Publications by authors named "Livia Casciola-Rosen"

103 Publications

Association of systemic lupus erythematosus autoantibody diversity with breast cancer protection.

Arthritis Res Ther 2021 Feb 25;23(1):64. Epub 2021 Feb 25.

Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Building Center Tower, Suite 4100, Baltimore, MD, 21224, USA.

Background: Epidemiologic data suggest that patients with systemic lupus erythematosus (SLE) have a lower risk of breast cancer than women in the general population. In light of mechanistic studies suggesting that anti-DNA antibodies have anti-cancer effects, we sought to examine breast cancer risk in autoantibody strata in a well-characterized SLE cohort.

Methods: SLE patients without a cancer diagnosis prior to entry in the Hopkins Lupus Cohort were studied (N = 2431). Overall and site-specific cancer incidence was calculated in racial strata and compared with the US Surveillance, Epidemiology and End Results (SEER) registry. Breast cancer incidence was further examined in autoantibody subsets. Patients were considered positive for an autoantibody if they were ever positive for a specificity during their disease course.

Results: Patients with SLE had a 37% lower risk of breast cancer (SIR 0.63, 95% CI 0.39-0.95). The risk of HPV-associated cancers (SIR 4.39, 95% CI 2.87-6.44) and thyroid cancer (SIR 2.27, 95% CI 1.04-4.30) was increased. Cancer risk varied by race, with breast cancer protection occurring in non-African Americans (SIR 0.29, 95% CI 0.11-0.63) and the increased risk of HPV-associated cancers occurring in African Americans (SIR 7.23, 95% CI 4.35-11.3). Breast cancer risk was decreased in patients ever positive for anti-dsDNA (SIR 0.55, 95% CI 0.29-0.96), anti-La (SIR 0.00, 95% CI 0.00-0.78), and lupus anticoagulant (SIR 0.37, 95% CI 0.10-0.94). Patients who were positive for fewer (0-2) SLE autoantibodies did not have a lower risk of breast cancer (SIR 0.84, 95% CI 0.47-1.39), but patients with 3+ autoantibodies had a 59% decreased risk (SIR 0.41, 95% CI 0.16-0.84).

Conclusions: Positivity for multiple SLE autoantibodies was associated with a lower risk of breast cancer, supporting the hypothesis that a highly diversified immune response may exert an anti-cancer effect against some cancers. Validation of racial differences in cancer risk in SLE is required to determine whether cancer screening strategies should be targeted to racial subgroups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-021-02449-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905617PMC
February 2021

Autoantibodies targeting telomere-associated proteins in systemic sclerosis.

Ann Rheum Dis 2021 Jan 25. Epub 2021 Jan 25.

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

Objectives: Systemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.

Methods: Sera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.

Results: In a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher's exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.

Conclusions: Autoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2020-218918DOI Listing
January 2021

Granzyme B Induces IRF-3 Phosphorylation through a Perforin-Independent Proteolysis-Dependent Signaling Cascade without Inducing Cell Death.

J Immunol 2021 Jan 7;206(2):335-344. Epub 2020 Dec 7.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224;

Granzyme B (GrB) is an immune protease implicated in the pathogenesis of several human diseases. In the current model of GrB activity, perforin determines whether the downstream actions of GrB occur intracellularly or extracellularly, producing apoptotic cytotoxicity or nonapoptotic effects, respectively. In the current study, we demonstrate the existence of a broad range of GrB-dependent signaling activities that 1) do not require perforin, 2) occur intracellularly, and 3) for which cell death is not the dominant outcome. In the absence of perforin, we show that GrB enzymatic activity still induces substoichiometric activation of caspases, which through nonlethal DNA damage response signals then leads to activity-associated phosphorylation of IFN regulatory factor-3. These findings illustrate an unexpected potential interface between GrB and innate immunity separate from the traditional role of GrB in perforin-dependent GrB-mediated apoptosis that could have mechanistic implications for human disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.2000546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785649PMC
January 2021

Study of Tofacitinib In Refractory Dermatomyositis (STIR): An open label pilot study of 10 patients.

Arthritis Rheumatol 2020 Dec 1. Epub 2020 Dec 1.

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

Objectives: This open-label 12-week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in active, treatment-refractory dermatomyositis.

Methods: Tofacitinib was given as 11 mg XR daily to 10 subjects. All subjects underwent complete washout of all steroid sparing agents. The primary outcome measure was the IMACS definition of improvement. The response rate was measured by the 2016 ACR/EULAR Myositis Response Criteria using the total improvement score (TIS). The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), chemokine levels, skin STAT 1 expression by immunohistochemistry, RNA sequencing analysis, and safety were secondary outcome measures.

