Development of a computed tomography calcium scoring technique for assessing calcinosis distribution, pattern and burden in dermatomyositis.

OBJECTIVES: To utilize whole-body CT imaging and calcium scoring techniques as tools for calcinosis assessment in a prospective cohort of patients with adult and juvenile dermatomyositis (DM and JDM, respectively). METHODS: Thirty-one patients (14 DM and 17 JDM) who fulfilled Bohan and Peter Classification criteria as probable or definite DM, the EULAR-ACR criteria for definite DM, and with calcinosis identified by physical examination or prior imaging studies were included. Non-contrast whole-body CT scans were obtained using low-dose radiation procedures. Scans were read qualitatively and quantitated. We calculated the sensitivity and specificity of calcinosis detection of physician physical exam against CT. We quantified calcinosis burden using the Agatston scoring technique. RESULTS: We identified five distinct calcinosis patterns: Clustered, Disjoint, Interfascial, Confluent and Fluid-filled. Novel locations of calcinosis were observed, including the cardiac tissue, pelvic and shoulder bursa, and the spermatic cord. Quantitative measures using Agatston scoring for calcinosis were used in regional distributions across the body. Physician physical exams had a sensitivity of 59% and a specificity of 90% compared with CT detection. A higher calcium score correlated with higher Physician Global Damage, Calcinosis Severity scores, and disease duration. CONCLUSION: Whole-body CT scans and the Agatston scoring metric define distinct calcinosis patterns and provide novel insights relating to calcinosis in DM and JDM patients. Physicians' physical examinations underrepresented the presence of calcium. Calcium scoring of CT scans correlated with clinical measures, which suggests that this method may be used to assess calcinosis and follow its progression.

Anti-dense fine speckled 70 (DFS70) autoantibodies: correlates and increasing prevalence in the United States.

Objective: Recent studies report high-titer anti-dense fine speckled 70 (DFS70) autoantibodies in persons with inflammatory conditions, but the clinical significance remains unclear. Our goals were to estimate anti-DFS70 autoantibody prevalence, identify correlates, and assess time trends. Methods: Serum antinuclear antibodies (ANA) were measured by indirect immunofluorescence assay on HEp-2 cells in 13,519 participants ≥12 years old from three time periods (1988-1991, 1999-2004, 2011-2012) of the National Health and Nutrition Examination Survey. ANA-positive participants with dense fine speckled staining were evaluated for anti-DFS70 antibodies by enzyme-linked immunosorbent assay. We used logistic models adjusted for survey-design variables to estimate period-specific anti-DFS70 antibody prevalence in the US, and we further adjusted for sex, age, and race/ethnicity to identify correlates and assess time trends. Results: Women were more likely than men (odds ratio (OR)=2.97), black persons were less likely than white persons (OR=0.60), and active smokers were less likely than nonsmokers (OR=0.28) to have anti-DFS70 antibodies. The prevalence of anti-DFS70 antibodies increased from 1.6% in 1988-1991 to 2.5% in 1999-2004 to 4.0% in 2011-2012, which corresponds to 3.2 million, 5.8 million, and 10.4 million seropositive individuals, respectively. This increasing time trend in the US population (P<0.0001) was modified in some subgroups and was not explained by concurrent changes in tobacco smoke exposure. Some, but not all, anti-DFS70 antibody correlates and time trends resembled those reported for total ANA. Conclusion: More research is needed to elucidate anti-DFS70 antibody triggers, their pathologic or potentially protective influences on disease, and their possible clinical implications.

Shared and Distinctive Transcriptomic and Proteomic Pathways in Adult and Juvenile Dermatomyositis.

