiorentino, D., Richman, L. K., Jallal, B., Herbst, R., Yao, Y., Ranade, K. 2014; 66 (1): 173-184

  Abstract

  Production of pathogenic autoantibodies by self-reactive plasma cells (PCs) is a hallmark of autoimmune diseases. We undertook this study to investigate the prevalence of PCs and their relationship to known pathogenic pathways to increase our understanding of the role of PCs in disease progression and treatment response.We developed a sensitive gene expression-based method to overcome the challenges of measuring PCs using flow cytometry. Whole-genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA1, IGJ, IGKC, IGKV4-1, and TNFRSF17, expressed predominantly in PCs. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy, for evaluating the relationship between PCs and other autoimmune disease-related genes, and for estimating PC levels in affected blood and tissue from patients with multiple autoimmune diseases.The PC signature was highly sensitive and capable of detecting a change in as few as 360 PCs. The PC signature was reduced more than 90% in scleroderma patients following anti-CD19 treatment, and this reduction was highly correlated (r = 0.80) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed that 30-35% of lupus and rheumatoid arthritis patients had increased levels of PCs.This newly developed PC signature provides a robust and accurate method of measuring PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases who may benefit from PC-depleting therapy.

  View details for DOI 10.1002/art.38194

  View details for PubMedID 24431284

• A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-alpha monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients ANNALS OF THE RHEUMATIC DISEASES Higgs, B. W., Zhu, W., Morehouse, C., White, W. I., Brohawn, P., Guo, X., Rebelatto, M., Le, C., Amato, A., Fiorentino, D., Greenberg, S. A., Drappa, J., Richman, L., Greth, W., Jallal, B., Yao, Y. 2014; 73 (1): 256-262

  Abstract

  To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure.A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab.The IFNGS was suppressed by a median of 53-66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle.Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

  View details for DOI 10.1136/annrheumdis-2012-202794

  View details for Web of Science ID 000327835100044

  View details for PubMedID 23434567

  View details for PubMedCentralID PMC3888620

• Most Patients With Cancer-Associated Dermatomyositis Have Antibodies to Nuclear Matrix Protein NXP-2 or Transcription Intermediary Factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962

  Abstract

  Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1γ on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

  View details for DOI 10.1002/art.38093

  View details for PubMedID 24037894

• Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962

  Abstract

  Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1γ on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

  View details for DOI 10.1002/art.38093

  View details for PubMedID 24037894

• Validation Of The ICD-CM-9 Code For Systemic Sclerosis Using Updated ACR/EULAR Classification Criteria Yaqub, A., Chung, L., Fiorentino, D., Krishnan, E. WILEY-BLACKWELL. 2013: S772–S773

  View details for Web of Science ID 000325359204270

• A Phase I Single-Dose Crossover Study To Evaluate The Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy Of AMG 811 (anti-IFN-gamma) In Subjects With Discoid Lupus Erythematosus Werth, V. P., Fiorentino, D., Cohen, S. B., Fivenson, D., Hansen, C., Zoog, S., Arnold, G., Wang, C., Boedigheimer, M., Welcher, A., Chung, J., Sullivan, B., Martin, D. A. WILEY-BLACKWELL. 2013: S682–S683

  View details for Web of Science ID 000325359204072

• Validation Of a Novel Radiographic Scoring System For Calcinosis Affecting The Hands Of Patients With Systemic Sclerosis. Chung, L., Vergara, A., Fiorentino, D., Stevens, K., Li, S., Harris, J., Hutchinson, C. E., Assassi, S., Beretta, L., Lakshminarayanan, S., Reyna, T., Denton, C. P., Taillefer, R. G., Tatibouet, S., Herrick, A., Baron, M. WILEY-BLACKWELL. 2013: S289–S290

  View details for Web of Science ID 000325359202186

• Pregnancy Outcomes In Adult Patients With Dermatomyositis and Polymyositis Chung, L., Fiorentino, D., Li, S., Chakravarty, E. WILEY-BLACKWELL. 2013: S886–S887

  View details for Web of Science ID 000325359205028

• Validation Of The Cutaneous Dermatomyositis Disease Area and Severity Index: Characterizing Severity and Assessing Responsiveness To Clinical Change Anyanwu, C. O., Fiorentino, D., Chung, L., Wang, Y., Propert, K. J., Werth, V. P. WILEY-BLACKWELL. 2013: S824

  View details for Web of Science ID 000325359204393

• Identification Of Clinical Features and Risk Factors Associated With Calcinosis In Adult Patients With Dermatomyositis Valenzuela, A., Chung, L., Casciola-Rosen, L., Rosen, A., Fiorentino, D. WILEY-BLACKWELL. 2013: S889

  View details for Web of Science ID 000325359205033

• Serious infection events in the psoriasis longitudinal assessment and registry study: current status of observations Leonardi, C., Fiorentino, D., Kalb, R., Chevrier, M., PSOLAR Steering Comm WILEY-BLACKWELL. 2013: 7–8

  View details for Web of Science ID 000325916200018

• Malignancy events in the psoriasis longitudinal assessment and registry study: current status of observations Langley, R., Strober, B., Lebwohl, M., Ho, V., Fiorentino, D., Fakharzadeh, S., Calabro, S., Langholff, W., Chevrier, M., PSOLAR Steering Comm WILEY-BLACKWELL. 2013: 23–24

  View details for Web of Science ID 000325916200056

• INVESTIGATING THE PLASMA CELL SIGNATURE IN AUTOIMMUNE DISEASE Streicher, K., Morehouse, C., Groves, C., Rajan, B., Pilataxi, F., Lehmann, K., Brohawn, P. Z., Higgs, B. W., McKeever, K., Greenberg, S. A., Fiorentino, D., Richman, L., Jallal, B., Herbst, R., Yao, Y., Ranade, K. BMJ PUBLISHING GROUP. 2013: 166

  View details for Web of Science ID 000331587901531

• MOLECULAR CHARACTERIZATION OF COLLAGEN IN MUSCLE OF POLYMYOSITIS AND DERMATOMYOSITIS Liu, Z., Morehouse, C., Higgs, B. W., Czapiga, M., Rebelatto, M., Brohawn, P., Richman, L., Fiorentino, D., Jallal, B., Greenberg, S. A., Yao, Y. BMJ PUBLISHING GROUP. 2013: 477–78

  View details for DOI 10.1136/annrheumdis-2012-eular.2968

  View details for Web of Science ID 000208898502370

• GENOMIC SIGNATURES CHARACTERIZE LEUKOCYTE INFILTRATION IN MYOSITIS MUSCLES Zhu, W., Streicher, K., Shen, N., Higgs, B. W., Morehouse, C., Greenlees, L., Ranade, K., Richman, L., Fiorentino, D., Jallal, B., Greenberg, S. A., Yao, Y. BMJ PUBLISHING GROUP. 2013: 472

  View details for DOI 10.1136/annrheumdis-2012-eular.2952

  View details for Web of Science ID 000208898502354

• Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: results from a phase IIb randomized, controlled study HEALTH AND QUALITY OF LIFE OUTCOMES Strand, V., Fiorentino, D., Hu, C., Day, R. M., Stevens, R. M., Papp, K. A. 2013; 11

  Abstract

  Apremilast, a specific inhibitor of phosphodiesterase 4, modulates pro-inflammatory and anti-inflammatory cytokine production.Apremilast's effect on patient-reported outcomes (PROs) in patients with moderate to severe psoriasis was evaluated in a phase IIb randomized, controlled trial (NCT00773734).In this 16-week, placebo-controlled study, 352 patients with moderate to severe plaque psoriasis received placebo or apremilast (10, 20, or 30 mg BID). PROs included Dermatology Life Quality Index (DLQI), pruritus visual analog scale (VAS), and Short-Form Health Survey (SF-36) to assess health-related quality of life (HRQOL). Changes from baseline and patients reporting improvements ≥minimum clinically important differences (MCID) were analyzed. Correlations between changes across various PRO instruments were explored.Baseline DLQI (>10 points) and SF-36 MCS and domain scores indicated impairments in HRQOL. At 16 weeks, greater improvements from baseline in DLQI scores were reported with apremilast 20 (-5.9) and 30 mg BID (-4.4) compared with placebo (1.9; P≤0.005 for both), and a greater proportion of patients reported improvements ≥MCID (20 mg BID, 49.4%, 30 mg BID, 44.3%) versus placebo (25.0%; P<0.04). Greater improvements from baseline in pruritus VAS scores were reported with apremilast 20 (-35.5%) and 30 mg BID (-43.7%) versus placebo (-6.1%; P≤0.005). Significant and clinically meaningful improvements in SF-36 mental component summary scores (P≤0.008) and Bodily Pain, Mental Health, and Role-Emotional domains were reported with all apremilast doses (P<0.05), and Social Functioning with 20 and 30 mg BID (P<0.05) and Physical Functioning with 20 mg BID (P<0.03). Correlations between SF-36 scores and DLQI were moderate (r>0.30 and ≤0.60) and low between SF-36 and pruritus VAS (r≤0.30), indicating they measure different aspects of the disease.Apremilast treatment resulted in improved HRQOL, including DLQI and pruritus VAS over 16 weeks of treatment, in patients with moderate to severe psoriasis.

  View details for DOI 10.1186/1477-7525-11-82

  View details for Web of Science ID 000319268200001

  View details for PubMedID 23663752

  View details for PubMedCentralID PMC3661377

• Localized cutaneous fibrosing disorders. Rheumatic diseases clinics of North America Yaqub, A., Chung, L., Rieger, K. E., Fiorentino, D. F. 2013; 39 (2): 347-364

  Abstract

  This article acquaints the reader with disorders of the skin that might mimic systemic sclerosis but whose pathology is localized to the skin and/or has extracutaneous manifestations that are different than systemic sclerosis. These disorders include localized scleroderma (morphea), eosinophilic fasciitis, scleredema, scleromyxedema, nephrogenic systemic fibrosis, and chronic graft-versus-host disease. Particular emphasis is placed on clinical and histopathologic features that help the clinician differentiate between these disorders. Treatment options are briefly reviewed.

  View details for DOI 10.1016/j.rdc.2013.02.013

  View details for PubMedID 23597968

• Localized cutaneous fibrosing disorders. Rheumatic diseases clinics of North America Yaqub, A., Chung, L., Rieger, K. E., Fiorentino, D. F. 2013; 39 (2): 347-364

  View details for DOI 10.1016/j.rdc.2013.02.013

  View details for PubMedID 23597968

• Serious infection events in the psoriasis longitudinal assessment and registry (PSOLAR) study: Current status of observations Leonardi, C., Fiorentino, D., Chevrier, M., Kalb, R. MOSBY-ELSEVIER. 2013: AB213

  View details for Web of Science ID 000315412600846

• Inflammatory arthritis following ustekinumab treatment for psoriasis: a report of two cases BRITISH JOURNAL OF DERMATOLOGY de Souza, A., Ali-Shaw, T., Reddy, S. M., Fiorentino, D., Strober, B. E. 2013; 168 (1): 210-212

  Abstract

  Psoriasis is a chronic inflammatory skin condition, characterized by T-helper (Th) 1 and Th17 cell activation. Ustekinumab is a fully human immunoglobulin G1κ monoclonal antibody that targets the common p40 subunit that is shared by both interleukin (IL)-12 and IL-23, consequently inhibiting T-cell differentiation along both Th1 and Th17 pathways. This is a report of two patients who developed psoriatic arthritis during ustekinumab treatment for psoriasis. Neither patient had a personal or family history of arthritis.

  View details for DOI 10.1111/j.1365-2133.2012.11206.x

  View details for Web of Science ID 000314469000060

  View details for PubMedID 23278559

• Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of the Nationwide Inpatient Sample survey. Arthritis research & therapy Linos, E., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2013; 15 (1): R7-?

  Abstract

  ABSTRACT: INTRODUCTION: Increased rates of cardiovascular disease are implicated in several rheumatologic diseases. Our aim was to characterize dermatomyositis hospitalizations and evaluate cardiovascular-associated mortality in this patient population. METHODS: We examined the frequency and mortality rates of several atherosclerotic cardiovascular diagnoses and procedures among hospitalized adult patients with dermatomyositis using data from the US Nationwide Inpatient Sample (NIS) from 1993 to 2007. We compared the odds of death among hospitalized dermatomyositis patients with each cardiovascular diagnosis or procedure to those without, as well as to controls with cardiovascular diagnoses, using logistic regression. RESULTS: A total of 50,322 hospitalizations of dermatomyositis patients occurred between 1993 and 2007 (mean age 58 years, and 73% female). Of all dermatomyositis hospitalizations, 20% were associated with a concurrent atherosclerotic cardiovascular diagnosis or procedure. The overall in-hospital mortality was 5.7%. Dermatomyositis patients with any associated atherosclerotic cardiovascular diagnosis or procedure were twice as likely to die during the inpatient stay compared to dermatomyositis patients who did not have atherosclerotic cardiovascular disease (OR = 2.0 95% CI 1.7-2.5, p < 0.0001). The odds ratio for death in patients with both dermatomyositis and cardiovascular disease compared to controls with cardiovascular disease alone was 1.98 (95% CI 1.57-2.48) in multivariate adjusted models. CONCLUSIONS: Approximately one fifth of dermatomyositis hospitalizations in the US were associated with an atherosclerotic cardiovascular diagnosis or procedure. These patients have double the risk of in-hospital death in comparison with controls and dermatomyositis patients without a cardiovascular diagnosis, making identification of these groups important for both prognostic purposes and clinical care.