Results: All 10 subjects met the primary outcome at 12 weeks. 5 of 10 (50%) had moderate improvement and the other half had minimal improvement on the TIS. The secondary outcome of the mean change in the CDASI activity score from baseline to 12 weeks was statistically significant (28 ± 15.4 vs. 9.5 ± 8.5, p=0.0005). Serum chemokine data (CXCL 9/10) showed a statistically significant change from baseline. Three of the 9 subjects who had a skin biopsy demonstrated a marked decrease in STAT1 signaling in association with suppression of IFN target gene expression. The mean creatine kinase was 82 ± 34.8 highlighting that those treated had skin predominant disease.

Conclusions: This is the first prospective, open-label clinical trial of tofacitinib in dermatomyositis that demonstrates strong clinical efficacy for a pan JAK inhibitor as measured by validated myositis response criteria. Future randomized controlled trials using JAK-inhibitors should be considered for treating dermatomyositis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.41602DOI Listing
December 2020

Cancer in Systemic Sclerosis: Analysis of Antibodies Against Components of the Th/To Complex.

Arthritis Rheumatol 2021 02 26;73(2):315-323. Epub 2020 Dec 26.

Johns Hopkins University, Baltimore, Maryland.

Objective: The aim of this study is to describe 4 of the most common autoantibodies against components of the Th/To complex: human POP1 (hPOP1), RPP25, RPP30, and RPP40. We report their prevalence and clinical characteristics in a systemic sclerosis (SSc) population, and determine whether these specificities are associated with cancer.

Methods: A case-control study was performed using data from the Johns Hopkins Scleroderma Center Cohort. A total of 804 adult patients with SSc were included; 401 SSc patients with no history of cancer after at least 5 years of disease were compared to 403 SSc patients who ever had a history of cancer. Antibodies against hPOP1, RPP25, RPP30, and RPP40 were assayed by immunoprecipitation of S-methionine-labeled proteins generated by in vitro transcription/translation. Demographic and clinical characteristics were compared between groups.

Results: Of 804 patients, 67 (8.3%) had antibodies against any component of the Th/To complex. Patients with antibodies to any component were significantly more likely to have limited cutaneous disease, less likely to have tendon friction rubs, and more likely to have findings consistent with interstitial lung disease or pulmonary hypertension. Patients with antibodies against hPOP1, RPP25, RPP30, and/or RPP40 were significantly less likely to develop cancer within 2 years of SSc onset (0% versus 11% of antibody-negative patients; P = 0.009).

Conclusion: SSc patients who produce autoantibodies to components of the Th/To complex have a clinical phenotype characterized by limited cutaneous disease and pulmonary involvement. Our findings show that the presence of any Th/To autoantibody may have a protective effect against contemporaneous cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.41493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884482PMC
February 2021

Expression of the Autoantigen Topoisomerase-1 is Enriched in the Lung Tissues of Patients With Autoimmune Interstitial Lung Disease: A Case Control Study.

ACR Open Rheumatol 2020 Nov 29;2(11):657-661. Epub 2020 Oct 29.

Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Background: Among the autoimmune rheumatic diseases, it is striking that autoantibodies targeting ubiquitously expressed proteins (eg, topoisomerase-1) associate with specific clinical complications (eg, interstitial lung disease [ILD]). It has been proposed that enriched antigen expression in inflamed target tissue may play a role in focusing the autoimmune response. We sought to determine whether topoisomerase-1 expression is enriched in lungs from patients with autoimmune/inflammatory diseases relative to normal lung.

Methods: We used a 99-core lung tissue microarray (TMA) containing lung tissue from 40 patients with autoimmune inflammatory ILD (cases) and 46 control subjects with normal lungs. We stained the TMA with antibodies to compare topoisomerase-1 and CD8 expression between patients and control subjects and evaluated whether expression is enriched in specific cell types. Staining was analyzed, and statistical comparisons were performed.

Results: Cases were more likely to have global topoisomerase-1 expression (53% vs 21%; P = 0.003), specifically in pneumocytes (47% vs 16%; P = 0.003) and stromal/immune cells (32% vs 5%; P = 0.002) compared with control subjects. CD8 cell density (223 cells/mm vs 102 cells/mm ; P = 0.018) was significantly higher in topoisomerase-1-positive lung tissues compared with topoisomerase-1-negative lung tissues. Interestingly, topoisomerase-1 expression was significantly more common in scleroderma compared with normal lung (67% vs 21%; P = 0.036) and was present more frequently in pneumocytes in these patients (67% vs 16%; P = 0.018).

Conclusions: Pulmonary expression of topoisomerase-1 is increased in the setting of autoimmune ILD relative to normal lung, specifically in pneumocytes. This may contribute to the amplification of pulmonary disease in patients with scleroderma with a loss of tolerance to topoisomerase-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acr2.11191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672300PMC
November 2020

IgM autoantibodies recognizing ACE2 are associated with severe COVID-19.

medRxiv 2020 Oct 15. Epub 2020 Oct 15.