OBJECTIVE: Transcript and protein expression were interrogated to examine gene locus and pathway regulation in the peripheral blood of active adult dermatomyositis (DM) and juvenile DM patients receiving immunosuppressive therapies. METHODS: Expression data from 14 DM and 12 juvenile DM patients were compared to matched healthy controls. Regulatory effects at the transcript and protein level were analyzed by multi-enrichment analysis for assessment of affected pathways within DM and juvenile DM. RESULTS: Expression of 1,124 gene loci were significantly altered at the transcript or protein levels across DM or juvenile DM, with 70 genes shared. A subset of interferon-stimulated genes was elevated, including CXCL10, ISG15, OAS1, CLEC4A, and STAT1. Innate immune markers specific to neutrophil granules and neutrophil extracellular traps were up-regulated in both DM and juvenile DM, including BPI, CTSG, ELANE, LTF, MPO, and MMP8. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling, whose central components were broadly up-regulated in DM, while peripheral upstream and downstream components were differentially regulated in both DM and juvenile DM. Up-regulated components shared by DM and juvenile DM included cytokine:receptor pairs LGALS9:HAVCR2, LTF/NAMPT/S100A8/HSPA1A:TLR4, CSF2:CSF2RA, EPO:EPOR, FGF2/FGF8:FGFR, several Bcl-2 components, and numerous glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling. CONCLUSION: The combination of proteomics and transcript expression by multi-enrichment analysis broadened the identification of up- and down-regulated pathways among active DM and juvenile DM patients. These pathways, particularly those which feed into PI3K/AKT and MAPK signaling and neutrophil degranulation, may be potential therapeutic targets.

Autoantibodies Recognizing Specificity Protein 4 Co-occur With Anti-Transcription Intermediary Factor 1 and Are Associated With Distinct Clinical Features and Immunogenetic Risk Factors in Juvenile Myositis.

OBJECTIVE: Autoantibodies recognizing specificity protein 4 (Sp4) were recently discovered in adults with idiopathic inflammatory myopathies (IIM). Anti-Sp4 autoantibodies co-occurred in patients with anti-transcription intermediary factor 1 (anti-TIF1) autoantibody-positive dermatomyositis (DM) and were associated with a reduced risk of cancer. In the present study, the prevalence and clinical features associated with anti-Sp4 autoantibodies in juvenile-onset IIM were investigated. METHODS: Serum samples from 336 patients with juvenile myositis in a cross-sectional cohort and 91 healthy controls were screened for anti-Sp4 autoantibodies using enzyme-linked immunosorbent assay. Clinical characteristics, outcomes, and HLA alleles of those with and those without anti-Sp4 autoantibodies were compared. RESULTS: Anti-Sp4 autoantibodies were present in 23 patients (7%) with juvenile myositis and were not present in any of the controls. Anti-Sp4 autoantibodies were found among each clinical myositis subgroup. The frequency of TIF1 autoantibody positivity was significantly higher among those with anti-Sp4 autoantibodies (21 [91%] versus 92 [30%], P < 0.001). In the anti-TIF1 autoantibody-positive subgroup, Raynaud's phenomenon (8 [38%] versus 2 [2%], P < 0.001) was more common and peak aspartate aminotransferase was significantly lower in those with anti-Sp4 autoantibodies. None of the patients with anti-Sp4 autoantibodies required a wheelchair. Among White patients, DQA1*04 and DRB1*08 were associated with anti-Sp4 autoantibodies. CONCLUSION: Anti-Sp4 autoantibodies were found in patients with juvenile-onset IIM, predominantly those with coexisting anti-TIF1 autoantibodies. Patients with anti-Sp4 autoantibodies represent a phenotypic subset of anti-TIF1 autoantibody-positive myositis characterized by frequent Raynaud's phenomenon and less pronounced muscle involvement, similar to adults with these autoantibodies. Novel immunogenetic risk factors for White patients with IIM were identified among juveniles with anti-Sp4 autoantibodies.

A novel estrogen receptor 1: sphingomyelin phosphodiesterase acid-like 3B pathway mediates rituximab response in myositis patients.