  View details for DOI 10.1186/ar4135

  View details for PubMedID 23298514

• Molecular Profiling to Diagnose a Case of Atypical Dermatomyositis. The Journal of investigative dermatology 2013

  View details for PubMedID 23732751

• Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of the Nationwide Inpatient Sample survey ARTHRITIS RESEARCH & THERAPY Linos, E., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2013; 15 (1)

  Abstract

  ABSTRACT: INTRODUCTION: Increased rates of cardiovascular disease are implicated in several rheumatologic diseases. Our aim was to characterize dermatomyositis hospitalizations and evaluate cardiovascular-associated mortality in this patient population. METHODS: We examined the frequency and mortality rates of several atherosclerotic cardiovascular diagnoses and procedures among hospitalized adult patients with dermatomyositis using data from the US Nationwide Inpatient Sample (NIS) from 1993 to 2007. We compared the odds of death among hospitalized dermatomyositis patients with each cardiovascular diagnosis or procedure to those without, as well as to controls with cardiovascular diagnoses, using logistic regression. RESULTS: A total of 50,322 hospitalizations of dermatomyositis patients occurred between 1993 and 2007 (mean age 58 years, and 73% female). Of all dermatomyositis hospitalizations, 20% were associated with a concurrent atherosclerotic cardiovascular diagnosis or procedure. The overall in-hospital mortality was 5.7%. Dermatomyositis patients with any associated atherosclerotic cardiovascular diagnosis or procedure were twice as likely to die during the inpatient stay compared to dermatomyositis patients who did not have atherosclerotic cardiovascular disease (OR = 2.0 95% CI 1.7-2.5, p < 0.0001). The odds ratio for death in patients with both dermatomyositis and cardiovascular disease compared to controls with cardiovascular disease alone was 1.98 (95% CI 1.57-2.48) in multivariate adjusted models. CONCLUSIONS: Approximately one fifth of dermatomyositis hospitalizations in the US were associated with an atherosclerotic cardiovascular diagnosis or procedure. These patients have double the risk of in-hospital death in comparison with controls and dermatomyositis patients without a cardiovascular diagnosis, making identification of these groups important for both prognostic purposes and clinical care.

  View details for DOI 10.1186/ar4135

  View details for Web of Science ID 000317932600021

• Genomic signatures characterize leukocyte infiltration in myositis muscles BMC MEDICAL GENOMICS Zhu, W., Streicher, K., Shen, N., Higgs, B. W., Morehouse, C., Greenlees, L., Amato, A. A., Ranade, K., Richman, L., Fiorentino, D., Jallal, B., Greenberg, S. A., Yao, Y. 2012; 5

  Abstract

  Leukocyte infiltration plays an important role in the pathogenesis and progression of myositis, and is highly associated with disease severity. Currently, there is a lack of: efficacious therapies for myositis; understanding of the molecular features important for disease pathogenesis; and potential molecular biomarkers for characterizing inflammatory myopathies to aid in clinical development.In this study, we developed a simple model and predicted that 1) leukocyte-specific transcripts (including both protein-coding transcripts and microRNAs) should be coherently overexpressed in myositis muscle and 2) the level of over-expression of these transcripts should be correlated with leukocyte infiltration. We applied this model to assess immune cell infiltration in myositis by examining mRNA and microRNA (miRNA) expression profiles in muscle biopsies from 31 myositis patients and 5 normal controls.Several gene signatures, including a leukocyte index, type 1 interferon (IFN), MHC class I, and immunoglobulin signature, were developed to characterize myositis patients at the molecular level. The leukocyte index, consisting of genes predominantly associated with immune function, displayed strong concordance with pathological assessment of immune cell infiltration. This leukocyte index was subsequently utilized to differentiate transcriptional changes due to leukocyte infiltration from other alterations in myositis muscle. Results from this differentiation revealed biologically relevant differences in the relationship between the type 1 IFN pathway, miR-146a, and leukocyte infiltration within various myositis subtypes.Results indicate that a likely interaction between miR-146a expression and the type 1 IFN pathway is confounded by the level of leukocyte infiltration into muscle tissue. Although the role of miR-146a in myositis remains uncertain, our results highlight the potential benefit of deconvoluting the source of transcriptional changes in myositis muscle or other heterogeneous tissue samples. Taken together, the leukocyte index and other gene signatures developed in this study may be potential molecular biomarkers to help to further characterize inflammatory myopathies and aid in clinical development. These hypotheses need to be confirmed in separate and sufficiently powered clinical trials.

  View details for DOI 10.1186/1755-8794-5-53

  View details for Web of Science ID 000313563800001

  View details for PubMedID 23171592

  View details for PubMedCentralID PMC3541209

• Skin disease in dermatomyositis CURRENT OPINION IN RHEUMATOLOGY Zaba, L. C., Fiorentino, D. F. 2012; 24 (6): 597-601

  Abstract

  This review will provide the clinician with an update on the pathogenesis, clinical manifestations, and therapy for skin disease in dermatomyositis. Recent insights into the role for interferon in skin disease as well as the development and validation of quantitative tools to measure skin disease activity allow the possibility that, for the first time, dermatomyositis skin disease can serve as a valid outcome for clinical trials of targeted therapies. Also, the increasing appreciation of the heterogeneity of skin disease in dermatomyositis has already provided evidence that clinical subtypes of disease can provide important prognostic and diagnostic information to the clinician.It is becoming apparent that the skin inflammation alone has implications for systemic and malignancy risk in dermatomyositis patients, and that there may be several pathogenic similarities between muscle and skin inflammation in dermatomyositis. Recent data on therapy for calcinosis cutis highlights that more prospective studies are needed to evaluate how best to manage all manifestations of skin inflammation in dermatomyositis.A more careful description and classification of skin disease in dermatomyositis may allow the clinician to predict more accurately which patients will be at higher risk for cancer, lung disease, or muscle inflammation. In addition, given the similarities in perturbed gene expression between skin and muscle tissue, it is likely that analysis of a more readily evaluable target organ such as skin might shed light on mechanisms of disease propagation throughout the body.

  View details for DOI 10.1097/BOR.0b013e3283585748

  View details for PubMedID 22907594

• Immune Responses to NXP-2 and TIF-g Are Associated with Distinct Clinical Phenotypes and Prognosis for Skin Disease in Dermatomyositis Patients. Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Fiorentino, D., Chung, L., Zaba, L., Lingala, B., Rosen, A., Casciola-Rosen, L. WILEY-BLACKWELL. 2012: S828–S828

  View details for Web of Science ID 000309748304231

• Sifalimumab, an Anti-IFN-Alpha Monoclonal Antibody Shows Target Suppression of a Type I IFN Signature in Blood and Muscle of Dermatomyositis and Polymyositis Patients. Higgs, B. W., Zhu, W., Morehouse, C., White, W., Brohawn, P., Le, C., Amato, A. A., Fiorentino, D., Greenberg, S. A., Richman, L., Greth, W., Jallal, B., Yao, Y. WILEY-BLACKWELL. 2012: S325

  View details for Web of Science ID 000309748301292

• Excess Mortality From Atherosclerotic Cardiovascular Disease in Systemic Sclerosis Compared to Lupus and Rheumatoid Arthritis Dave, A. J., Lingala, B., Fiorentino, D., Krishnan, E., Chung, L. WILEY-BLACKWELL. 2012: S302–S303

  View details for Web of Science ID 000309748301244

• Cutaneous Ulceration in Dermatomyositis: Association with MDA-5 and Interstitial Lung Disease. Narang, N., Casciola-Rosen, L., Rosen, A., Fiorentino, D., Chung, L. WILEY-BLACKWELL. 2012: S326

  View details for Web of Science ID 000309748301295

• Antibodies to NXP-2 and Transcriptional Intermediary Factor-Gamma Identify Patients with Cancer-Associated Dermatomyositis. Fiorentino, D., Christopher-Stine, L., Chung, L., Lingala, B., Mammen, A. L., Rosen, A., Casciola-Rosen, L. WILEY-BLACKWELL. 2012: S828

  View details for Web of Science ID 000309748304230

• Clinical presentation and evaluation of dermatomyositis. Indian journal of dermatology Marvi, U., Chung, L., Fiorentino, D. F. 2012; 57 (5): 375-381

  Abstract

  Dermatomyositis (DM) is a chronic inflammatory disorder of the skin and muscles. Evidence supports that DM is an immune-mediated disease and 50-70% of patients have circulating myositis-specific auto-antibodies. Gene expression microarrays have demonstrated upregulation of interferon signaling in the muscle, blood, and skin of DM patients. Patients with classic DM typically present with symmetric, proximal muscle weakness, and skin lesions that demonstrate interface dermatitis on histopathology. Evaluation for muscle inflammation can include muscle enzymes, electromyogram, magnetic resonance imaging, and/or muscle biopsy. Classic skin manifestations of DM include the heliotrope rash, Gottron's papules, Gottron's sign, the V-sign, and shawl sign. Additional cutaneous lesions frequently observed in DM patients include periungual telangiectasias, cuticular overgrowth, "mechanic's hands", palmar papules overlying joint creases, poikiloderma, and calcinosis. Clinically amyopathic DM is a term used to describe patients who have classic cutaneous manifestations for more than 6 months, but no muscle weakness or elevation in muscle enzymes. Interstitial lung disease can affect 35-40% of patients with inflammatory myopathies and is often associated with the presence of an antisynthetase antibody. Other clinical manifestations that can occur in patients with DM include dysphagia, dysphonia, myalgias, Raynaud phenomenon, fevers, weight loss, fatigue, and a nonerosive inflammatory polyarthritis. Patients with DM have a three to eight times increased risk for developing an associated malignancy compared with the general population, and therefore all patients with DM should be evaluated at the time of diagnosis for the presence of an associated malignancy. This review summarizes the immunopathogenesis, clinical manifestations, and evaluation of patients with DM.

  View details for DOI 10.4103/0019-5154.100486

  View details for PubMedID 23112358

  View details for PubMedCentralID PMC3482801

• Homology of Cytokine Synthesis Inhibitory Factor (IL-10) to the Epstein-Barr Virus Gene BCRFI JOURNAL OF IMMUNOLOGY Moore, K. W., Vieira, P., Fiorentino, D. F., Trounstine, M. L., Khan, T. A., Mosmann, T. R. 2012; 189 (5): 1230-1234

  View details for DOI 10.1126/science.2161559

  View details for Web of Science ID 000308083600002

• Treatment of Recalcitrant Eosinophilic Cellulitis With Adalimumab ARCHIVES OF DERMATOLOGY Sarin, K. Y., Fiorentino, D. 2012; 148 (9): 990-992

  View details for Web of Science ID 000308883500002

  View details for PubMedID 22986848

• A Novel Dermato-Pulmonary Syndrome Associated With MDA-5 Antibodies Report of 2 Cases and Review of the Literature MEDICINE Chaisson, N. F., Paik, J., Orbai, A., Casciola-Rosen, L., Fiorentino, D., Danoff, S., Rosen, A. 2012; 91 (4): 220-228

  Abstract

  Melanoma differentiation-associated protein 5 (MDA-5) is a novel autoantibody frequently characterized by interstitial lung disease and a distinct cutaneous phenotype with palmar papules, ulceration, and rash. Virtually all patients have underlying dermatomyositis, but many lack the characteristic clinical myopathy associated with it. In the setting of amyopathic disease, the absence of clinically available biomarkers or clear pathologic diagnosis can complicate effective prognostic and therapeutic intervention. Until recently the presence of MDA-5 antibody associated dermato-pulmonary syndrome was described only in Asian populations. We present 2 cases of MDA-5-associated dermato-pulmonary syndrome and provide a comprehensive review of available literature.