SARS-CoV-2 infection induces severe disease in a subpopulation of patients, but the underlying mechanisms remain unclear. We demonstrate robust IgM autoantibodies that recognize angiotensin converting enzyme-2 (ACE2) in 18/66 (27%) patients with severe COVID-19, which are rare (2/52; 3.8%) in hospitalized patients who are not ventilated. The antibodies do not undergo class-switching to IgG, suggesting a T-independent antibody response. Purified IgM from anti-ACE2 patients activates complement. Pathological analysis of lung obtained at autopsy shows endothelial cell staining for IgM in blood vessels in some patients. We propose that vascular endothelial ACE2 expression focuses the pathogenic effects of these autoantibodies on blood vessels, and contributes to the angiocentric pathology observed in some severe COVID-19 patients. These findings may have predictive and therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.10.13.20211664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574257PMC
October 2020

A Bayesian approach to restricted latent class models for scientifically structured clustering of multivariate binary outcomes.

Biometrics 2020 Oct 8. Epub 2020 Oct 8.

Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland.

This paper presents a model-based method for clustering multivariate binary observations that incorporates constraints consistent with the scientific context. The approach is motivated by the precision medicine problem of identifying autoimmune disease patient subsets or classes who may require different treatments. We start with a family of restricted latent class models or RLCMs. However, in the motivating example and many others like it, the unknown number of classes and the definition of classes using binary states are among the targets of inference. We use a Bayesian approach to RLCMs in order to use informative prior assumptions on the number and definitions of latent classes to be consistent with scientific knowledge so that the posterior distribution tends to concentrate on smaller numbers of clusters and sparser binary patterns. The paper derives a posterior sampling algorithm based on Markov chain Monte Carlo with split-merge updates to efficiently explore the space of clustering allocations. Through simulations under the assumed model and realistic deviations from it, we demonstrate greater interpretability of results and superior finite-sample clustering performance for our method compared to common alternatives. The methods are illustrated with an analysis of protein data to detect clusters representing autoantibody classes among scleroderma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/biom.13388DOI Listing
October 2020

Accuracy of commercial panels to evaluate myositis autoantibodies: A single-institution perspective.

J Am Acad Dermatol 2021 Feb 4;84(2):572-574. Epub 2020 Sep 4.

Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.08.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841648PMC
February 2021

Cancer and Scleroderma.

Rheum Dis Clin North Am 2020 08 10;46(3):551-564. Epub 2020 Jun 10.

Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224, USA. Electronic address:

Individuals with scleroderma have an increased risk of cancer compared with the general population. This heightened risk may be from chronic inflammation and tissue damage, malignant transformation provoked by immunosuppressive therapies, or a common inciting factor. In unique subsets of patients with scleroderma, there is a close temporal relationship between the onset of cancer and scleroderma, suggesting cancer-induced autoimmunity. This article discusses the potential mechanistic links between cancer and scleroderma, the serologic and clinical risk factors associated with increased cancer risk in patients with scleroderma, and implications for cancer screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rdc.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340850PMC
August 2020

Anti-retinoblastoma Protein Antibodies: A New Specificity in Systemic Lupus Erythematosus Associated With Protection Against Lupus Nephritis.

ACR Open Rheumatol 2019 Jul 6;1(5):287-291. Epub 2019 Jun 6.

School of Medicine Johns Hopkins University Baltimore Maryland.

Objective: Retinoblastoma (Rb) protein is a nuclear protein with several important functions, including the ability to stabilize heterochromatin. Because antibodies against the nucleosome and chromatin are key in systemic lupus erythematosus (SLE), we sought to determine whether Rb was an autoantigen in SLE and to evaluate any associated clinical phenotypes.

Methods: Sera from 222 patients with SLE from the Hopkins longitudinal cohort were studied. Additional cohorts tested included sera from 100 patients with primary Sjögren syndrome (pSS) (disease controls) evaluated at the Johns Hopkins Jerome L. Greene Sjögren's Center and sera from 36 healthy individuals. Anti-Rb antibodies were assayed by immunoprecipitation of S-methionine-labeled Rb, which was generated by in vitro transcription/translation. Fisher's exact test was used for the univariate analysis. Multivariable exact logistic regression was used to model for the presence of proteinuria in patients with SLE.

Results: Anti-Rb antibodies were present in 15 of 222 (6.8%) patients with SLE, in 3 of 100 patients with pSS (3%), and in 0 of 36 healthy individuals. Among patients with SLE, Rb antibodies were strongly negatively associated with proteinuria ( = 0.0031), renal involvement (odds ratio [OR] = 0.11; = 0.01), and anemia (OR = 0.05; < 0.0001) and were positively associated with stroke (OR = 7.65; = 0.05). The negative association with lupus nephritis held true in multivariate models (adjusted OR = 0.11; = 0.01).

Conclusion: Anti-Rb antibodies are a novel specificity not previously described in SLE. These new data define a possible SLE subset that is protected against renal involvement, is positively associated with stroke, and is not associated with antiphospholipid antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acr2.1036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857985PMC
July 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

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

Protective Effect Against Cancer of Antibodies to the Large Subunits of Both RNA Polymerases I and III in Scleroderma.