OBJECTIVES: The B-cell depleting biologic, rituximab, is used to treat refractory autoimmune myositis. However, the beneficial effects of rituximab appear to outweigh the known contribution of B cells in myositis. We aimed to elucidate how myositis patients respond differently to rituximab and possible alternative mechanisms of action. METHODS: Here we have: (i) comprehensively investigated concurrent mRNA and microRNA expression in muscle biopsies taken at baseline and 16 weeks post treatment in 10 patients who were part of the rituximab in myositis (RIM) trial; and (ii) investigated the beneficial effect of rituximab on myositis muscle cells. RESULTS: Our analyses identified an increased number of changes in gene expression in biopsies from patients who had a clinical response to rituximab (n = 5) compared with non-responders (n = 5). The two groups had completely different changes in microRNA and mRNA expression following rituximab therapy, with the exception of one mRNA, BHMT2. Networks of mRNA and microRNA with opposite direction of expression changes highlighted ESR1 as upregulated in responders. We confirmed ESR1 upregulation upon rituximab treatment of immortalized myotubes and primary human dermatomyositis muscle cells in vitro, demonstrating a direct effect of rituximab on muscle cells. Notably, despite showing a response to rituximab, human dermatomyositis primary muscle cells did not express the rituximab target, CD20. However, these cells expressed a possible alternative target of rituximab, sphingomyelinase-like phosphodiesterase 3 b (SMPDL3B). CONCLUSION: In addition to B-cell depletion, rituximab may be beneficial in myositis due to increased ESR1 signalling mediated by rituximab binding to SMPDL3B on skeletal muscle cells.

Increasing Prevalence of Antinuclear Antibodies in the United States.

OBJECTIVE: Growing evidence suggests increasing frequencies of autoimmunity and autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. This study was undertaken to investigate whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25-year span in the US. METHODS: Serum ANA were measured by standard indirect immunofluorescence assays on HEp-2 cells in 13,519 participants age ≥12 years from the National Health and Nutrition Examination Survey, with approximately one-third from each of 3 time periods: 1988-1991, 1999-2004, and 2011-2012. We used logistic regression adjusted for sex, age, race/ethnicity, and survey design variables to estimate changes in ANA prevalence across the time periods. RESULTS: The prevalence of ANA was 11.0% (95% confidence interval [95% CI] 9.7-12.6%) in 1988-1991, 11.4% (95% CI 10.2-12.8%) in 1999-2004, and 16.1% (95% CI 14.4-18.0%) in 2011-2012 (P for trend <0.0001), corresponding to ~22.3 million, ~26.6 million, and ~41.5 million affected individuals, respectively. Among adolescents age 12-19 years, ANA prevalence increased substantially, with odds ratios of 2.07 (95% CI 1.18-3.64) and 2.77 (95% CI 1.56-4.91) in the second and third time periods relative to the first (P for trend = 0.0004). ANA prevalence increased in both sexes (especially in men), older adults (age ≥50 years), and non-Hispanic white individuals. These increases in ANA prevalence were not explained by concurrent trends in weight (obesity/overweight), smoking exposure, or alcohol consumption. CONCLUSION: The prevalence of ANA in the US has increased considerably in recent years. Additional studies to determine factors underlying these increases in ANA prevalence could elucidate causes of autoimmunity and enable the development of preventative measures.

Expanded assessment of xenobiotic associations with antinuclear antibodies in the United States, 1988-2012.