  View details for DOI 10.1097/MD.0b013e3182606f0b

  View details for Web of Science ID 000306113300006

  View details for PubMedID 22732950

• Comparison of health-related quality of life in rheumatoid arthritis, psoriatic arthritis and psoriasis and effects of etanercept treatment ANNALS OF THE RHEUMATIC DISEASES Strand, V., Sharp, V., Koenig, A. S., Park, G., Shi, Y., Wang, B., Zack, D. J., Fiorentino, D. 2012; 71 (7): 1143-1150

  Abstract

  To compare health-related quality of life (HRQoL) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis using spydergram representations.Data from randomised, controlled trials of etanercept in patients with RA, PsA and psoriasis were analysed. HRQoL was assessed by the medical outcomes survey short form 36 (SF-36) physical (PCS) and mental (MCS) component summary and domain scores. Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure.Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA, but near normative values in patients with psoriasis; MCS scores at baseline were near normal in PsA and psoriasis but low in RA. Treatment with etanercept resulted in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications. Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA; clinically meaningful improvements in SF-6D were observed in all three patient populations following treatment with etanercept.Patients with RA, PsA and psoriasis demonstrated unique HRQoL profiles at baseline. Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA, PsA and psoriasis.

  View details for DOI 10.1136/annrheumdis-2011-200387

  View details for Web of Science ID 000305293400007

  View details for PubMedID 22258482

  View details for PubMedCentralID PMC3375587

• Autoantibodies to transcription intermediary factor 1 in dermatomyositis shed insight into the cancer-myositis connection ARTHRITIS AND RHEUMATISM Fiorentino, D., Casciola-Rosen, L. 2012; 64 (2): 346-349

  View details for DOI 10.1002/art.33402

  View details for Web of Science ID 000299625700004

  View details for PubMedID 21987176

  View details for PubMedCentralID PMC3268010

• Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES Higgs, B. W., Zhu, W., Richman, L., Fiorentino, D. F., Greenberg, S. A., Jallal, B., Yao, Y. 2012; 15 (1): 25-35

  Abstract

  To develop genomic signatures of seven cytokines involved in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA), or systemic scleroderma (SSc) that could potentially help identify patients likely to respond to therapies that target these individual cytokines.Over-expressed transcripts in the whole blood (WB) were identified from 262 SLE, 44 DM, 33 PM, 38 SSc and 89 RA subjects and compared to 24 healthy subjects using Affymetrix arrays. Cytokine-inducible gene signatures such as type I interferon (IFN), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-10, IL-13, IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assessed in the WB of these subjects to identify subpopulations showing activation of specific cytokine pathways.Significant activation of the type I IFN pathway in a population of five diseases studied was universally observed. The TNF-α and IL-1β pathways were activated in subgroups of PM and RA subjects, respectively, with another subgroup of RA subjects showing activation of the IL-13 pathway. The GM-CSF pathway was activated in a subgroup of SSc subjects and the IL-17 pathway was activated in subgroups of all diseases except SLE.A novel gene expression measurement of activated cytokines in five different rheumatic diseases is presented. Characterizing the cytokine pathways most activated in specific patient subpopulations has the potential to help target the appropriate patient populations for corresponding anti-cytokine therapies.

  View details for DOI 10.1111/j.1756-185X.2011.01654.x

  View details for Web of Science ID 000300446600014

  View details for PubMedID 22324944

• Interferon and Biologic Signatures in Dermatomyositis Skin: Specificity and Heterogeneity across Diseases PLOS ONE Wong, D., Kea, B., Pesich, R., Higgs, B. W., Zhu, W., Brown, P., Yao, Y., Fiorentino, D. 2012; 7 (1)

  Abstract

  Dermatomyositis (DM) is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood.We analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. We observed a robust upregulation of interferon (IFN)-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The interferon (IFN)-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. We observed that the IFN signature in DM skin appears to be more closely related to type I than type II IFN based on in vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin shows that the majority of known type I IFNs, as well as IFN g, are overexpressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN) transcript levels were highly correlated with the degree of the in vivo IFN transcriptional response in DM skin.As in the blood and muscle, DM skin is characterized by an overwhelming presence of an IFN signature, although it is difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases will be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue.

  View details for DOI 10.1371/journal.pone.0029161

  View details for Web of Science ID 000301123400030

  View details for PubMedID 22235269

  View details for PubMedCentralID PMC3250414

• Consensus Guidelines for the Management of Plaque Psoriasis ARCHIVES OF DERMATOLOGY Hsu, S., Papp, K. A., Lebwohl, M. G., Bagel, J., Blauvelt, A., Duffin, K. C., Crowley, J., Eichenfield, L. F., Feldman, S. R., Fiorentino, D. F., Gelfand, J. M., Gottlieb, A. B., Jacobsen, C., Kalb, R. E., Kavanaugh, A., Korman, N. J., Krueger, G. G., Michelon, M. A., Morison, W., Ritchlin, C. T., Gold, L. S., Stone, S. P., Strober, B. E., Van Voorhees, A. S., Weiss, S. C., Wanat, K., Bebo, B. F. 2012; 148 (1): 95-102

  Abstract

  The Canadian Guidelines for the Management of Plaque Psoriasis were reviewed by the entire National Psoriasis Foundation Medical Board and updated to include newly approved agents such as ustekinumab and to reflect practice patterns in the United States, where the excimer laser is approved for psoriasis treatment. Management of psoriasis in special populations is discussed. In the updated guidelines, we include sections on children, pregnant patients or pregnant partners of patients, nursing mothers, the elderly, patients with hepatitis B or C virus infections, human immunodeficiency virus-infected patients, and patients with malignant neoplasms, as well as sections on tumor necrosis factor blockers, elective surgery, and vaccinations.

  View details for Web of Science ID 000299653900018

  View details for PubMedID 22250239

• Quality of life in dermatomyositis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Goreshi, R., Chock, M., Foering, K., Feng, R., Okawa, J., Rose, M., Fiorentino, D., Werth, V. 2011; 65 (6): 1107-1116

  Abstract

  Quality of life (QoL) for patients with inflammatory skin disease can be significant, but has been evaluated in just one study in dermatomyositis (DM).We sought to examine the relationship between the Cutaneous Dermatomyositis Area (CDASI) and Severity Index, a DM-specific cutaneous severity instrument, and various QoL study instruments and to determine the impact of DM on QoL.Skin-specific QoL instruments, the Skindex and the Dermatology Life Quality Index, and global medical QoL instruments, the Short Form 36 and the Health Assessment Questionnaire-Disability Index, were used. Pruritus was evaluated by a visual analog scale and a 0-to-10 scale in DM and cutaneous lupus erythematosus (CLE) populations, respectively.There was a significant correlation between the CDASI and all skin-specific QoL scores (lowest P = .0377). Using the Short Form 36, DM population was found to have significantly worse QoL scores than the general population with the exception of bodily pain (all subscore P values < .01). Furthermore, DM had a significantly lower vitality score, representing energy level, compared with CLE, hypertension, diabetes, and recent myocardial infarction scores (lowest P = .003). There was a significantly lower mental health score, representing overall mood, to all compared diseases except CLE and clinical depression (P values < .01 when significant). We found that DM produces more pruritus than CLE (P < .0001).A larger patient population needs to be studied to further assess QoL in patients with DM.We conclude that DM has a large impact on QoL, even when compared with other diseases, and that DM skin disease activity correlates with a poorer QoL.

  View details for DOI 10.1016/j.jaad.2010.10.016

  View details for Web of Science ID 000297717200004

  View details for PubMedID 21722989

  View details for PubMedCentralID PMC3189436

• Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway ANNALS OF THE RHEUMATIC DISEASES Higgs, B. W., Liu, Z., White, B., Zhu, W., White, W. I., Morehouse, C., Brohawn, P., Kiener, P. A., Richman, L., Fiorentino, D., Greenberg, S. A., Jallal, B., Yao, Y. 2011; 70 (11): 2029-2036

  Abstract

  To characterise activation of the type I interferon (IFN) pathway in patients with systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA) and systemic scleroderma (SSc) and to evaluate the potential to develop a molecular diagnostic tool from the peripheral blood that reflects this activation in disease-affected tissues.Overexpressed transcripts were identified in the whole blood (WB) of 262 patients with SLE, 44 with DM, 33 with PM, 28 with SSc and 89 with RA and compared with 24 healthy subjects using Affymetrix microarrays. A five gene type I IFN signature was assessed in these subjects to identify subpopulations showing both activation and concordance of the type I IFN pathway in the peripheral blood and disease-affected tissues of each disease and to correlate activation of this pathway in the WB with clinical measurements.A common set of 36 type I IFN inducible transcripts were identified among the most overexpressed in the WB of all subjects. Significant activation of the type I IFN pathway in subgroups of each of the five diseases studied was observed. Baseline disease activity measurements correlated with a type I IFN gene signature in the WB of subjects with SLE, PM and SSc, as did various serum autoantibody levels in subjects with SLE and DM. This signature was also well correlated between disease-affected tissue and WB in subjects with SLE, DM, PM and SSc.The results indicate that the type I IFN pathway is activated in patient subsets of five rheumatic diseases and suggest that these subsets may benefit from anti-IFN therapy.

  View details for DOI 10.1136/ard.2011.150326

  View details for Web of Science ID 000295399700026

  View details for PubMedID 21803750

• A Pilot Study of Abatacept for the Treatment of Patients with Diffuse Cutaneous Systemic Sclerosis. 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) Chakravarty, E. F., Fiorentino, D., Bennett, M., Chung, L. WILEY-BLACKWELL. 2011: S274–S275

  View details for Web of Science ID 000297621500703

• International Classification of Diseases-Clinical Modification-9 Codes for the Diagnosis of Dermatomyositis and Polymyositis in Discharge Summaries: Evidence of Acceptable Validity Narang, N., Fiorentino, D., Krishnan, E., Chung, L. WILEY-BLACKWELL. 2011: S90

  View details for Web of Science ID 000297621500244

• Effect of the ETA Selective Endothelin Receptor Antagonist Ambrisentan on Digital Ulcers in Patients with Systemic Sclerosis: Results of a Prospective Pilot Study. Chung, L., Arefiev, K., Yaqub, A., Strahs, D., Lingala, B., Fiorentino, D. WILEY-BLACKWELL. 2011: S259–S260

  View details for Web of Science ID 000297621500664

• Tyrosine kinases in inflammatory dermatologic disease JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Paniagua, R. T., Fiorentino, D. F., Chung, L., Robinson, W. H. 2011; 65 (2): 389-403

  Abstract

  Tyrosine kinases (TKs) are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific TKs have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of TKs are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight TK signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development.

  View details for DOI 10.1016/j.jaad.2010.04.026

  View details for PubMedID 20584561

• The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): A retrospective study JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D., Chung, L., Zwerner, J., Rosen, A., Casciola-Rosen, L. 2011; 65 (1): 25-34

  Abstract

  Dermatomyositis (DM) is a multisystem autoimmune disease, in which serologic evidence of immune responses to disease-specific antigenic targets is found in approximately 50% to 70% of patients. Recently, melanoma differentiation-associated gene 5 (MDA5) has been identified as a DM-specific autoantigen that appears to be targeted in patients with DM and mild or absent muscle inflammation and with an increased risk of interstitial lung disease.We wished to understand the role of MDA5 in DM skin inflammation by testing it to determine if a specific cutaneous phenotype is associated with MDA5 reactivity.We retrospectively screened plasma from 77 patients with DM in the outpatient clinics at the Stanford University Department of Dermatology in California.We found that 10 (13%) patients had circulating anti-MDA5 antibodies, and had a characteristic cutaneous phenotype consisting of skin ulceration, tender palmar papules, or both. Typical areas of skin ulceration included the lateral nailfolds, Gottron papules, and elbows. Biopsy specimens of the palmar papules showed a vasculopathy characterized by vascular fibrin deposition with variable perivascular inflammation. Patients with anti-MDA5 antibodies also had an increased risk of oral pain and/or ulceration, hand swelling, arthritis/arthralgia, and diffuse hair loss. Consistent with previous reports, these patients had little or no myositis and had increased risk of interstitial lung disease.This study was conducted at a tertiary referral center. Multiple associations with MDA5 antibodies were tested retrospectively on a relatively small cohort of 10 anti-MDA5-positive patients.We suggest that MDA5 reactivity in DM characterizes a patient population with severe vasculopathy.

  View details for DOI 10.1016/j.jaad.2010.09.016

  View details for Web of Science ID 000292222200003

  View details for PubMedID 21531040

  View details for PubMedCentralID PMC3167687

• Pathogenesis of dermatomyositis: role of cytokines and interferon. Current rheumatology reports Kao, L., Chung, L., Fiorentino, D. F. 2011; 13 (3): 225-232

  Abstract

  Dermatomyositis is a systemic autoimmune disease that primarily affects skeletal muscle, skin, and the lungs. Dermatomyositis is characterized by autoantibodies, tissue inflammation, parenchymal cell damage and death, and vasculopathy. This review focuses on recent advances regarding the role of cytokines and interferon in the pathogenesis of the disease. Evidence for the role of a particular cytokine is based on data showing dysregulated levels in tissue and/or blood; correlation with histopathologic or clinical markers of disease activity; and, rarely, clinical efficacy of targeted cytokine inhibitors. Many of the recent advances pertain to elucidation of the role of interferons in both muscle and skin disease in dermatomyositis. Although a great deal of progress has been made regarding the role of interferon in the disease, many critical questions remain unanswered.