Arthritis Rheumatol 2019 09 1;71(9):1571-1579. Epub 2019 Aug 1.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: While compelling data suggest a cancer-induced autoimmunity model in scleroderma patients with anti-RNA polymerase III large subunit (anti-RPC155) antibodies, ~85% of these patients do not manifest cancer. This study was undertaken to determine whether additional autoantigens are targeted in anti-RPC155-positive scleroderma patients without detectable cancer.

Methods: The study included 168 scleroderma patients with anti-RPC155 antibodies (80 with a history of cancer and 88 with no cancer diagnosis after >5 years of follow-up). Thirty-five sera (17 from patients with cancer and 18 from patients without cancer) were randomly selected for autoantibody discovery using immunoprecipitation (IP). An ~194-kd band was enriched in the subgroup without cancer; this was identified as RNA polymerase I large subunit (RPA194).

Results: RPA194 generated by in vitro transcription/translation was used for IPs performed on the entire cohort to test whether anti-RPA194 was enriched among anti-RPC155-positive patients without cancer. Anti-RPA194 antibodies were significantly more common in the group without cancer (16 [18.2%] of 88) than in the group with cancer (3 [3.8%] of 80) (P = 0.003). Patients with both anti-RPA194 and anti-RPC155 were significantly less likely to have severe gastrointestinal disease than patients with anti-RPC155 only (26.3% versus 51.0%; P = 0.043).

Conclusion: Anti-RPA194 antibodies are enriched in anti-RPC155-positive scleroderma patients without cancer. Since somatic mutations in the gene encoding RPC155 in cancer in scleroderma patients appears to play a role in immune response initiation against RPC155 in those patients, these data raise the possibility that the development of immune responses to both RPC155 and RPA194 may influence clinical cancer emergence. Further study is required to define whether different autoantibody combinations have utility as tools for cancer risk stratification in scleroderma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.40893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717013PMC
September 2019

Muscular and extramuscular features of myositis patients with anti-U1-RNP autoantibodies.

Neurology 2019 03 1;92(13):e1416-e1426. Epub 2019 Mar 1.

From the Muscle Disease Unit (M.C.-D., I.P.-F., A.L.M.), Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda; Departments of Neurology (M.C.-D., I.P.-F., A.M.C., L.C.-S., A.L.M.) and Medicine (J.P., J.A., L.C.-R., C.J., S.K.D., L.C.-S., E.T., A.L.M.), Johns Hopkins University School of Medicine, Baltimore, MD; and Faculty of Health Sciences (J.P.-F.), Universitat Oberta de Catalunya, Barcelona, Spain.

Objective: To define the clinical phenotype of patients with myositis with anti-U1-ribonucleoprotein (RNP) autoantibodies.

Methods: In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up in patients with anti-U1-RNP-positive myositis were compared to those with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), and the antisynthetase syndrome (AS).

Results: Twenty anti-U1-RNP-positive patients, 178 patients with DM, 135 patients with IMNM, and 132 patients with AS were included. Anti-U1-RNP-positive patients were younger (∼37 years) and more likely to be black (60%) than patients with AS, DM, or IMNM. Muscle weakness was a presenting feature in 15% of anti-U1-RNP-positive patients; 80% eventually developed weakness. Four of 7 anti-U1-RNP-positive patients had necrotizing muscle biopsies. Arthritis occurred in 60% of anti-U1-RNP-positive patients; this was increased compared to DM (18%) or IMNM (6%) (all < 0.01). DM-specific skin features developed in 60% of anti-U1-RNP-positive patients. Interstitial lung disease (ILD) occurred in 45% of anti-U1-RNP-positive patients; fewer patients with DM (13%) and IMNM (6%) and more patients with AS (80%) developed ILD (all < 0.01). Glomerulonephritis and pericarditis occurred in 25% and 40% of anti-U1-RNP-positive patients, respectively, but rarely in the other groups; these features occurred only in those with coexisting anti-Ro52 autoantibodies. No anti-U1-RNP patient had cancer-associated myositis or died during the study period.

Conclusions: Patients with anti-U1-RNP myositis typically present with proximal weakness and necrotizing muscle biopsies. Arthritis, dermatitis, and ILD are the most common extramuscular clinical features. Pericarditis and glomerulonephritis are uniquely found in patients with anti-U1-RNP-positive myositis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453768PMC
March 2019

Anti-RNPC-3 (U11/U12) Antibodies in Systemic Sclerosis in Patients With Moderate-to-Severe Gastrointestinal Dysmotility.

Arthritis Care Res (Hoboken) 2019 09 6;71(9):1164-1170. Epub 2019 Aug 6.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: To examine the association of anti-RNPC-3 antibodies in patients with systemic sclerosis (scleroderma or SSc) with selected gastrointestinal (GI) tract complications.