BACKGROUND: The prevalence of autoimmunity in the U.S. has increased recently for undetermined reasons. Little is known about associations between autoimmunity and environmental causes. OBJECTIVES: In a large representative sample of the U.S. population, we expanded our prior exploratory study of how exposures to selected xenobiotics and dioxin-like (DL) mixtures relate to antinuclear antibodies (ANA), the most common biomarker of autoimmunity. METHODS: We analyzed cross-sectional data on 12,058 participants aged ≥ 12 years from three time periods of the National Health and Nutrition Examination Survey between 1988 and 2012, of whom 14% were ANA-positive. We used lognormal regression models and censored-data methods to estimate ANA associations with xenobiotic concentrations overall and in sex, age, and race/ethnicity subgroups. Our analyses adjusted for potential confounders and appropriately handled concentrations below detection limits. RESULTS: Observed ANA associations were positive for most DL compounds and nonDL polychlorinated biphenyls (PCBs), negative for most phthalates, and mixed for other xenobiotic classes. After correcting for multiple comparisons, some associations remained statistically significant. In subgroup analyses, the most significant finding was a positive ANA association with N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (MHB2) in males, followed by positive associations with 2,2',3,5'-tetrachlorobiphenyl (PCB 44), 2,2',4,5'-tetrachlorobiphenyl (PCB 49), and 2,2',3,4',5',6-hexachlorobiphenyl (PCB 149) in 12-19 year-olds, and with 3,4,4',5-tetrachlorobiphenyl (PCB 81), 2,2',3,3',4,4',5,5',6-nonachlorobiphenyl (PCB 206), and N-acetyl-S-(phenyl)-L-cysteine (PMA) in Mexican Americans. Negative associations were found with mono-benzyl phthalate (MBzP) in 20-49 year-olds and mono-n-butyl phthalate (MnBP) in 12-19 year-olds. In overall analyses, combining stratum-specific results across race/ethnicity strata revealed a positive ANA association with PCB 81 and a negative ANA association with N-acetyl-S-(2-hydroxyethyl)-L-cysteine (HEMA). DISCUSSION: This study identified potential associations between ANA and various xenobiotics. Further investigation to confirm these observations and elucidate effects of certain xenobiotics on immune regulation could have important mechanistic, preventive, and treatment implications for a variety of immune-mediated disorders.

Defining anti-synthetase syndrome: a systematic literature review.

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

Whole genome sequencing of low input circulating cell-free DNA obtained from normal human subjects.

Cell-free DNA circulates in plasma at low levels as a normal by-product of cellular apoptosis. Multiple clinical pathologies, as well as environmental stressors can lead to increased circulating cell-free DNA (ccfDNA) levels. Plasma DNA studies frequently employ targeted amplicon deep sequencing platforms due to limited concentrations (ng/ml) of ccfDNA in the blood. Here, we report whole genome sequencing (WGS) and read distribution across chromosomes of ccfDNA extracted from two human plasma samples from normal, healthy subjects, representative of limited clinical samples at <1 ml. Amplification was sufficiently robust with ~90% of the reference genome (GRCh38.p2) exhibiting 10X coverage. Chromosome read coverage was uniform and directly proportional to the number of reads for each chromosome across both samples. Almost 99% of the identified genomic sequence variants were known annotated dbSNP variants in the hg38 reference genome. A high prevalence of C>T and T>C mutations was present along with a strong concordance of variants shared between the germline genome databases; gnomAD (81.1%) and the 1000 Genome Project (93.6%). This study demonstrates isolation and amplification procedures from low input ccfDNA samples that can detect sequence variants across the whole genome from amplified human plasma ccfDNA that can translate to multiple clinical research disciplines.

Accumulation of autophagosome cargo protein p62 is common in idiopathic inflammatory myopathies.

OBJECTIVES: The subsarcolemmal accumulation of p62 aggregates in myofibres has been proposed to be characteristic of sporadic inclusion body myositis (sIBM). The objective of this study was to analyse the patterns and prevalence of p62 immunostaining and to quantitate p62 gene expression in muscle biopsies from a large number of patients with different types of myopathic and neurogenic disorders. METHODS: For the p62 immunostaining analysis, all patients with a muscle biopsy immunostained for p62 at the Johns Hopkins Neuromuscular Pathology Laboratory from 2013 to 2017 were included (n=303). The prevalence and pattern of p62 immunostaining were compared between patients with histologically normal muscle (n=29), inflammatory myopathies (n=136), non-inflammatory myopathies (n=53), and neurogenic disorders (n=85). p62 expression levels were analysed using an existing RNAseq dataset including data from dermatomyositis (DM; n=39), immune-mediated necrotising myopathy (IMNM; n=49), antisynthetase syndrome (AS; n=18), and sIBM (n=23) patients as well as 20 histologically normal muscle biopsies. RESULTS: p62 staining was absent in normal biopsies, but present in biopsies from those with polymyositis (29%), non-inflammatory myopathies (all <31%), neurogenic disorders (31%), dermatomyositis (57%), sIBM (92%) and IMNM (87%). In all diseases studied, p62 accumulation was more prevalent in biopsies with more severe muscle damage. sIBM biopsies had decreased p62 expression levels compared to the other groups (corrected p<0.04). CONCLUSIONS: p62 accumulation is a general response to muscle injury and not a specific marker for sIBM. Also, in sIBM, p62 RNA levels are decreased, suggesting that, in this disease, p62 aggregation is not due to overexpression.