  View details for DOI 10.1007/s11926-011-0166-x

  View details for PubMedID 21318338

• Prevalence of Children with Severe Fetal Alcohol Spectrum Disorders in Communities Near Rome, Italy: New Estimated Rates Are Higher than Previous Estimates 7th International Symposium on Recent Advances in Environmental Health Research May, P. A., Fiorentino, D., Coriale, G., Kalberg, W. O., Hoyme, H. E., Aragon, A. S., Buckley, D., Stellavato, C., Gossage, J. P., Robinson, L. K., Jones, K. L., Manning, M., Ceccanti, M. MDPI AG. 2011: 2331–51

  Abstract

  To determine the population-based epidemiology of fetal alcohol syndrome (FAS) and other fetal alcohol spectrum disorders (FASD) in towns representative of the general population of central Italy.Slightly revised U.S. Institute of Medicine diagnostic methods were used among children in randomly-selected schools near Rome. Consented first grade children (n=976) were screened in Tier I for height, weight, or head circumference and all children≤10th centile on one of these measurements were included in the study. Also, teachers referred children for learning or behavioral problems. Children meeting either of these two criteria, along with randomly-selected controls, advanced to Tier II which began with a dysmorphology examination. Children with a possible FASD, and controls, advanced to Tier III for neurobehavioral testing, and their mothers were interviewed for maternal risks. Final diagnoses using indicators of dysmorphology, neurobehavior, and maternal risk were made in formally-structured, interdisciplinary case conferences.Case control comparisons of physical, neurobehavioral, and maternal risk variables are presented for 46 children with an FASD and 116 randomly-selected controls without a diagnosis on the FASD continuum. Rates of diagnoses within the FASD continuum are then estimated from these in-school data via three different methods. The range of rates of FAS produced by these methods is between 4.0 to 12.0 per 1,000; Partial FAS ranges from 18.1 to 46.3 per 1,000; and an FASD was found in 2.3% to 6.3% of the children.These rates are substantially higher than previous estimates of FAS and overall FASD for the general populations of Western Europe and the U. S., and raise questions as to the total impact of FASD on mental deficit in mainstream populations of Western Europe and the United States where the majority are middle class and are not believed to be characterized by heavy episodic drinking.

  View details for DOI 10.3390/ijerph8062331

  View details for Web of Science ID 000292022500034

  View details for PubMedID 21776233

  View details for PubMedCentralID PMC3138028

• Pathogenesis of Dermatomyositis: Role of Cytokines and Interferon CURRENT RHEUMATOLOGY REPORTS Kao, L., Chung, L., Fiorentino, D. F. 2011; 13 (3): 225-232

  Abstract

  Dermatomyositis is a systemic autoimmune disease that primarily affects skeletal muscle, skin, and the lungs. Dermatomyositis is characterized by autoantibodies, tissue inflammation, parenchymal cell damage and death, and vasculopathy. This review focuses on recent advances regarding the role of cytokines and interferon in the pathogenesis of the disease. Evidence for the role of a particular cytokine is based on data showing dysregulated levels in tissue and/or blood; correlation with histopathologic or clinical markers of disease activity; and, rarely, clinical efficacy of targeted cytokine inhibitors. Many of the recent advances pertain to elucidation of the role of interferons in both muscle and skin disease in dermatomyositis. Although a great deal of progress has been made regarding the role of interferon in the disease, many critical questions remain unanswered.

  View details for DOI 10.1007/s11926-011-0166-x

  View details for Web of Science ID 000208771200007

• The direct cellular target of topically applied pimecrolimus may not be infiltrating lymphocytes BRITISH JOURNAL OF DERMATOLOGY Fiorentino, D. F., Chen, R. O., STEWART, D. B., Brown, K. K., Sundram, U. N. 2011; 164 (5): 996-1003

  Abstract

  Topically applied calcineurin inhibitors have been shown to be effective in the treatment of atopic dermatitis. When systemically administered, these agents cause immunosuppression via inhibition of calcineurin in lymphocytes. As topical agents, the mechanism of action is poorly defined.To test the hypothesis that skin-infiltrating lymphocytes are directly targeted when calcineurin inhibitors are applied to the skin.Ten patients with atopic dermatitis were treated with 1% pimecrolimus cream twice daily to target lesions. Skin biopsies were performed before and 48 h after beginning therapy. We assessed the cellular localization of NFAT1 and NFAT2 as a surrogate measure of intracellular calcineurin activity (e.g. increasing cytoplasmic localization with increasing calcineurin inhibition).All patients showed a clinical response, at both 48 h and 2 weeks. As previously described, NFAT2 localized to the follicular keratinocytes, and its activation was partially inhibited by topical pimecrolimus. NFAT1 was found to be expressed by follicular and interfollicular keratinocytes, and its mostly nuclear localization was not affected by topical pimecrolimus therapy. Both NFAT1 and NFAT2 were found in the infiltrating lymphocytes. However, using both manual counting as well as an automated method to assess nuclear intensity of NFAT staining, we found that the proportion of infiltrating leucocytes with nuclear ('activated') NFAT did not change following therapy with pimecrolimus.Our results suggest that topical pimecrolimus does not act primarily by inhibiting the calcineurin/NFAT axis in lymphocytes but may instead act by other mechanisms, possibly by decreasing NFAT2 activity in follicular keratinocytes.

  View details for DOI 10.1111/j.1365-2133.2010.10190.x

  View details for Web of Science ID 000289898200012

  View details for PubMedID 21166661

• Dermatomyositis Autoantibodies Clinical Markers of Patients Past, Present, and Future ARCHIVES OF DERMATOLOGY Fiorentino, D., Werth, V. P. 2011; 147 (4): 492–94

  View details for DOI 10.1001/archdermatol.2011.41

  View details for Web of Science ID 000289677800020

  View details for PubMedID 21482900

• International consensus for a definition of disease flare in lupus LUPUS Ruperto, N., HANRAHAN, L. M., Alarcon, G. S., Belmont, H. M., Brey, R. L., Brunetta, P., Buyon, J. P., Costner, M. I., Cronin, M. E., Dooley, M. A., Filocamo, G., Fiorentino, D., Fortin, P. R., Franks, A. G., Gilkeson, G., Ginzler, E., Gordon, C., Grossman, J., Hahn, B., Isenberg, D. A., Kalunian, K. C., Petri, M., Sammaritano, L., Sanchez-Guerrero, J., Sontheimer, R. D., Strand, V., Urowitz, M., Von Feldt, J. M., Werth, V. P., Merrill, J. T. 2011; 20 (5): 453-462

  Abstract

  The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

  View details for DOI 10.1177/0961203310388445

  View details for Web of Science ID 000290213800003

  View details for PubMedID 21148601

• PSOLAR: Update of a multicenter registry of patients with psoriasis who are candidates for systemic therapy including biologics Strober, B. E., Kimball, A., Fiorentino, D., Chevrier, M. MOSBY-ELSEVIER. 2011: AB150

  View details for Web of Science ID 000286780500590

• Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis. International journal of rheumatology Arefiev, K., Fiorentino, D. F., Chung, L. 2011; 2011: 201787-?

  Abstract

  Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin, internal organs, and widespread vasculopathy. Raynaud's phenomenon and digital ulcers are vascular manifestations of this disease and cause significant morbidity. Current treatments are only moderately effective in reducing the severity of Raynaud's in a portion of patients and typically do not lead to substantial benefit in terms of the healing or prevention of digital ulcers. Several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 for the treatment of systemic sclerosis-associated vascular disease. The purpose of this paper is to summarize the published studies and case reports evaluating the efficacy of endothelin receptor antagonists in the treatment of Raynaud's phenomenon and digital ulcers associated with systemic sclerosis.

  View details for DOI 10.1155/2011/201787

  View details for PubMedID 22121371

  View details for PubMedCentralID PMC3205679

• A Pilot Study of Etanercept Treatment for Pemphigus Vulgaris ARCHIVES OF DERMATOLOGY Fiorentino, D. F., Garcia, M. S., Rehmus, W., Kimball, A. B. 2011; 147 (1): 117-118

  View details for Web of Science ID 000286229000031

  View details for PubMedID 21242406

• Evaluation of an imatinib response gene signature in patients with systemic sclerosis Chung, L., Ruiz, P., Wood, T., Shoor, S., Robinson, W., Whitfield, M., Chang, H., Fiorentino, D. CLINICAL & EXPER RHEUMATOLOGY. 2010: S62–S62

  View details for Web of Science ID 000284028600028

• Evaluating quality of life in dermatomyositis Goreshi, R., Chock, M., Fiorentino, D., Feng, R., Foering, K., Okawa, J., Rose, M., Werth, V. P. NATURE PUBLISHING GROUP. 2010: S54

  View details for Web of Science ID 000276455100319

• Modification of the Cutaneous Dermatomyositis Disease Area and Severity Index, an outcome instrument BRITISH JOURNAL OF DERMATOLOGY Yassaee, M., Fiorentino, D., Okawa, J., Taylor, L., Coley, C., Troxel, A. B., Werth, V. P. 2010; 162 (3): 669-673

  Abstract

  Validated outcome measures in dermatology help standardize and improve patient care. A scoring system of skin disease severity in dermatomyositis known as the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) has been developed.To simplify and improve the tool for clinical research and care, we modified the CDASI and validated the new version, v2.The original CDASI has four activity and two damage measures. The modified CDASI has three activity and two damage measures. The skin disease of 20 patients with dermatomyositis was evaluated by the same dermatologist using both the original and the modified CDASI. Global validation measures were implemented to assess overall skin disease state, skin disease activity and skin damage. Spearman's rho (r(sp)), adjusted for multiple observations on subjects, was used to determine the relationship between the two versions of the CDASI and their correlation with the physician global measures (PGMs).The total score and activity and damage subscores of the original and the modified CDASI correlated perfectly with each other (r(sp) = 0.99, 1.00, 1.00). The PGM-overall skin scale correlated with the total scores (r(sp) = 0.72, r(sp) = 0.76) and activity subscores (r(sp) = 0.68, r(sp) = 0.63) but not with the damage subscores (r(sp) = 0.14, r(sp) = 0.15) of the original and the modified CDASI, respectively. However, the PGM-activity and PGM-damage scales correlated with the activity (r(sp) = 0.76, r(sp) = 0.75) and damage subscores (r(sp) = 0.90, r(sp) = 0.90), respectively, of the original and the modified CDASI.The modified CDASI is perfectly correlated with the original CDASI. It has equally good concurrent validity with the PGM-overall skin and PGM-activity scales. The CDASI subscores have equally good concurrent validity with the PGM-activity and PGM-damage scales. We suggest that PGMs of skin disease activity and damage should be assessed separately for greater specificity. The modified CDASI is a refined and equally as useful outcome measure.

  View details for DOI 10.1111/j.1365-2133.2009.09521.x

  View details for Web of Science ID 000274550600031

  View details for PubMedID 19863510

  View details for PubMedCentralID PMC2852630

• Conditioned Pharmacotherapeutic Effects: A Preliminary Study PSYCHOSOMATIC MEDICINE Ader, R., Mercurio, M. G., Walton, J., James, D., Davis, M., Ojha, V., Kimball, A. B., Fiorentino, D. 2010; 72 (2): 192-197

  Abstract

  To test the hypothesize that psoriasis patients treated under a partial schedule of pharmacologic (corticosteroid) reinforcement would show less severe symptoms and relapse than those given the same amount of drug under standard conditions. Behavioral conditioning as an inherent component of many pharmacotherapeutic protocols has never been examined.A double-blind, simple randomization intervention was conducted with 46 patients from California and New York. Initially, lesions were treated with 0.1% acetonide triamcinolone under standard treatment conditions. Thereafter, a Standard Therapy group continued on continuous reinforcement (active drug every treatment) with 100% of the initial dose; Partial Reinforcement patients received a full dose 25% to 50% of the time and placebo medication other times; Dose Control patients received continuous reinforcement with 25% to 50% of the initial dose.Severity of disease scores in California neither supported nor refuted the hypothesis. In New York, where there was no difference between Partial Reinforcement and Dose Control groups at baseline, partial reinforcement effected a greater reduction in lesion severity than Dose Control conditions and did not differ from Standard Therapy patients receiving two to four times more drug. For the entire population, the frequency of relapse under partial reinforcement (26.7%) was lower than in Dose Control patients (61.5%) and did not differ from full-dose treatment (22.2%).A partial schedule of pharmacotherapeutic reinforcement could maintain psoriasis patients with a cumulative amount of corticosteroid that was relatively ineffective when administered under standard treatment conditions. Conceivably, corticosteroid administration only one quarter or half as frequently as currently prescribed is sufficient to treat psoriasis. We posit, however, that these preliminary observations implicate conditioning processes in-and for the design of-regimens of pharmacotherapy.