Methods: Sera from patients with SSc with or without severe GI dysfunction (total parenteral nutrition dependence) from the Johns Hopkins Scleroderma Center were screened for anti-RNPC-3 antibodies. We then examined anti-RNPC-3-positive cases and negative SSc controls from the University of Pittsburgh and the University of Pittsburgh Medical Center (UPMC) scleroderma cohort to confirm our findings and to examine whether specific GI features were associated with anti-RNPC-3 antibodies.

Results: In the discovery cohort, patients with SSc with severe GI dysfunction (n = 37) and without GI dysfunction (n = 38) were screened for anti-RNPC-3 antibodies. The former were more likely to have anti-RNPC-3 antibodies (14% versus 3%; P = 0.11). In the Pittsburgh cohort, moderate-to-severe GI dysfunction (Medsger GI score ≥2) was present in 36% of anti-RNPC-3-positive patients versus 15% of anti-RNPC-3-negative patients (P ≤ 0.01). Anti-RNPC-3-positive patients were more likely to be male (31% versus 15%; P = 0.04), African American (18% versus 6%; P = 0.02), have esophageal dysmotility (93% versus 62%; P < 0.01), and interstitial lung disease (ILD) (77% versus 35%; P < 0.01). After adjusting for relevant covariates and potential confounders, moderate-to-severe GI disease was associated with anti-RNPC-3 antibodies (odds ratio [OR] 3.8 [95% confidence interval (95% CI) 1.0-14.3]), and ILD trended toward significance (OR 2.8 [95% CI 1.0-8.2]).

Conclusion: Patients with SSc and anti-RNPC-3 antibodies are more likely to be male and African American and to have moderate-to-severe GI disease and ILD. Further studies on larger patient cohorts may be helpful in further defining subsets of patients with SSc at risk for severe GI involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acr.23763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430701PMC
September 2019

IFI16 filament formation in salivary epithelial cells shapes the anti-IFI16 immune response in Sjögren's syndrome.

JCI Insight 2018 09 20;3(18). Epub 2018 Sep 20.

Division of Rheumatology and.

IFN-inducible protein 16 (IFI16) is an innate immune sensor that forms filamentous oligomers when activated by double-stranded DNA (dsDNA). Anti-IFI16 autoantibodies occur in patients with Sjögren's syndrome (SS) and associate with severe phenotypic features. We undertook this study to determine whether the structural and functional properties of IFI16 play a role in its status as an SS autoantigen. IFI16 immunostaining in labial salivary glands (LSGs) yielded striking evidence of filamentous IFI16 structures in the cytoplasm of ductal epithelial cells, representing the first microscopic description of IFI16 oligomerization in human tissues, to our knowledge. Transfection of cultured epithelial cells with dsDNA triggered the formation of cytoplasmic IFI16 filaments with similar morphology to those observed in LSGs. We found that a majority of SS anti-IFI16 autoantibodies immunoprecipitate IFI16 more effectively in the oligomeric dsDNA-bound state. Epitopes in the C-terminus of IFI16 are accessible to antibodies in the DNA-bound oligomer and are preferentially targeted by SS sera. Furthermore, cytotoxic lymphocyte granule pathways (highly enriched in the SS gland) induce striking release of IFI16•dsDNA complexes from cultured cells. Our studies reveal that IFI16 is present in a filamentous state in the target tissue of SS and suggest that this property of DNA-induced filament formation contributes to its status as an autoantigen in SS. These studies highlight the role that tissue-specific modifications and immune effector pathways might play in the selection of autoantigens in rheumatic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.120179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237237PMC
September 2018

An update on autoantibodies in scleroderma.

Curr Opin Rheumatol 2018 11;30(6):548-553

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

Purpose Of Review: New research continues to provide important insights into the utility of antibody specificities. This review provides an update of recent findings, and the important insights they provide into disease mechanism.

Recent Findings: A growing number of autoantibodies have been discovered in scleroderma patients with unique clinical associations. A subgroup of these antibodies may have functional consequences and contribute to disease pathogenesis, driving the vascular and fibrotic phenotype. Recent research into the relationship between malignancy and scleroderma onset provides important new insights into disease mechanism, and highlights the utility of autoantibodies as unique research probes.

Summary: Continued advances in the study of scleroderma antibody specificities has led to important insights into disease pathogenesis and clinical subgrouping. These advances include newly described specificities, functional antibodies and an emerging understanding of the cancer-scleroderma relationship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BOR.0000000000000550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546089PMC
November 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamadermatol.2018.2549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233745PMC
October 2018

Brief Report: Anti-Calponin 3 Autoantibodies: A Newly Identified Specificity in Patients With Sjögren's Syndrome.

Arthritis Rheumatol 2018 10 3;70(10):1610-1616. Epub 2018 Sep 3.

Johns Hopkins University, Baltimore, Maryland.

