Publications by authors named "David F Fiorentino"

41 Publications

A Mortality Risk Score Model for Clinically Amyopathic Dermatomyositis-Associated Interstitial Lung Disease: Will It Have the Necessary "FLAIR" to Improve Clinical Outcomes?

Chest 2020 Oct;158(4):1307-1309

Department of Dermatology, Stanford University, Stanford, CA.

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http://dx.doi.org/10.1016/j.chest.2020.06.001DOI Listing
October 2020

A phase 2, double-blinded, placebo-controlled trial of toll-like receptor 7/8/9 antagonist, IMO-8400, in dermatomyositis.

J Am Acad Dermatol 2020 Aug 8. Epub 2020 Aug 8.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.07.122DOI Listing
August 2020

Distinct dermatomyositis populations are detected with different autoantibody assay platforms.

Clin Exp Rheumatol 2019 Nov-Dec;37(6):1048-1051. Epub 2019 Jul 19.

Johns Hopkins University School of Medicine, Division of Rheumatology, Baltimore, MD, USA.

Objectives: To compare autoantibody-defined dermatomyositis sub-populations using immunoprecipitation-based assays, a commercially available line immunoblot assay and alternate commercial ELISA assays.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039699PMC
December 2019

Clinical factors associated with cutaneous histopathologic findings in dermatomyositis.

J Cutan Pathol 2019 Jun 3;46(6):401-410. Epub 2019 Apr 3.

Department of Dermatology, Stanford University School of Medicine, Stanford, California.

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.
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http://dx.doi.org/10.1111/cup.13442DOI Listing
June 2019

Association Between Autoantibody Phenotype and Cutaneous Adverse Reactions to Hydroxychloroquine in Dermatomyositis.

JAMA Dermatol 2018 10;154(10):1199-1203

Department of Dermatology, Stanford University School of Medicine, Redwood City, California.

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 1γ [TIF-1γ], 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.
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http://dx.doi.org/10.1001/jamadermatol.2018.2549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233745PMC
October 2018

Clinical significance of autoantibodies in dermatomyositis and systemic sclerosis.

Clin Dermatol 2018 Jul - Aug;36(4):508-524. Epub 2018 Apr 12.

Department of Medicine, Division of Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clindermatol.2018.04.008DOI Listing
December 2018

Dermatomyositis Clinical and Pathological Phenotypes Associated with Myositis-Specific Autoantibodies.

Curr Rheumatol Rep 2018 04 10;20(5):28. Epub 2018 Apr 10.

Department of Dermatology, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA.

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.
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http://dx.doi.org/10.1007/s11926-018-0733-5DOI Listing
April 2018

Factors Associated With Clinical Remission of Skin Disease in Dermatomyositis.

JAMA Dermatol 2018 01;154(1):44-51

Stanford University School of Medicine, Department of Dermatology, Stanford, California.

Importance: 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.

Objective: To characterize cutaneous disease course in adult patients with dermatomyositis.

Design, Setting, And Participants: 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.

Main Outcomes And Measures: The percentage of patients who achieved clinical remission of their cutaneous disease as measured by the CDASI over a 3-year follow-up.

Results: 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.

Conclusions And Relevance: 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.
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http://dx.doi.org/10.1001/jamadermatol.2017.3758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833585PMC
January 2018

Cutaneous and Systemic Findings Associated With Nuclear Matrix Protein 2 Antibodies in Adult Dermatomyositis Patients.

Arthritis Care Res (Hoboken) 2017 12 2;69(12):1909-1914. Epub 2017 Nov 2.

Stanford University School of Medicine, Stanford, California.

Objective: To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with antinuclear matrix protein 2 (anti-NXP-2) antibodies.

Methods: We conducted a retrospective cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. An 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.

Results: Antibodies to NXP-2 were detected in 20 of the 178 patients (11%). Anti-NXP-2 antibodies were associated with male sex (50% versus 25%; P = 0.02), dysphagia (74% versus 39%; P = 0.006), myalgia (89% versus 52%; P = 0.002), peripheral edema (35% versus 11%; P = 0.016), and calcinosis (37% versus 11%; P = 0.007). These patients were less likely to be clinically amyopathic (5% versus 23%; P = 0.08). Five of the 20 patients with anti-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% versus 75%; P = 0.012) and a greater likelihood of having mild skin disease.