  View details for Web of Science ID 000274797700013

  View details for PubMedID 20028830

  View details for PubMedCentralID PMC2850283

• Treatment recommendations for psoriatic arthritis ANNALS OF THE RHEUMATIC DISEASES Ritchlin, C. T., Kavanaugh, A., Gladman, D. D., Mease, P. J., Helliwell, P., Boehncke, W., de Vlam, K., Fiorentino, D., Fitzgerald, O., Gottlieb, A. B., McHugh, N. J., Nash, P., Qureshi, A. A., Soriano, E. R., Taylor, W. J. 2009; 68 (9): 1387-1394

  Abstract

  To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion.Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire.Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective.Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

  View details for DOI 10.1136/ard.2008.094946

  View details for Web of Science ID 000268888600003

  View details for PubMedID 18952643

  View details for PubMedCentralID PMC2719080

• Modification of the cutaneous dermatomyositis disease area and severity index, an outcome instrument Yassaee, M., Fiorentino, D., Taylor, L., Coley, C., Troxel, A. B., Werth, V. NATURE PUBLISHING GROUP. 2009: S43

  View details for Web of Science ID 000264994000253

• MQX-503, a Novel Formulation of Nitroglycerin, Improves the Severity of Raynaud's Phenomenon A Randomized, Controlled Trial ARTHRITIS AND RHEUMATISM Chung, L., Shapiro, L., Fiorentino, D., Baron, M., Shanahan, J., Sule, S., Hsu, V., Rothfield, N., Steen, V., Martin, R. W., Smith, E., Mayes, M., Simms, R., Pope, J., Kahaleh, B., Csuka, M. E., Gruber, B., Collier, D., Sweiss, N., Gilbert, A., Dechow, F. J., Gregory, J., Wigley, F. M. 2009; 60 (3): 870-877

  Abstract

  Raynaud's phenomenon (RP) affects 3-9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting.We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0-10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline.The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo.MQX-503 is well tolerated and more effective than placebo for the treatment of RP.

  View details for DOI 10.1002/art.24351

  View details for Web of Science ID 000264211900029

  View details for PubMedID 19248104

• Use of imatinib to treat systemic sclerosis: A prospective case series Arefiev, K., Fiorentino, D., Chung, L., Robinson, W. MOSBY-ELSEVIER. 2009: AB3

  View details for Web of Science ID 000263934100010

• Molecular Framework for Response to Imatinib Mesylate in Systemic Sclerosis ARTHRITIS AND RHEUMATISM Chung, L., Fiorentino, D. F., Benbarak, M. J., Adler, A. S., Mariano, M. M., Paniagua, R. T., Milano, A., Connolly, M. K., Ratiner, B. D., Wiskocil, R. L., Whitfield, M. L., Chang, H. Y., Robinson, W. H. 2009; 60 (2): 584-591

  Abstract

  Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRbeta and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10(-8)). The response of these patients and the findings of the analyses suggest that PDGFRbeta and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.

  View details for DOI 10.1002/art.24221

  View details for PubMedID 19180499

• Similar topology of injury to keratinocytes and myofibres in dermatomyositis skin and muscle BRITISH JOURNAL OF DERMATOLOGY Greenberg, S. A., Fiorentino, D. 2009; 160 (2): 464–65

  View details for DOI 10.1111/j.1365-2133.2008.08967.x

  View details for Web of Science ID 000262509000042

  View details for PubMedID 19077075

• Cutaneous Lupus Erythematosus CLINICAL AND BASIC IMMUNODERMATOLOGY Fiorentino, D. F., Sontheimer, R. D., Gaspari, A. A., Tyring, S. K. 2009: 703–19

  View details for Web of Science ID 000271919100040

• Imatinib in the Treatment of Nephrogenic Systemic Fibrosis AMERICAN JOURNAL OF KIDNEY DISEASES Chandran, S., Petersen, J., Jacobs, C., Forentino, D., Doeden, K., Lafayette, R. A. 2009; 53 (1): 129-132

  Abstract

  Nephrogenic systemic fibrosis is a disabling progressive condition that is being reported with increased frequency in patients with kidney disease. Treatment is extremely limited and largely supportive. We report a case of severe nephrogenic systemic fibrosis in a dialysis patient exposed to multiple doses of gadolinium who improved clinically and histologically with treatment with imatinib.

  View details for DOI 10.1053/j.ajkd.2008.08.029

  View details for Web of Science ID 000262172200018

  View details for PubMedID 19012999

• Type I Interferon in the Induction or Exacerbation of Dermatomyositis What This Observation Tells Us About the Naturally Occurring Disease ARCHIVES OF DERMATOLOGY Fiorentino, D. F. 2008; 144 (10): 1379-1382

  View details for Web of Science ID 000260199400015

  View details for PubMedID 18936404

• Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis BRITISH JOURNAL OF DERMATOLOGY Klein, R. Q., Bangert, C. A., Costner, M., Connolly, M. K., Tanikawa, A., Okawa, J., Rose, M., Fakharzadeh, S. S., Fiorentino, D., Lee, L. A., Sontheimer, R. D., Taylor, L., Troxel, A. B., Werth, V. P. 2008; 159 (4): 887-894

  Abstract

  Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments.We sought to demonstrate reliability and validity of the CDASI, and to compare the CDASI with other potential tools for use in measuring disease severity in cutaneous dermatomyositis.CDASI has four activity and two damage measures, with scores from 0 to 148. DSSI assesses activity based on body surface area and severity on a scale of 0-72. CAT uses 21 activity and damage items, for a range of 0-175 for activity and 0-33 for damage. Ten dermatologists used the instruments to score the same 12-16 patients in one session. Global validation measures were administered to physicians and patients.Global validation measures correlated with the three outcome instruments (P < 0.0001). CAT displayed lower inter- and intrarater reliability relative to the CDASI. All scales correlate better with physician than patient global skin measures.It appears that the CDASI may be a useful outcome measure for studies of cutaneous DM. Further testing to compare responsiveness of all three measures is necessary.

  View details for DOI 10.1111/j.1365-2133.2008.08711.x

  View details for Web of Science ID 000259307700015

  View details for PubMedID 18616782

  View details for PubMedCentralID PMC2829655

• Molecular framework for response to imatinib mesylate in systemic sclerosis 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Fiorentino, D. F., Benbarak, M. J., Adler, A. S., Mariano, M. M., Paniagua, R. T., Milano, A., Connolly, M. K., Ratiner, B. D., Wiskocil, R. L., Whitfield, M. L., Chang, H. Y., Robinson, W. H. WILEY-BLACKWELL. 2008: S819–S820

  View details for Web of Science ID 000259244202263

• Safety and tolerability of MQX-503, a novel investigational topical formulation of nitroglycerin for the treatment of Raynaud's phenomenon Rothfield, N., Shapiro, L., Fiorentino, D., Chung, L., Denton, C., Herrick, A., Baron, M., Shanahan, J., Hsu, V., Belch, J., Steen, V., Scheja, A., Martin, R., Smith, E., Mayes, M., Simms, R., Pope, J., Kahaleh, B., Csuka, M., Gruber, B., Collier, D., Sweiss, N., Sule, S., Emery, P., Wigey, F. M. WILEY-LISS. 2008: S821

  View details for Web of Science ID 000259244202266

• MQX-503, a novel topical nitroglycerin formulation, improves severity of symptoms associated with Raynaud's phenomenon Belch, J., Fiorentino, D., Denton, C., Herrick, A., Sule, S., Steen, V., Rothfield, N., Scheja, A., Shapiro, L., Shanahan, J., Emery, P., Chung, L., Gregory, J. K. WILEY-LISS. 2008: S622

  View details for Web of Science ID 000259244201475

• Comparison of responders and non-responders to MQX-503, a novel investigational topical nitroglycerin formulation, in treatment of scieroderma-related and non-scleroderma-related Raynaud'S phenomenon Herrick, A., Denton, C., Fiorentino, D., Sule, S., Rothfield, N., Belch, J., Shapiro, L., Scheja, A., Shanahan, J., Steen, V., Chung, L., Emery, P., Wigley, F., Gregory, J. WILEY-LISS. 2008: S822

  View details for Web of Science ID 000259244202270

• Clinical characteristics and treatment response of patients with dermatomyositis seen at a tertiary dermatology department: The Stanford experience Sanderson, E. A., Chung, L. S., Fiorentino, D. F. NATURE PUBLISHING GROUP. 2008: 1606

  View details for Web of Science ID 000255953600048

• Palisaded neutrophilic and granulomatous dermatitis associated with limited systemic sclerosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Hantash, B. M., Chiang, D., Kohler, S., Fiorentino, D. 2008; 58 (4): 661-664

  Abstract

  Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a condition that is characterized histopathologically by a characteristic pattern of granulomatous inflammation in the presence or absence of leukocytoclastic vasculitis. It has been associated with systemic diseases, especially autoimmune conditions such as rheumatoid arthritis and Behçet's disease. A 44-year-old woman with underlying limited systemic sclerosis presented with painful erythematous nodules located on her face and scalp. Histopathologic analysis confirmed a diagnosis of PNGD, which self-resolved within weeks of the biopsy. To our knowledge, this is the first report of a case of PNGD associated with systemic sclerosis. A review of the literature revealed that PNGD is a female-predominant disease that is most commonly associated with rheumatoid arthritis, followed closely by lupus erythematosus. Most patients with PNGD respond to treatment of the underlying systemic disease, although spontaneous resolution is not uncommonly observed.

  View details for DOI 10.1016/j.jaad.2007.09.019

  View details for Web of Science ID 000254315000018

  View details for PubMedID 17945384

• Capillary Regeneration in Scleroderma: Stem Cell Therapy Reverses Phenotype? PLOS ONE Fleming, J. N., Nash, R. A., McLeod, D. O., Fiorentino, D. F., Shulman, H. M., Connolly, M. K., Molitor, J. A., Henstorf, G., Lafyatis, R., Pritchard, D. K., Adams, L. D., Furst, D. E., Schwartz, S. M. 2008; 3 (1)

  Abstract

  Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease.We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon alpha (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.

  View details for DOI 10.1371/journal.pone.0001452

  View details for Web of Science ID 000260503800022

  View details for PubMedID 18197262

  View details for PubMedCentralID PMC2175530

• Dermatomyositis. Current directions in autoimmunity Krathen, M. S., Fiorentino, D., Werth, V. P. 2008; 10: 313-332

  Abstract

  Dermatomyositis (DM) is a chronic inflammatory disorder of the skin and muscles. Although thought to be autoimmune in origin, many questions remain as to the etiopathogenesis of this disease. DM has classically been considered a humorally mediated disease. Current evidence, however, seems to increasingly support alternative (though not mutually exclusive) mechanisms of pathogenesis, including cell-mediated and innate immune system dysfunction. Pathologic findings of DM in muscle include infarcts, perifascicular atrophy, endothelial cell swelling and necrosis, vessel wall membrane attack complex deposition, and myocyte-specific MHC I upregulation. As for the skin, histopathologic findings include hyperkeratosis, epidermal basal cell vacuolar degeneration and apoptosis, increased dermal mucin deposition, and a cell-poor interface dermatitis. Autoantibodies, particularly those that bind nuclear or cytoplasmic ribonucleoprotein antigens, are also commonly found in DM, although their importance in pathogenesis remains unclear. Defective cellular clearance, genetic predilection and environmental exposures, such as viral infection, may also play an important role in the pathogenesis of DM. The seminal work regarding the pathogenesis of DM is reviewed and an update on the recent basic and molecular advances in the field is provided.

  View details for DOI 10.1159/000131751

  View details for PubMedID 18460893

• A multi-center crossover study of MQX-503, a topical formulation of nitroglycerin, in patients with Raynaud's phenomenon Denton, C. P., Fiorentino, D., Herrick, A., Sule, S., Rothfield, N., Belch, J., Shapiro, L., Scheja, A., Shanahan, J., Steen, V., Emery, P., Chung, L., Gregory, J., Batson, E., Dooley, T., Gilbert, A., Dechow, F., Wigley, F. M. WILEY-LISS. 2007: 4238

  View details for Web of Science ID 000251781200057

• Localized scleroderma and systemic sclerosis: Is there a connection? BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY Gupta, R. A., Fiorentino, D. 2007; 21 (6): 1025-1036

  Abstract

  Excess fibrosis of the skin is a clinical hallmark of both localized scleroderma and systemic sclerosis. Localized scleroderma is generally thought to be a skin-limited disease whereas systemic sclerosis can have a wide range of internal organ involvement. Recent data suggest that a subset of patients with juvenile localized scleroderma can go on to develop systemic involvement of their disease. This raises the question of what the connection is, if any, between localized scleroderma and systemic sclerosis.