Objective: Autoantibodies are clinically useful for phenotyping patients across the spectrum of autoimmune rheumatic diseases. Using serum from a patient with Sjögren's syndrome (SS), we detected a new specificity by immunoblotting. This study was undertaken to identify this autoantibody and to evaluate its disease specificity.

Methods: A prominent 40-kd band was detected when immunoblotting was performed using SS patient serum and lysate from rat dorsal root ganglia (DRGs). Using 2-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing, the autoantigen was identified as calponin 3. Anti-calponin 3 antibodies were evaluated in sera from patients with primary SS (n = 209), patients with systemic lupus erythematosus (SLE; n = 138), patients with myositis (n = 138), patients with multiple sclerosis (MS; n = 44), and healthy controls (n = 46) by enzyme-linked immunosorbent assay. Expression of calponin 3 was assessed by immunohistochemistry.

Results: Calponin 3 was identified as a new autoantigen. Anti-calponin 3 antibodies were detected in 23 (11.0%) of the 209 SS patients, 12 (8.7%) of the 138 SLE patients, 7 (5.1%) of the 138 myositis patients, 3 (6.8%) of the 44 MS patients, and 1 (2.2%) of the 46 healthy controls. Among SS patients, the frequency of anti-calponin 3 antibodies was highest in those with neuropathies (7 [17.9%] of 39). In this subset, the frequency of anti-calponin 3 antibodies differed significantly from that in the control group (P = 0.02). Calponin 3 was expressed primarily in rat DRG perineuronal satellite cells but not neurons.

Conclusion: Calponin 3 is a novel autoantigen. Antibodies against this protein are found in SS and associate with the subset of patients experiencing neuropathies. Intriguingly, we found that calponin 3 is expressed in DRG perineuronal satellite cells, suggesting that these may be a target in SS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.40550DOI Listing
October 2018

Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer.

Ann Rheum Dis 2018 08 20;77(8):1179-1186. Epub 2018 Apr 20.

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

Objectives: Recent studies demonstrate autoantibodies are powerful tools to interrogate molecular events linking cancer and the development of autoimmunity in scleroderma. Investigating cancer risk in these biologically relevant subsets may provide an opportunity to develop personalised cancer screening guidelines. In this study, we examined cancer risk in distinct serologic and phenotypic scleroderma subsets and compared estimates with the general population.

Methods: Patients in the Johns Hopkins Scleroderma Center observational cohort were studied. Overall and site-specific cancer incidence was calculated in distinct autoantibody and scleroderma phenotypic subsets, and compared with the Surveillance, Epidemiology and End Results registry, a representative sample of the US population.

Results: 2383 patients with scleroderma contributing 37 686 person-years were studied. 205 patients (8.6%) had a diagnosis of cancer. Within 3 years of scleroderma onset, cancer risk was increased in patients with RNA polymerase III autoantibodies (antipol; standardised incidence ratio (SIR) 2.84, 95% CI 1.89 to 4.10) and those lacking centromere, topoisomerase-1 and pol antibodies (SIR 1.83, 95% CI 1.10 to 2.86). Among antipol-positive patients, cancer-specific risk may vary by scleroderma subtype; those with diffuse scleroderma had an increased breast cancer risk, whereas those with limited scleroderma had high lung cancer risk. In contrast, patients with anticentromere antibodies had a lower risk of cancer during follow-up (SIR 0.59, 95% CI 0.44 to 0.76).

Conclusions: Autoantibody specificity and disease subtype are biologically meaningful filters that may inform cancer risk stratification in patients with scleroderma. Future research testing the value of targeted cancer screening strategies in patients with scleroderma is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2018-212999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272061PMC
August 2018

Mechanistic and clinical insights at the scleroderma-cancer interface.

J Scleroderma Relat Disord 2017 Sep-Dec;2(3):153-159. Epub 2017 Oct 5.

Johns Hopkins University School of Medicine, Division of Rheumatology.

Emerging data suggest tantalizing links between cancer and systemic inflammatory rheumatic syndromes. In scleroderma, patients may have an increased risk of cancer secondary to chronic inflammation and damage from the disease, malignant transformation promoted by immunosuppressive therapies, a shared susceptibility to both cancer and autoimmunity, or a common inciting exposure. However, it is increasingly recognized that a subset of patients develop cancer around the time that scleroderma clinically manifests, raising the question of cancer-induced autoimmunity. In this review, we discuss data suggesting a mechanistic link between cancer and the development of scleroderma, and the clinical implications of these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5301/jsrd.5000250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734659PMC
October 2017

Estimating autoantibody signatures to detect autoimmune disease patient subsets.

Biostatistics 2019 01;20(1):30-47

Department of Biostatistics, The Johns Hopkins University, 615 N Wolfe Street, Baltimore, MD, USA.