Anti-MDA5 autoantibodies associated with juvenile dermatomyositis constitute a distinct phenotype in North America.

OBJECTIVE: Myositis-specific autoantibodies have defined distinct phenotypes of patients with juvenile myositis (JIIM). We assessed the frequency and clinical significance of anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-associated JIIM in a North American registry. METHODS: Retrospective examination of the characteristics of 35 JIIM patients with anti-MDA5 autoantibodies was performed, and differences from other myositis-specific autoantibody groups were evaluated. RESULTS: Anti-MDA5 autoantibodies were present in 35/453 (7.7%) of JIIM patients and associated with older age at diagnosis, and lower serum creatine kinase and aldolase levels. Patients with anti-MDA5 autoantibodies had more frequent weight loss, adenopathy, arthritis, interstitial lung disease (ILD), and less frequent falling compared with anti-transcriptional intermediary factor 1 (TIF1), anti-nuclear matrix protein 2 (NXP2) and myositis-specific autoantibody/myositis-associated autoantibody-negative patients. They had a different season of diagnosis and less frequent mechanic's hands and ILD compared with those with anti-synthetase autoantibodies. Anti-MDA5 patients received fewer medications compared with anti-TIF1, and corticosteroid treatment was shorter compared with anti-TIF1 and anti-nuclear matrix protein 2 autoantibody groups. The frequency of remission was higher in anti-MDA5 than anti-synthetase autoantibody-positive JIIM. In multivariable analyses, weight loss, arthritis and arthralgia were most strongly associated with anti-MDA5 autoantibody-positive JIIM. CONCLUSION: Anti-MDA5 JIIM is a distinct subset, with frequent arthritis, weight loss, adenopathy and less severe myositis, and is also associated with ILD. Anti-MDA5 is distinguished from anti-synthetase autoantibody-positive JIIM by less frequent ILD, lower creatine kinase levels and differing seasons of diagnosis. Anti-MDA5 has comparable outcomes, but with the ability to discontinue steroids more rapidly and less frequent flares compared with anti-TIF1 autoantibodies, and more frequent remission compared with anti-synthetase JIIM patients.

Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis.

OBJECTIVES: Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM. METHODS: RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis. RESULTS: The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM. CONCLUSIONS: Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.

Increasing Prevalence of Antinuclear Antibodies in the United States.

OBJECTIVE: Growing evidence suggests increasing frequencies of autoimmunity and certain autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. This study was undertaken to investigate whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25-year span in the US. METHODS: Serum ANA were measured by standard indirect immunofluorescence assays on HEp-2 cells in 14,211 participants age ≥12 years from the National Health and Nutrition Examination Survey, with approximately one-third from each of 3 time periods: 1988-1991, 1999-2004, and 2011-2012. We used logistic regression adjusted for sex, age, race/ethnicity, and survey design variables to estimate changes in ANA prevalence across the time periods. RESULTS: The prevalence of ANA was 11.0% (95% confidence interval [95% CI] 9.7-12.6%) in 1988-1991, 11.5% (95% CI 10.3-12.8%) in 1999-2004, and 15.9% (95% CI 14.3-17.6%) in 2011-2012 (P for trend < 0.0001), which corresponds to ~22 million, ~27 million, and ~41 million affected individuals, respectively. Among adolescents age 12-19 years, ANA prevalence increased substantially, with odds ratios (ORs) of 2.02 (95% CI 1.16-3.53) and 2.88 (95% CI 1.64-5.04) in the second and third time periods relative to the first (P for trend < 0.0001). ANA prevalence increased in both sexes (especially in men), older adults (age ≥50 years), and non-Hispanic whites. These increases in ANA prevalence were not explained by concurrent trends in weight (obesity/overweight), smoking exposure, or alcohol consumption. CONCLUSION: The prevalence of ANA in the US has increased considerably in recent years. Additional studies to determine factors underlying these increases in ANA prevalence could elucidate causes of autoimmunity and enable the development of preventative measures.