  View details for DOI 10.1016/j.berh.2007.09.003

  View details for Web of Science ID 000252093900005

  View details for PubMedID 18068859

• Nephrogenic systemic fibrosis - Relationship to gadolinium and response to photopheresis ARCHIVES OF DERMATOLOGY Richmond, H., Zwerner, J., Kim, Y., Fiorentino, D. 2007; 143 (8): 1025-1030

  Abstract

  Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an idiopathic condition seen in patients with renal disease that is characterized by cutaneous sclerosis that can often result in contractures, pain, and functional disability as well as systemic complications. Recent reports have suggested a possible link with exposure to gadolinium, a commonly used radiocontrast agent. No current therapy has clearly demonstrated efficacy for NSF, although case reports suggest that extracorporeal photopheresis (ECP) may be of benefit. The purpose of this study was to explore the plausibility of a gadolinium linkage with NSF as well as to assess the efficacy of ECP in the treatment of a cohort of patients with NSF.We report our experience with 8 consecutive patients with NSF seen at the Stanford Medical Center, Palo Alta, California, from 2004 to 2006. Of the 8 patients, 6 had a history of arterial or venous thrombotic disease and 7 had a documented exposure to gadolinium within 1 week to several months prior to the onset of NSF. Specifically, all patients were exposed to gadodiamide. We treated 5 of the patients with ECP. After a mean number of 34 treatment sessions over a mean of 8.5 months, 3 patients experienced a mild improvement in skin tightening, range of motion, and/or functional capacity.Our data support the hypothesis that exposure to gadolinium, perhaps specifically gadodiamide, plays a role in the pathogenesis of NSF. Larger epidemiologic studies will be needed to confirm this association. In addition, our experience suggests that, if used for extended periods, ECP might have some mild benefit for patients with NSF. Larger, randomized, placebo-controlled trials of ECP should be performed to more specifically assess the benefit of ECP in the treatment of NSF.

  View details for Web of Science ID 000248723900008

  View details for PubMedID 17709661

• Mycophenolate mofetil DERMATOLOGIC THERAPY Zwerner, J., Fiorentino, D. 2007; 20 (4): 229-238

  Abstract

  Mycophenolate mofetil (MMF) is a relatively new systemic immunosuppressive agent whose use is rapidly increasing within the field of dermatologic. Originally used in the 1970s for the treatment of psoriasis, MMF has demonstrated efficacy in multiple types of inflammatory skin diseases. Although the safety data within the dermatologic literature is sparse, MMF's extensive use within the field of organ transplantation has demonstrated a favorable safety profile. MMF's lack of hepatic or renal toxicity is a significant advantage over immunosuppressive medications currently used in dermatology and make MMF an attractive candidate for multidrug regimens. In this review the present authors discuss the pharmacology, mechanisms of action, side effects and current uses of MMF reported within the dermatologic literature. The present authors also provide practical information regarding the use of the MMF culled from the literature as well as from the present authors' own clinical experience with the medication.

  View details for Web of Science ID 000250497200007

  View details for PubMedID 17970888

• A pilot trial of rituximab in the treatment of patients with dermatomyositis ARCHIVES OF DERMATOLOGY Chung, L., Genovese, M. C., Fiorentino, D. F. 2007; 143 (6): 763-767

  Abstract

  Dermatomyositis is an autoimmune disease that is associated with muscle and skin inflammation. Using quantitative scales, we sought to evaluate the effects of rituximab therapy on muscle strength and skin disease in patients with dermatomyositis.An open-label trial of rituximab therapy was conducted in 8 adult patients with dermatomyositis. Patients received 2 infusions of rituximab (1 g each) 2 weeks apart without peri-infusional steroids. The primary outcome was partial remission at week 24 (prespecified reduction in elevated creatine phosphokinase levels, muscle strength deficit (Manual Muscle Test), or skin disease (Dermatomyositis Skin Severity Index). After the first infusion of rituximab, all patients achieved sustained depletion of peripheral B cells. One patient withdrew at week 16 owing to a lack of treatment efficacy. Three patients (38%) achieved partial remission at week 24, in each case by improvement in muscle strength. Muscle enzyme levels and skin scores at week 24 were not significantly changed from those at baseline. Rituximab infusions were well tolerated, with no serious infectious complications. One patient died of metastatic cancer 9 months after his last infusion.Depletion of peripheral B cells had modest effects on muscle disease and limited effects on skin disease in our cohort of patients with dermatomyositis.

  View details for Web of Science ID 000247207400012

  View details for PubMedID 17576943

• Comparison of the reliability & validity of outcome instruments for cutaneous dermatomyositis 68th Annual Meeting of the Society-for-Investigative-Dermatology Quain, R. D., Bangert, C. C., Costner, M., Connolly, M. K., Dugan, E., Tanikawa, A., Okawa, J., Rose, M., Fakharzadeh, S. S., Fiorentino, D., Lee, L. A., Sontheimer, R. D., Taylor, L., Werth, V. P. NATURE PUBLISHING GROUP. 2007: S59–S59

  View details for Web of Science ID 000245387800346

• The yin and yang of TNF-alpha inhibition ARCHIVES OF DERMATOLOGY Fiorentino, D. F. 2007; 143 (2): 233–36

  View details for DOI 10.1001/archderm.143.2.233

  View details for Web of Science ID 000244211500010

  View details for PubMedID 17310003

• Update on cutaneous vasculitis SEMINARS IN CUTANEOUS MEDICINE AND SURGERY Grzeszkiewicz, T. M., Fiorentino, D. F. 2006; 25 (4): 221-225

  Abstract

  Vasculitis presents with a range of clinical manifestations, many of which affect the skin. Diagnosing and classifying vasculitis can prove challenging. Particularly given the lack of unified criteria that are both useful as a research tool and clinically relevant. Also, vasculitis may be secondary to a wide range of conditions, making the prompt recognition and treatment of associated disorders essential for appropriate patient management. This article will highlight the classification, pathogenesis, clinical presentation, diagnosis, evaluation, and treatment of the cutaneous vasculitides.

  View details for DOI 10.1016/j.sder.2006.08.005

  View details for Web of Science ID 000243158300007

  View details for PubMedID 17174842

• Successful use of rituximab for cutaneous vasculitis ARCHIVES OF DERMATOLOGY Chung, L., Funke, A. A., Chakravarty, E. F., Callen, J. P., Fiorentino, D. F. 2006; 142 (11): 1407-1410

  View details for Web of Science ID 000242157600002

  View details for PubMedID 17116830

• Systemic and locatized scleroderma CLINICS IN DERMATOLOGY Chung, L., Lin, J., Furst, D. E., Fiorentino, D. 2006; 24 (5): 374-392

  Abstract

  Sclerosing conditions of the skin are manifested by a full spectrum of presentations that includes skin-limited forms as well as those which can involve internal organs and result in death. At this point, we are just beginning to understand the mechanisms of tissue fibrosis, and it is likely that the fibrotic processes are a heterogeneous group of disorders in which perturbation of multiple molecular pathways, including vascular and immunologically mediated pathways, can lead to fibrosis. We now have some moderately effective therapies for vascular aspects of systemic sclerosis (eg, bosentan for pulmonary arterial hypertension, calcium-channel blockers for Raynaud's, or angiotensin-converting enzyme inhibitors for renal crisis). We also are beginning to find treatments interrupting the immunologic pathways that manifest as systemic sclerosis (eg, methotrexate for the skin or cyclophosphamide for the lungs). The basic process of fibrosis, however, awaits proven, effective therapy.

  View details for DOI 10.1016/j.clindermatol.2006.07.004

  View details for Web of Science ID 000240864500004

  View details for PubMedID 16966019

• Epidemiology of FASD in a province in Italy: Prevalence and characteristics of children in a random sample of schools ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH May, P. A., Fiorentino, D., Gossage, J. P., Kalberg, W. O., Hoyme, H. E., Robinson, L. K., Coriale, G., Jones, K. L., del Campo, M., Tarani, L., Romeo, M., Kodituwakku, P. W., Deiana, L., Buckley, D., Ceccanti, M. 2006; 30 (9): 1562-1575

  Abstract

  Accurate estimates of the prevalence and characteristics of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD) in a Western European population are lacking and are of particular interest in settings where the usual pattern of alcohol consumption is thought to be daily drinking with meals. To address these issues, an epidemiology study of FAS and other FASD was undertaken in Italian schools.Primary schools (n = 25) in 2 health districts of the Lazio region were randomly selected and recruited for the study. Five hundred forty-three children, 50% of those enrolled in first-grade classes, received parental permission to participate in a 2-tiered, active case ascertainment screening process. Detailed evaluation of children selected in a preliminary screening phase was carried out on those who were small for height, weight, and head circumference and/or referred by teachers for suspected learning and behavioral problems. Detailed evaluation was carried out on each child's: (1) physical growth and dysmorphology, (2) psychological development and behavior, and (3) prenatal exposure to alcohol and other risk factors for FASD via maternal interviews. A group of 67 randomly selected children without FASD from the same classes was utilized as a comparison group.Using 2 denominators for prevalence estimation, a conservative one and a strict sample-based estimate, the prevalence of FAS in this province of Italy was 3.7 to 7.4 per 1,000 children. When cases of partial FAS (PFAS) and a case of alcohol-related neurodevelopmental deficits (ARND) were added to FAS cases, the rate of FASD was 20.3 to 40.5 per 1,000 and estimated at 35 per 1,000 overall or between 2.3 and 4.1% of all children. This exceeds previously published estimates of both FAS and FASD for the western world. Detailed data are presented that demonstrate the utility of the guidelines of the revised Institute of Medicine diagnostic criteria for FASD. Children with FASD are significantly more impaired/affected (p < 0.05) than randomly selected comparison children on all measures of growth deficiency, key facial features of FASD, overall dysmorphology scores, language comprehension, nonverbal IQ, and behavior. Maternal reports of current drinking were significantly higher for mothers of FASD children than comparison mothers, but reported rates of overall drinking during pregnancy were not significantly different. In contrast to expectations, daily drinking among mothers of the comparison group was not common. However, dysmorphology scores of the children were significantly correlated with drinking in the second and third trimesters, drinks per current drinking day, and current drinks per month. Finally, children with the physical features of FASD had lower IQs; nonverbal IQ was significantly correlated with head circumference and negatively correlated with overall dysmorphology score, smooth philtrum, and several other facial and physical anomalies characteristic of FAS.Using careful measures of ascertainment in a primary school setting, these results provide relatively high estimates of the prevalence of FASD and raise the question of whether FASD is more common in the western world than previously estimated.

  View details for DOI 10.1111/j.1530-0277.2006.00188.x

  View details for Web of Science ID 000239939500013

  View details for PubMedID 16930219

• A pilot trial of treprostinil for the treatment and prevention of digital ulcers in patients with systemic sclerosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chung, L., Fiorentino, D. 2006; 54 (5): 880-882

  Abstract

  We performed a pilot trial of subcutaneous treprostinil for the treatment of digital ulcers in scleroderma. Of the 5 patients completing therapy, ulcer size significantly decreased and no new ulcers occurred on continuous therapy. Although effective, the high rate of injection site reactions may limit the utility of this therapy.

  View details for DOI 10.1016/j.jaad.2006.02.004

  View details for Web of Science ID 000237119600019

  View details for PubMedID 16635673

• Cellular automata model of phase transition in binary mixtures INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH Vannozzi, C., Fiorentino, D., D'Amore, M., Rumshitzki, D. S., Dress, A., Mauri, R. 2006; 45 (8): 2892-2896

  View details for DOI 10.1021/ie051240w

  View details for Web of Science ID 000236754900060

• An open-label trial of rituximab in the treatment of patients with dermatomyositis Chung, L., Fiorentino, D. MOSBY, INC. 2006: AB77

  View details for Web of Science ID 000235721000300

• Digital ulcers in patients with systemic sclerosis CIS Spring School on Systemic Autoimmune Diseases Chung, L., Fiorentino, D. ELSEVIER SCIENCE BV. 2006: 125–28

  Abstract

  Digital ulcers (DU), defined as necrotic lesions located at distal digits or overlying bony prominences, occur in up to 50% of patients with limited or diffuse systemic sclerosis (SSc). These lesions are extremely painful and lead to substantial functional disability. The pathogenesis of DU differs depending on their location. DU located at distal aspects of digits are thought to be related to tissue ischemia from several processes, including vasospasm secondary to Raynaud's phenomenon, intimal fibro-proliferation, and thrombosis of digital arteries. DU located over bony prominences, such as the phalangeal joints and elbows, are thought to be due to repetitive microtrauma and difficulty healing due to atrophic, avascular tissue overlying the joints. Management of DU include non-pharmacologic and pharmacologic modalities. This review summarizes the current available and investigational therapies for the treatment and prevention of DU in patients with SSc.