Autoimmune diseases are characterized by highly specific immune responses against molecules in self-tissues. Different autoimmune diseases are characterized by distinct immune responses, making autoantibodies useful for diagnosis and prediction. In many diseases, the targets of autoantibodies are incompletely defined. Although the technologies for autoantibody discovery have advanced dramatically over the past decade, each of these techniques generates hundreds of possibilities, which are onerous and expensive to validate. We set out to establish a method to greatly simplify autoantibody discovery, using a pre-filtering step to define subgroups with similar specificities based on migration of radiolabeled, immunoprecipitated proteins on sodium dodecyl sulfate (SDS) gels and autoradiography [Gel Electrophoresis and band detection on Autoradiograms (GEA)]. Human recognition of patterns is not optimal when the patterns are complex or scattered across many samples. Multiple sources of errors-including irrelevant intensity differences and warping of gels-have challenged automation of pattern discovery from autoradiograms.In this article, we address these limitations using a Bayesian hierarchical model with shrinkage priors for pattern alignment and spatial dewarping. The Bayesian model combines information from multiple gel sets and corrects spatial warping for coherent estimation of autoantibody signatures defined by presence or absence of a grid of landmark proteins. We show the pre-processing creates more clearly separated clusters and improves the accuracy of autoantibody subset detection via hierarchical clustering. Finally, we demonstrate the utility of the proposed methods with GEA data from scleroderma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/biostatistics/kxx061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657300PMC
January 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

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

Inflammatory myopathy associated with anti-mitochondrial antibodies: A distinct phenotype with cardiac involvement.

Semin Arthritis Rheum 2018 02 13;47(4):552-556. Epub 2017 Jun 13.

Division of Rheumatology, Johns Hopkins University, School of Medicine, Baltimore, MD. Electronic address:

Objective: In the context of clinical evaluations performed on our prospective myositis cohort, we noted a striking association of severe cardiac disease in myositis patients with anti-mitochondrial antibodies. We sought to review all cases of anti-mitochondrial antibody (AMA) associated myositis in our cohort to describe the clinical features of this disease subset.

Methods: We identified 7 patients with confirmed anti-mitochondrial antibodies who presented as an inflammatory myopathy. A retrospective chart review was completed to assess their clinical presentation, laboratory, imaging, electrophysiologic, and histopathologic features.

Results: One patient presented with dermatomyositis and 6 were classified as polymyositis using Bohan and Peter criteria. In all but one patient, a chronic course of muscle involvement was appreciated with an average of 6.5 years of weakness prior to presentation. Muscle atrophy was often noted, as well as atypical findings of scapular winging in 2 of the patients. Muscle biopsies were consistent with immune-mediated necrotizing myopathy in 4 patients, dermatomyositis in 1, polymyositis in 1 and nonspecific or granulomatous myositis in 1 patient. Changes pointing to mitochondrial alterations were seen in 2 of the 7 patients. Cardiac involvement (including myocarditis, atrial and ventricular arrhythmias, and cardiomyopathy), was seen in 5 out of 7 (71%) of the patients, and usually preceded the muscle involvement. Coexisting autoimmune conditions were seen in 3/7of the patients and included primary biliary cirrhosis, autoimmune hepatitis, psoriasis, and Hashimoto's thyroiditis.

Conclusions: Anti-mitochondrial antibodies identify a distinct inflammatory myopathy phenotype that is frequently associated with chronic skeletal muscle disease and severe cardiac involvement. Early recognition of this rare entity as an immune-mediated process is important due to implications for treatment. We propose that anti-mitochondrial antibody status should be determined in patients with a compatible clinical picture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semarthrit.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581062PMC
February 2018

Evaluation of cancer-associated myositis and scleroderma autoantibodies in breast cancer patients without rheumatic disease.

Clin Exp Rheumatol 2017 Sep-Oct;35 Suppl 106(4):71-74. Epub 2017 Jun 19.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore; and Division of Medical Oncology, Department of Medicine, Johns Hopkins University School of Medicine Baltimore MD, USA.

Objectives: Systemic sclerosis (scleroderma) and dermatomyositis are two prototypic autoimmune diseases that are strongly associated with malignancy. While specific autoantibodies in these diseases are markers of an increased risk of cancer at scleroderma and dermatomyositis onset, it is not known whether these autoantibodies are biomarkers of cancer risk in patients without rheumatic disease.

Methods: In a matched case-control study of women without rheumatic disease, identified from a familial breast cancer cohort, 50 breast cancer cases and 50 controls were assayed for 3 autoantibodies that are known markers of cancer-associated scleroderma and dermatomyositis: anti-RNA polymerase III, anti-NXP2, and anti-TIF1γ.

Results: No subject had moderate or strong autoantibody positivity. Eleven women were borderline positive for at least one autoantibody. The prevalence of borderline autoantibody positivity did not differ between cases and controls.