Conclusion: Dermatomyositis patients with anti-NXP-2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema, and significant dysphagia, despite having milder inflammatory skin disease.
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http://dx.doi.org/10.1002/acr.23210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529261PMC
December 2017

Ovoid Palatal Patch in Dermatomyositis: A Novel Finding Associated With Anti-TIF1γ (p155) Antibodies.

JAMA Dermatol 2016 09;152(9):1049-51

Department of Dermatology, Stanford University School of Medicine, Redwood City, California.

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http://dx.doi.org/10.1001/jamadermatol.2016.1429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224833PMC
September 2016

Characterization of patients with clinical overlap of morphea and systemic sclerosis: A case series.

J Am Acad Dermatol 2016 Jun;74(6):1272-4

Department of Dermatology, Stanford University, Stanford, CA.

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http://dx.doi.org/10.1016/j.jaad.2015.12.051DOI Listing
June 2016

Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension.

Hypertension 2015 Dec 5;66(6):1227-1239. Epub 2015 Oct 5.

VA Palo Alto Health Care System, Palo Alto, CA 94304.

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.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646718PMC
December 2015

PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjögren's syndrome.

Ann Rheum Dis 2016 Jun 7;75(6):1145-51. Epub 2015 Aug 7.

Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objectives: 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.

Methods: 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).

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1136/annrheumdis-2015-207509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828328PMC
June 2016

Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis: Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

JAMA Dermatol 2015 Sep;151(9):961-9

Department of Dermatology, Saint Louis University School of Medicine, St Louis, Missouri.

Importance: The efficacy of treatment for psoriasis must be balanced against potential adverse events.

Objective: To determine the effect of treatment on the risk of serious infections in patients with psoriasis.

Design, Setting, And Participants: 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.

Exposures: 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.

Main Outcomes And Measures: 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.

Results: 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.

Conclusions And Relevance: 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.

Trial Registration: clinicaltrials.gov Identifier: NCT00508547.
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http://dx.doi.org/10.1001/jamadermatol.2015.0718DOI Listing
September 2015

Distinctive cutaneous and systemic features associated with antitranscriptional intermediary factor-1γ antibodies in adults with dermatomyositis.

J Am Acad Dermatol 2015 Mar 14;72(3):449-55. Epub 2015 Jan 14.

Johns Hopkins University School of Medicine, Division of Rheumatology, Baltimore, Maryland.

Background: Antibodies against transcriptional intermediary factor (TIF)-1γ are associated with malignancy in dermatomyositis (DM). Identification of clinical findings associated with anti-TIF-1γ antibodies in DM is a high priority for both patient diagnosis and risk assessment.

Objective: We sought to define the clinical phenotype of patients with anti-TIF-1γ DM.

Methods: Using a novel, sensitive, and specific assay for anti-TIF-1γ antibodies, we retrospectively tested plasma from 134 adult patients with DM and examined associations between anti-TIF-1γ antibodies and particular clinical and laboratory features.

Results: In all, 55 (41%) patients had autoantibodies to TIF-1γ. Anti-TIF-1γ positive patients were less likely to have systemic features including interstitial lung disease, Raynaud phenomenon, and arthritis/arthralgia. Patients with TIF-1γ autoantibodies had more extensive skin involvement, and some patients manifested characteristic findings including palmar hyperkeratotic papules, psoriasis-like lesions and a novel finding of hypopigmented and telangiectatic ("red on white") patches.

Limitations: This was a retrospective study from a single tertiary referral center.

Conclusion: TIF-1γ is the most commonly targeted DM-specific autoantigen in adults in a large US cohort. Although these patients tend to have less systemic involvement, their skin disease is often extensive and characteristic. Recognition of cutaneous findings in anti-TIF-1γ positive patients may allow more accurate and timely diagnosis and effective treatment of patients with DM.
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http://dx.doi.org/10.1016/j.jaad.2014.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351728PMC
March 2015

Surgical treatment of systemic sclerosis--is it justified to offer peripheral sympathectomy earlier in the disease process?

Microsurgery 2015 Sep 14;35(6):441-6. Epub 2015 Jan 14.

Division of Plastic and Reconstructive Surgery, Stanford University Medical Center, Palo Alto, CA.