  View details for DOI 10.1016/j.autrev.2005.08.004

  View details for Web of Science ID 000235349400011

  View details for PubMedID 16431342

• Liver enzyme abnormalities in patients with atopic dermatitis treated with mycophenolate mofetil ARCHIVES OF DERMATOLOGY Hantash, B., Fiorentino, D. 2006; 142 (1): 109-110

  View details for Web of Science ID 000234605500021

  View details for PubMedID 16415398

• Rituximab in the treatment of patients with dermatomyositis: 12 week interim analysis of a pilot trial. Chung, L., Genovese, M. C., Fiorentino, D. WILEY-LISS. 2005: 4088

  View details for Web of Science ID 000234131500136

• An open-label trial of treprostenil for the treatment and prevention of digital ischemic lesions in patients with systemic sclerosis Chung, L., Fiorentino, D. MOSBY, INC. 2005: P65

  View details for Web of Science ID 000227632400256

• A pilot trial of treprostinil (Remodulin (R)) for the treatment and prevention of digital ischemic lesions in patients with systemic sclerosis. Chung, L., Fiorentino, D. WILEY-LISS. 2004: 4086

  View details for Web of Science ID 000225750200068

• Muir-Torre syndrome: Confirmation of diagnosis by immunohistochemical analysis of cutaneous lesions JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D. F., Nguyen, J. C., Egbert, B. M., Swetter, S. M. 2004; 50 (3): 476-478

  View details for DOI 10.1016/j.jaad.2003.07.027

  View details for Web of Science ID 000220080500026

  View details for PubMedID 14988697

• Cutaneous vasculitis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D. F. 2003; 48 (3): 311-340

  Abstract

  Vasculitis can range in severity from a self-limited single-organ disorder to a life-threatening disease with the prospect of multiple-organ failure. This condition presents many challenges to the physician, including classification and diagnosis, appropriate laboratory workup, treatment, and the need for careful follow-up. The physician must not only be able to recognize vasculitis but also be able to provide a specific diagnosis (if possible) as well as recognize and treat any underlying etiologic condition. Most diagnostic criteria are based on the size of vessel involvement, which often correlates with specific dermatologic findings. This may allow the dermatologist to provide an initial diagnosis and direct the medical evaluation. This article reviews the classification and diagnosis of cutaneous vasculitic syndromes and current treatment options; it also presents a comprehensive approach to diagnosing and treating the patient with suspected cutaneous vasculitis. (J Am Acad Dermatol 2003;48:311-40.)At the completion of this learning activity, participants should be familiar with the classification and clinical features of the various forms of cutaneous vasculitis. They should also have a rational approach to diagnosing and treating a patient with vasculitis.

  View details for DOI 10.1067/mjd.2003.212

  View details for Web of Science ID 000181643900001

  View details for PubMedID 12637912

• Characterization of Saccharomyces cerevisiae dna2 mutants suggests a role for the helicase late in S phase MOLECULAR BIOLOGY OF THE CELL Fiorentino, D. F., Crabtree, G. R. 1997; 8 (12): 2519-2537

  Abstract

  The TOR proteins, originally identified as targets of the immunosuppressant rapamycin, contain an ATM-like "lipid kinase" domain and are required for early G1 progression in eukaryotes. Using a screen to identify Saccharomyces cerevisiae mutants requiring overexpression of Tor1p for viability, we have isolated mutations in a gene we call ROT1 (requires overexpression of Tor1p). This gene is identical to DNA2, encoding a helicase required for DNA replication. As with its role in cell cycle progression, both the N-terminal and C-terminal regions, as well as the kinase domain of Tor1p, are required for rescue of dna2 mutants. Dna2 mutants are also rescued by Tor2p and show synthetic lethality with tor1 deletion mutants under specific conditions. Temperature-sensitive (Ts) dna2 mutants arrest irreversibly at G2/M in a RAD9- and MEC1-dependent manner, suggesting that Dna2p has a role in S phase. Frequencies of mitotic recombination and chromosome loss are elevated in dna2 mutants, also supporting a role for the protein in DNA synthesis. Temperature-shift experiments indicate that Dna2p functions during late S phase, although dna2 mutants are not deficient in bulk DNA synthesis. These data suggest that Dna2p is not required for replication fork progression but may be needed for a later event such as Okazaki fragment maturation.

  View details for Web of Science ID A1997YK93000013

  View details for PubMedID 9398673

  View details for PubMedCentralID PMC25725

• The mechanism of action of cyclosporin A and FK506 Symposium on New Frontiers in the Immunoregulation of Allergic and Autoimmune Diseases Ho, S., Clipstone, N., Timmermann, L., Northrop, J., Graef, I., Fiorentino, D., Nourse, J., Crabtree, G. R. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1996: S40–S45

  Abstract

  The immunosuppressants cyclosporin A (CsA), FK506, and rapamycin suppress the immune response by inhibiting evolutionary conserved signal transduction pathways. CsA, FK506, and rapamycin bind to their intracellular receptors, immunophilins, creating composite surfaces that block the activity of specific targets. For CsA/cyclophilin and FK506/FKBP the target is calcineurin. Because of the large surface area of interaction of the drug-immunophilin complex with calcineurin, FK506 and CsA have a specificity for their biologic targets that is equivalent to growth factor-receptor interactions. To date, all the therapeutic as well as toxic effects of these drugs have been shown to be due to inhibition of calcineurin. Inhibition of the action of calcineurin results in a complete block in the translocation of the cytosolic component of the nuclear factor of activated T cells (NF-AT), resulting in a failure to activate the genes regulated by the NF-AT transcription factor. These genes include those required for B-cell help such as interleukin (IL-4) and CD40 ligand as well as those necessary for T-cell proliferation such as IL-2. The purpose of this article is to illustrate the means by which these drugs produce immunosuppression.

  View details for Web of Science ID A1996VG75000006

  View details for PubMedID 8811062

• TOR KINASE DOMAINS ARE REQUIRED FOR 2 DISTINCT FUNCTIONS, ONLY ONE OF WHICH IS INHIBITED BY RAPAMYCIN CELL Zheng, X. F., Fiorentino, D., Chen, J., Crabtree, G. R., Schreiber, S. L. 1995; 82 (1): 121-130

  Abstract

  The rapamycin-sensitive signaling pathway is required to transduce specific mitogenic signals to the cell cycle machinery responsible for G1 progression. Genetic studies in yeast identified two related genes on this pathway, TOR1 and TOR2, thought to encode novel phosphatidylinositol kinases. We now show that an intact kinase domain is required for the G1 cell cycle functions of both proteins, for the ability of a mutation in a neighboring FKBP12-rapamycin-binding domain of the TOR1 protein to inhibit the growth of yeast cells when overexpressed, and for the essential function of the TOR2 protein. The G1 function of both TOR proteins is sensitive to rapamycin, but the essential function of TOR2 is not. Thus, FKBP12-rapamycin does not appear to inhibit the kinase activity of TOR proteins in a general way; instead, it may interfere selectively with TOR protein binding to or phosphorylation of G1 effectors.

  View details for Web of Science ID A1995RK42400015

• IMMUNOPHILINS INTERACT WITH CALCINEURIN IN THE ABSENCE OF EXOGENOUS IMMUNOSUPPRESSIVE LIGANDS EMBO JOURNAL Cardenas, M. E., Hemenway, C., Muir, R. S., Ye, R., Fiorentino, D., Heitman, J. 1994; 13 (24): 5944-5957

  Abstract

  The peptidyl-prolyl isomerases FKBP12 and cyclophilin A (immunophilins) form complexes with the immunosuppressants FK506 and cyclosporin A that inhibit the phosphatase calcineurin. With the yeast two hybrid system, we detect complexes between FKBP12 and the calcineurin A catalytic subunit in both the presence and absence of FK506. Mutations in FKBP12 surface residues or the absence of the calcineurin B regulatory subunit perturb the FK506-dependent, but not the ligand-independent, FKBP12-calcineurin complex. By affinity chromatography, both FKBP12 and cyclophilin A bind calcineurin A in the absence of ligand, and FK506 and cyclosporin A respectively potentiate these interactions. Both in vivo and in vitro, the peptidyl-prolyl isomerase active sites are dispensable for ligand-independent immunophilin-calcineurin complexes. Lastly, by genetic analyses we demonstrate that FKBP12 modulates calcineurin functions in vivo. These findings reveal that immunophilins interact with calcineurin in the absence of exogenous ligands and suggest that immunosuppressants may take advantage of the inherent ability of immunophilins to interact with calcineurin.

  View details for Web of Science ID A1994QA63700018

  View details for PubMedID 7529175

  View details for PubMedCentralID PMC395570

• MOLECULAR ANALYSIS OF THE INTERACTION OF CALCINEURIN WITH DRUG-IMMUNOPHILIN COMPLEXES JOURNAL OF BIOLOGICAL CHEMISTRY Clipstone, N. A., Fiorentino, D. F., Crabtree, G. R. 1994; 269 (42): 26431-26437

  Abstract

  The calcium/calmodulin-regulated phosphatase calcineurin (CN) is the site of action of the immunosuppressive drugs cyclosporin A (CsA) and FK506. CN has recently been established as a key signaling enzyme in the T cell signal transduction cascade and an important regulator of transcription factors such as NF-AT and OAP/Oct-1, which are involved in the expression of a number of important T cell early genes. CsA and FK506 act by forming complexes with their respective intracellular receptors cyclophilin and FKBP (immunophilins), which can then bind to CN, inhibiting its enzymatic activity and thereby preventing early gene expression. CN is comprised of two subunits: a 59-kDa catalytic subunit (CNA), which contains a calmodulin binding domain and autoinhibitory region, and a 19-kDa intrinsic calcium binding regulatory subunit (CNB). In this study, we have utilized a series of deletion mutants of the CNA subunit to investigate the subunit and molecular requirements that govern the interaction of CN with drug-immunophilin complexes. The calmodulin binding and autoinhibitory domains of the CNA subunit were found to be dispensable for the binding of CN to drug-immunophilin complexes. In contrast, we found that the regulatory CNB subunit appears to play an obligatory role in this interaction and have defined an amino acid sequence of the CNA subunit which forms the binding site for CNB. Although necessary, the CNB subunit per se is not sufficient to mediate an interaction with drug-immunophilin complexes; amino acid residues of the CNA subunit, specifically a region located within the putative catalytic domain, are also required for the interaction of CN with both FKBP-FK506 and cyclophilin A-CsA.

  View details for Web of Science ID A1994PQ93000075

  View details for PubMedID 7523407

• RAPAMYCIN SELECTIVELY INHIBITS INTERLEUKIN-2 ACTIVATION OF P70 S6 KINASE NATURE Kuo, C. J., Chung, J. K., Fiorentino, D. F., Flanagan, W. M., Blenis, J., Crabtree, G. R. 1992; 358 (6381): 70-73

  Abstract

  The macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05-0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9-11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.

  View details for Web of Science ID A1992JB34100056

  View details for PubMedID 1614535

• IL-10 INHIBITS CYTOKINE PRODUCTION BY ACTIVATED MACROPHAGES JOURNAL OF IMMUNOLOGY Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M., OGARRA, A. 1991; 147 (11): 3815-3822

  Abstract

  IL-10 inhibits the ability of macrophage but not B cell APC to stimulate cytokine synthesis by Th1 T cell clones. In this study we have examined the direct effects of IL-10 on both macrophage cell lines and normal peritoneal macrophages. LPS (or LPS and IFN-gamma)-induced production of IL-1, IL-6, and TNF-alpha proteins was significantly inhibited by IL-10 in two macrophage cell lines. Furthermore, IL-10 appears to be a more potent inhibitor of monokine synthesis than IL-4 when added at similar concentrations. LPS or LPS- and IFN-gamma-induced expression of IL-1 alpha, IL-6, or TNF-alpha mRNA was also inhibited by IL-10 as shown by semiquantitative polymerase chain reaction or Northern blot analysis. Inhibition of LPS-induced IL-6 secretion by IL-10 was less marked in FACS-purified peritoneal macrophages than in the macrophage cell lines. However, IL-6 production by peritoneal macrophages was enhanced by addition of anti-IL-10 antibodies, implying the presence in these cultures of endogenous IL-10, which results in an intrinsic reduction of monokine synthesis after LPS activation. Consistent with this proposal, LPS-stimulated peritoneal macrophages were shown to directly produce IL-10 detectable by ELISA. Furthermore, IFN-gamma was found to enhance IL-6 production by LPS-stimulated peritoneal macrophages, and this could be explained by its suppression of IL-10 production by this same population of cells. In addition to its effects on monokine synthesis, IL-10 also induces a significant change in morphology in IFN-gamma-stimulated peritoneal macrophages. The potent action of IL-10 on the macrophage, particularly at the level of monokine production, supports an important role for this cytokine not only in the regulation of T cell responses but also in acute inflammatory responses.