Conclusions: Our results suggest that scleroderma and dermatomyositis autoantibodies are cancer biomarkers only in patients with clinical manifestations of specific rheumatic diseases and are unlikely to improve risk stratification for cancer in the general population. However, prospective studies are needed to examine whether scleroderma and dermatomyositis autoantibodies are markers of malignancy in other cancer types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947318PMC
December 2017

Association of Fibrosing Myopathy in Systemic Sclerosis and Higher Mortality.

Arthritis Care Res (Hoboken) 2017 11;69(11):1764-1770

Johns Hopkins University School of Medicine, Baltimore, Maryland, and National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH, Bethesda, Maryland.

Objective: To determine if a unique subtype of scleroderma muscle disease exists by comparing the clinical features of systemic sclerosis (SSc; scleroderma) patients with predominant fibrosis on muscle biopsy to those with inflammatory muscle histopathology.

Methods: This retrospective, cross-sectional study included SSc patients with muscle weakness and an available muscle biopsy. Biopsies with fibrosis but without inflammation/necrosis were designated as "fibrosing myopathy," and those with inflammation and/or necrosis were assigned a category of "inflammatory myopathy." Clinical data, including features of SSc, serum creatine kinase (CK) levels, electromyography, autoantibody profile, and survival, were compared between the 2 groups.

Results: The study population consisted of 37 weak SSc patients, 8 with fibrosing myopathy and 29 with inflammatory myopathy. Compared to those with inflammatory myopathy, patients with fibrosing myopathy were more likely to have diffuse SSc skin subtype (87% versus 62%; P = 0.18), African American race (62.5% versus 37.9%; P = 0.20), and a lower mean ± SD forced vital capacity (55.5 ± 31.9 versus 66.4 ± 17.6; P = 0.23). They also had lower mean ± SD CK values (516 ± 391 versus 2,477 ± 3,511 IU/liter; P = 0.007) and lower aldolase values (13.8 ± 4.7 versus 27.3 ± 4.7; P = 0.01). Patients with fibrosing myopathy had a significantly higher mortality (5 of 8 [62.5%] versus 4 of 29 [14.3%]; P = 0.005).

Conclusion: Fibrosing myopathy is a unique histologic subtype of muscle disease among weak patients with SSc and is associated with significantly worse mortality compared to those with inflammation and/or necrosis on muscle biopsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acr.23291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791890PMC
November 2017

Reply.

Arthritis Rheumatol 2017 09 11;69(9):1915-1916. Epub 2017 Jul 11.

Johns Hopkins University School of Medicine, Baltimore, MD.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.40132DOI Listing
September 2017

Brief Report: Anti-RNPC-3 Antibodies As a Marker of Cancer-Associated Scleroderma.

Arthritis Rheumatol 2017 06;69(6):1306-1312

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: Prior studies have demonstrated an increased risk of cancer-associated scleroderma in patients with anti-RNA polymerase III (anti-RNAP III) autoantibodies as well as in patients who are triple-negative for anticentromere (anti-CENP), anti-topoisomerase I (anti-topo I), and anti-RNAP III (also known as anti-POL) autoantibodies (referred to as CTP negative). In a recent study of 16 CTP-negative scleroderma patients with coincident cancer, 25% of the patients were found to have autoantibodies to RNPC-3, a member of the minor spliceosome complex. This investigation was undertaken to validate the relationship between anti-RNPC-3 antibodies and cancer and examine the associated clinical phenotype in a large sample of scleroderma patients.

Methods: Scleroderma patients with cancer were assayed for anti-CENP, anti-topo I, anti-RNAP III, and anti-RNPC-3 autoantibodies. Disease characteristics and the cancer-scleroderma interval were compared across autoantibody groups. The relationship between autoantibody status and cancer-associated scleroderma was assessed by logistic regression.

Results: Of 318 patients with scleroderma and cancer, 70 (22.0%) were positive for anti-RNAP III, 54 (17.0%) were positive for anti-topo I, and 96 (30.2%) were positive for anti-CENP. Twelve patients (3.8% of the overall group or 12.2% of CTP-negative patients) were positive for anti-RNPC-3. Patients with anti-RNPC-3 had a short cancer-scleroderma interval (median 0.9 years). Relative to patients with anti-CENP, patients with anti-RNPC-3 and those with anti-RNAP III had a >4-fold increased risk of cancer within 2 years of scleroderma onset (for anti-RNPC-3-positive patients, odds ratio [OR] 4.3, 95% confidence interval [95% CI] 1.10-16.9 [P = 0.037]; for anti-RNAP III-positive patients, OR 4.49, 95% CI 1.98-10.2 [P < 0.001]). Patients with anti-RNPC-3 had severe restrictive lung disease, gastrointestinal disease, Raynaud's phenomenon, and myopathy.

Conclusion: Anti-RNPC-3 autoantibodies, similar to anti-RNAP III autoantibodies, are associated with an increased risk of cancer at the onset of scleroderma. These data suggest the possibility of cancer-induced autoimmunity in this subset of patients with scleroderma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.40065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449218PMC
June 2017