Long-term outcomes in Juvenile Myositis patients.

OBJECTIVE: Juvenile idiopathic inflammatory myopathies (JIIM) are rare, chronic autoimmune muscle diseases of childhood, with the potential for significant morbidity. Data on long-term outcomes is limited. In this study we investigate correlations between clinical and demographic features with long-term outcomes in a referral population of adult patients with JIIM. METHODS: Forty-nine adults with JIIM were assessed at two referral centers between 1994 and 2016. Features of active disease and damage at a cross-sectional assessment were obtained. Regression modeling was used to examine factors associated with long-term outcomes, defined by the presence of calcinosis or a higher adjusted Myositis Damage Index (MDI) score. A multivariable model of MDI was constructed using factors that were statistically significant in bivariate models. RESULTS: At a median of 11.5 [IQR 4.5-18.9] years following diagnosis, median American College of Rheumatology (ACR) functional class was 2 [1.5-3.0], Health Assessment Questionnaire (HAQ) score was 0.4 out of 3.0 [0.0-1.0], and manual muscle testing (MMT) score was 229 out of 260 [212.6-256.8]. Median MDI score was 6.0 [3.5-8.9], with the most commonly damaged organ systems being cutaneous and musculoskeletal. Factors associated with an elevated MDI score were the presence of erythroderma and other cutaneous manifestations, disease duration, and ACR functional class. Calcinosis was present in 55% of patients. The strongest predictors of calcinosis were disease duration, periungual capillary changes, and younger age at diagnosis. CONCLUSION: In a tertiary referral population, long-term functional outcomes of JIIM are generally favorable, with HAQ scores indicative of mild disability. Although most patients had mild disease activity and virtually all had significant disease damage, severe or systemic damage was rare. Certain clinical features are associated with long-term damage and calcinosis.

Association of Ultraviolet Radiation Exposure With Dermatomyositis in a National Myositis Patient Registry.

OBJECTIVE: Dermatomyositis (DM) has been associated with geospatial differences in ultraviolet (UV) radiation, but the role of individual determinants of UV exposure prior to diagnosis is unknown. The objective was to examine the role of those individual determinants. METHODS: We analyzed questionnaire data from 1,350 adults in a US national myositis registry (638 with DM, 422 with polymyositis [PM], and 290 with inclusion body myositis [IBM] diagnosed at ages 18-65 years), examining the likelihood of DM compared with PM and IBM diagnosis, in relation to self-reported sunburn history and job- and hobby-related sun exposures in the year prior to diagnosis. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression adjusted for age, skin tone, and sex, to determine the association of individual UV exposures with DM diagnosis. We also evaluated the proportion of DM by maximum daily ambient UV exposure, based on UVB erythemal irradiances for participant residence in the year prior to diagnosis. RESULTS: DM was associated with sunburn in the year before diagnosis (2 or more sunburns OR 1.77 [95% CI 1.28-2.43] versus PM/IBM; 1 sunburn OR 1.44 [95% CI 1.06-1.95]) and with having elevated job- or hobby-related sun exposure (high exposure OR 1.64 [95% CI 1.08-2.49] or moderate exposure OR 1.35 [95% CI 1.02-1.78] versus low or no exposure). Ambient UV intensity was associated with DM in females (ß = 3.97, P = 0.046), but not overall. CONCLUSION: Our findings suggest that high or moderate personal exposure to intense sunlight is associated with developing DM compared with other types of myositis. Prospective research on UV exposure as a modifiable risk factor for DM is warranted.