  View details for Web of Science ID A1991GQ83700021

  View details for PubMedID 1940369

• PRODUCTION OF IL-10 BY CD4+ LYMPHOCYTES-T CORRELATES WITH DOWN-REGULATION OF TH1 CYTOKINE SYNTHESIS IN HELMINTH INFECTION JOURNAL OF IMMUNOLOGY Sher, A., Fiorentino, D., Caspar, P., Pearce, E., Mosmann, T. 1991; 147 (8): 2713-2716

  Abstract

  After the onset of parasite egg deposition, mice infected with the helminth Schistosoma mansoni mount strong Th2 cytokine responses in the absence of significant Th1 cytokine synthesis. To examine the basis of this immunoregulatory state, spleen or lymph node cells from schistosome-infected mice were stimulated with parasite-specific Ag and the supernatants tested for their capacity to suppress IFN-gamma synthesis by a Th1 cell line. Strong inhibition was observed that was neutralized by a mAb against IL-10, a cytokine previously shown to down-regulate Th1 cytokine synthesis. By means of ELISA measurements the production of IL-10 in schistosome infection was confirmed and shown to depend on CD4+ T cells. IL-10 synthesis stimulated by either mitogen or Ag was observed only at those stages of infection when Th2 response induction and Th1 cytokine down-regulation also occurred and was not detected in mice vaccinated with attenuated parasites. Moreover, the addition of the neutralizing anti-IL-10 mAb to Ag-stimulated spleen cell cultures from infected mice caused a dramatic augmentation in IFN-gamma synthesis. These findings suggest that IL-10 is responsible for the down-regulation of Th1 responses observed in schistosome infections, a phenomenon that may enable the parasite to escape potentially harmful cell-mediated responses.

  View details for Web of Science ID A1991GK97200042

  View details for PubMedID 1680917

• DIVERSITY OF CYTOKINE SYNTHESIS AND FUNCTION OF MOUSE CD4+ T-CELLS IMMUNOLOGICAL REVIEWS Mosmann, T. R., SCHUMACHER, J. H., STREET, N. F., Budd, R., OGARRA, A., Fong, T. A., Bond, M. W., MOORE, K. W., Sher, A., Fiorentino, D. F. 1991; 123: 209-229

  View details for Web of Science ID A1991GP27300010

  View details for PubMedID 1684780

• IL-10 ACTS ON THE ANTIGEN-PRESENTING CELL TO INHIBIT CYTOKINE PRODUCTION BY TH1 CELLS JOURNAL OF IMMUNOLOGY Fiorentino, D. F., Zlotnik, A., Vieira, P., Mosmann, T. R., Howard, M., Moore, K. W., OGARRA, A. 1991; 146 (10): 3444-3451

  Abstract

  Murine IL-10 (cytokine synthesis inhibitory factor) inhibits cytokine production by Th1 cell clones when they are activated under conditions requiring the presence of APC. By preincubating APC with IL-10, we demonstrate that IL-10 acts principally on APC to inhibit IFN-gamma production by Th1 clones. Moreover, IL-10 is not active when Th1 cells are stimulated with glutaraldehyde-fixed APC, which also indicates that its action involves regulation of APC function. Furthermore, IL-10 inhibits cytokine synthesis by Th1 cells stimulated with the super-antigen Staphylococcus enterotoxin B, which does not appear to require processing. Flow microfluorimetry purified splenic or peritoneal B cells and macrophages, and B cell and macrophage cell lines can present Ag to Th1 clones. However, IL-10 acts only on sorted macrophages and the macrophage cell line to suppress IFN-gamma production by Th1 clones. IL-10 does not show this effect when B cells are used as APC. In contrast, IL-10 does not impair the ability of APC to stimulate cytokine production by Th2 cells. IL-10 does not decrease IFN-gamma-induced I-Ad levels on a macrophage cell line. Inasmuch as IL-10 also inhibits IL-2-induced IFN-gamma production by Th1 cells in an Ag-free system requiring only the presence of accessory cells, these data suggest that IL-10 may inhibit macrophage accessory cell function which is independent of TCR-class II MHC interactions.

  View details for Web of Science ID A1991FL83600024

  View details for PubMedID 1827484

• ISOLATION AND EXPRESSION OF HUMAN CYTOKINE SYNTHESIS INHIBITORY FACTOR CDNA CLONES - HOMOLOGY TO EPSTEIN-BARR-VIRUS OPEN READING FRAME BCRFI PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vieira, P., DEWAALMALEFYT, R., Dang, M. N., Johnson, K. E., Kastelein, R., Fiorentino, D. F., deVries, J. E., Roncarolo, M. G., Mosmann, T. R., Moore, K. W. 1991; 88 (4): 1172-1176

  Abstract

  We have demonstrated the existence of human cytokine synthesis inhibitory factor (CSIF) [interleukin 10 (IL-10)]. cDNA clones encoding human IL-10 (hIL-10) were isolated from a tetanus toxin-specific human T-cell clone. Like mouse IL-10, hIL-10 exhibits strong DNA and amino acid sequence homology to an open reading frame in the Epstein-Barr virus, BCRFI. hIL-10 and the BCRFI product inhibit cytokine synthesis by activated human peripheral blood mononuclear cells and by a mouse Th1 clone. Both hIL-10 and mouse IL-10 sustain the viability of a mouse mast cell line in culture, but BCRFI lacks comparable activity in this assay, suggesting that BCRFI may have conserved only a subset of hIL-10 activities.

  View details for Web of Science ID A1991EY61700019

  View details for PubMedID 1847510

• EXPRESSION OF INTERLEUKIN-10 ACTIVITY BY EPSTEIN-BARR-VIRUS PROTEIN BCRF1 SCIENCE Hsu, D. H., Malefyt, R. D., Fiorentino, D. F., Dang, M. N., Vieira, P., Devries, J., Spits, H., Mosmann, T. R., Moore, K. W. 1990; 250 (4982): 830-832

  Abstract

  Cytokine synthesis inhibitory factor (CSIF; interleukin-10), a product of mouse TH2 T cell clones that inhibits synthesis of cytokines by mouse TH1 T cell clones, exhibits extensive sequence similarity to an uncharacterized open reading frame in the Epstein-Barr virus BCRF1. Recombinant BCRF1 protein mimics the activity of interleukin-10, suggesting that BCRF1 may have a role in the interaction of the virus with the host's immune system.

  View details for Web of Science ID A1990EG88300043

  View details for PubMedID 2173142

• ISOLATION OF MONOCLONAL-ANTIBODIES SPECIFIC FOR IL-4, IL-5, IL-6, AND A NEW TH2-SPECIFIC CYTOKINE (IL-10), CYTOKINE SYNTHESIS INHIBITORY FACTOR, BY USING A SOLID-PHASE RADIOIMMUNOADSORBENT ASSAY JOURNAL OF IMMUNOLOGY Mosmann, T. R., SCHUMACHER, J. H., Fiorentino, D. F., LEVERAH, J., Moore, K. W., Bond, M. W. 1990; 145 (9): 2938-2945

  Abstract

  Hybridomas were produced from a rat that was immunized with partially purified proteins from supernatants of induced Th2 cells. These preparations were enriched for cytokine synthesis inhibitory factor (CSIF, IL-10). The mAb in the supernatants were screened by a solid phase radioimmunoadsorbent assay using 35S-methionine-labeled secreted proteins from a lectin-stimulated Th2 clone. A total of 18 anticytokine mAb were isolated, comprising 6 anti-CSIF, 1 anti-IL-4, 1 anti-IL-5, and 10 anti-IL-6 mAb. The anti-CSIF mAb were separable into three groups. mAb in groups A and B neutralized and depleted bioactivity, and bound to overlapping but nonidentical subpopulations of CSIF molecules. The 2 mAb in group C did not neutralize CSIF activity, and bound to CSIF molecules not recognized by mAb from groups A or B. A two-site sandwich ELISA for CSIF could be established with the group A antibody, SXC1, combined with any of the three group B antibodies. The sensitivity of this assay was equivalent to that of the CSIF bioassay. These antibodies have been used to show that CSIF is responsible for most or all of the ability of Th2 supernatants to inhibit cytokine synthesis by Th1 cells. In addition, the ELISA has been used to confirm that CSIF is produced by Th2 but not Th1 clones.

  View details for Web of Science ID A1990EF11800023

  View details for PubMedID 2145365

• HOMOLOGY OF CYTOKINE SYNTHESIS INHIBITORY FACTOR (IL-10) TO THE EPSTEIN-BARR-VIRUS GENE BCRFI SCIENCE Moore, K. W., Vieira, P., Fiorentino, D. F., TROUNSTINE, M. L., Khan, T. A., Mosmann, T. R. 1990; 248 (4960): 1230-1234

  Abstract

  Complementary DNA clones encoding mouse cytokine synthesis inhibitory factor (CSIF; interleukin-10), which inhibits cytokine synthesis by TH1 helper T cells, were isolated and expressed. The predicted protein sequence shows extensive homology with an uncharacterized open reading frame, BCRFI, in the Epstein-Barr virus genome, suggesting the possibility that this herpes virus exploits the biological activity of a captured cytokine gene to enhance its survival in the host.

  View details for Web of Science ID A1990DH14400037

  View details for PubMedID 2161559

• HETEROGENEITY OF MOUSE HELPER T-CELLS - EVIDENCE FROM BULK CULTURES AND LIMITING DILUTION CLONING FOR PRECURSORS OF TH1 AND TH2 CELLS JOURNAL OF IMMUNOLOGY Street, N. E., SCHUMACHER, J. H., Fong, T. A., Bass, H., Fiorentino, D. F., LEVERAH, J. A., Mosmann, T. R. 1990; 144 (5): 1629-1639

  Abstract

  Many long term mouse Th clones express either the type 1 or type 2 Th cell (Th1 or Th2) cytokine secretion phenotype. In this report we present two lines of evidence for the existence of additional Th differentiation states. Lectin-stimulated spleen cells secreted moderate levels of IL-2 compared with long term Th1 clones, whereas the levels of other cytokines were more than 100-fold lower than those produced by either Th1 or Th2 clones. This suggests that many spleen cells produce substantial amounts of IL-2 but little or no IL-4, IL-5, IFN-gamma, IL-3, and granulocyte/macrophage-CSF. In contrast to long term Th clones, many short term alloreactive clones displayed cytokine secretion phenotypes intermediate between the Th1 and Th2 patterns. The proportion of recognizable Th1 and Th2 clones at early times in culture was greatly increased by immunization of the mice from which the responder and stimulator cells were derived; Brucella abortus immunization resulted in the isolation of exclusively Th1 clones, whereas infection with Nippostrongylus brasiliensis resulted in a strong trend toward the isolation of Th2 clones. The immunization of mice from which responder cells were derived strongly affected the type of Th clone obtained, whereas the source of stimulator cells had much less effect, suggesting that the commitment of Th cells to the Th1 or Th2 phenotypes occurred mainly in vivo. A model for the possible relationships of the various Th cells is presented.

  View details for Web of Science ID A1990CR42900012

  View details for PubMedID 1968485

• 2 TYPES OF MOUSE T-HELPER CELL .4. TH2 CLONES SECRETE A FACTOR THAT INHIBITS CYTOKINE PRODUCTION BY TH1 CLONES JOURNAL OF EXPERIMENTAL MEDICINE Fiorentino, D. F., Bond, M. W., Mosmann, T. R. 1989; 170 (6): 2081-2095

  Abstract

  A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.

  View details for Web of Science ID A1989CD27200022

  View details for PubMedID 2531194

• HETEROGENEITY OF MOUSE HELPER T-CELLS AND CROSS-REGULATION OF TH1 AND TH2 CLONES 7TH INTERNATIONAL CONGRESS OF IMMUNOLOGY Mosmann, T. R., Street, N. E., Fiorentino, D. F., Bond, M. W., Fong, T. A., Schumacher, J., LEVERAH, J. A., Trounstine, M., Vieira, P., Moore, K. W. SPRINGER-VERLAG BERLIN. 1989: 611–618

  View details for Web of Science ID A1989BP83Z00082