Purpose: 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.

Patients And Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1002/micr.22379DOI Listing
September 2015

Amyopathic dermatomyositis: definitions, diagnosis, and management.

Curr Rheumatol Rep 2014 Dec;16(12):465

Department of Dermatology, Stanford University School of Medicine, 450 Broadway Drive, Redwood City, 94063, CA, USA.

Amyopathic dermatomyositis can be a challenging diagnosis because patients lack traditional muscle findings. "Clinically amyopathic" dermatomyositis (CADM) accounts for the presence of subclinical muscle disease in some of these patients. These patients represent a substantial minority of dermatomyositis cases and have similar co-morbidities to "classic" dermatomyositis patients, including interstitial lung disease and malignancy. Clinically amyopathic dermatomyositis patients should not be considered as a distinct clinical entity from "classic" dermatomyositis, as they share antibody sub-types and associated co-morbidities, likely representing clinical spectrum of a common disease. It is essential for the clinician to be familiar with the clinical presentation of clinically amyopathic dermatomyositis, in order to facilitate early, accurate diagnosis and appropriate clinical management.
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http://dx.doi.org/10.1007/s11926-014-0465-0DOI Listing
December 2014

Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease.

Arthritis Care Res (Hoboken) 2015 May;67(5):667-72

Stanford University, Stanford, California.

Objective: To identify clinical and serologic correlates of cutaneous ulcers in dermatomyositis (DM).

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1002/acr.22498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404195PMC
May 2015

Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ.

Arthritis Rheum 2013 Nov;65(11):2954-62

Stanford University School of Medicine, Stanford, California.

Objective: 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.

Methods: 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).

Results: 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]).

Conclusion: 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.
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http://dx.doi.org/10.1002/art.38093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073292PMC
November 2013

Molecular profiling to diagnose a case of atypical dermatomyositis.

J Invest Dermatol 2013 Dec 3;133(12):2796-2799. Epub 2013 Jun 3.

Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1038/jid.2013.240DOI Listing
December 2013

Localized cutaneous fibrosing disorders.

Rheum Dis Clin North Am 2013 May 16;39(2):347-64. Epub 2013 Mar 16.

Division of Immunology and Rheumatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.

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.
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http://dx.doi.org/10.1016/j.rdc.2013.02.013DOI Listing
May 2013

Clinical presentation and evaluation of dermatomyositis.

Indian J Dermatol 2012 Sep;57(5):375-81

Division of Immunology and Rheumatology, Stanford University, USA.

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.
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http://dx.doi.org/10.4103/0019-5154.100486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482801PMC
September 2012

Skin disease in dermatomyositis.

Curr Opin Rheumatol 2012 Nov;24(6):597-601

Department of Dermatology, Stanford University School of Medicine, California 94063, USA.

Purpose Of Review: 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.

Recent Findings: 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.

Summary: 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.
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http://dx.doi.org/10.1097/BOR.0b013e3283585748DOI Listing
November 2012

Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients.

Int J Rheum Dis 2012 Feb 31;15(1):25-35. Epub 2011 Aug 31.

Translational Sciences, MedImmune, LLC, Gaithersburg, MD 20878, USA.

Aim: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1111/j.1756-185X.2011.01654.xDOI Listing
February 2012

Consensus guidelines for the management of plaque psoriasis.

Arch Dermatol 2012 Jan;148(1):95-102

Department of Dermatology, Baylor College of Medicine, Houston, TX 77030, USA.

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.
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http://dx.doi.org/10.1001/archdermatol.2011.1410DOI Listing
January 2012

Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis.

Int J Rheumatol 2011 27;2011:201787. Epub 2011 Oct 27.

Division of Immunology and Rheumatology, Departments of Dermatology and Medicine, Stanford University School of Medicine, Palo Alto VA Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.

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.
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http://dx.doi.org/10.1155/2011/201787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205679PMC
August 2012

Pathogenesis of dermatomyositis: role of cytokines and interferon.

Curr Rheumatol Rep 2011 Jun;13(3):225-32

Division of Immunology and Rheumatology, Stanford University School of Medicine, 1000 Welch Road, #203, Palo Alto, CA 94304, USA.

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.
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http://dx.doi.org/10.1007/s11926-011-0166-xDOI Listing
June 2011