Identification of distinctive interferon gene signatures in different types of myositis.

OBJECTIVE: Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies. METHODS: The expression of IFN1- and IFN2-inducible genes was compared between the different groups. RESULTS: The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies. CONCLUSIONS: IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.

Prescription medication use and antinuclear antibodies in the United States, 1999-2004.

BACKGROUND: Clinical reports link specific medications with the development of antinuclear antibodies (ANA), but population-based evidence is limited. OBJECTIVE: The present study investigated associations between prescription medication use and ANA in a representative sample of the adult noninstitutionalized US population, first focusing on medications previously related to ANA and then considering all medications reported in the National Health and Nutrition Examination Survey (NHANES). METHODS: Based on NHANES data (1999-2004) for 3608 adults (ages ≥18 years), we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess associations between recent medication use and ANA (overall and in sex and age subgroups), adjusted for potential confounders and the survey sampling design. RESULTS: We found no evidence that most medications previously associated with ANA in specific individuals were risk factors for ANA in the general population, although statistical power was limited for some medications. Overall, ANA were less prevalent in adults who recently used any prescription medications compared with those who did not (OR = 0.73; CI = 0.57,0.93), and likewise several classes of medications were inversely associated with ANA, including hormones (OR = 0.73; CI = 0.55,0.98), thiazide diuretics (OR = 0.43; CI = 0.24,0.79), sulfonylureas (OR = 0.41; CI = 0.19,0.89), and selective serotonin reuptake inhibitor antidepressants (OR = 0.65; CI = 0.42,0.98). Positive associations with ANA were seen for loop diuretics (OR = 1.72; CI = 1.03,2.88) in all adults, and for benzodiazepines (OR = 2.11; CI = 1.09,4.10) and bronchodilators (OR = 1.83; CI = 1.00,3.38) in older (ages ≥60) adults. Estrogens were positively associated with ANA in older women (OR = 1.80; CI = 1.00,3.23) but inversely associated with ANA in younger (ages 18-59) women (OR = 0.43; CI = 0.20,0.93). Regarding individual medications, ANA were positively associated with ciprofloxacin (OR = 4.23; CI = 1.21,14.8), furosemide (OR = 1.79; CI = 1.09,2.93), and omeprazole (OR = 2.05; CI = 1.03,4.10) in all adults, and with salmeterol (OR = 3.76; CI = 1.66,8.52), tolterodine (OR = 6.64; CI = 1.45,30.5), and triamterene (OR = 3.10; CI = 1.08,8.88) in older adults. Also, in younger adults, hydrochlorothiazide was inversely associated with ANA (OR = 0.44; CI = 0.20,0.98). CONCLUSIONS: Our findings in the general population do not confirm most clinically reported positive associations between specific medications and ANA in some individuals. However, novel positive ANA associations with other medications, as well as unexplained inverse associations with certain classes of medications and overall medication use, deserve further research to clarify the possible roles of medications as risk and protective factors in the development of autoantibodies and autoimmune disease.

The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis.

OBJECTIVE: Cigarette smoking is associated with immune-mediated disorders. We explored the contribution of smoking to polymyositis (PM) and dermatomyositis (DM) phenotypes and attempted to determine whether cigarette smoking effects differ by race and genotype. METHODS: Associations of tobacco smoking with disease features, autoantibodies, HLA types, and race were evaluated using multiple logistic regressions in 465 patients. RESULTS: Caucasian ever-smokers (n = 140) were more likely to have PM (adjusted OR = 2.24, 95% CI: 1.41\x963.57), anti-synthetase (adjusted OR = 1.93, 95% CI: 1.12\x963.34) and anti-Jo-1 autoantibodies (adjusted OR = 1.94, 95% CI: 1.08\x963.46) and less likely to have anti-p155/140 autoantibodies (adjusted OR = 0.36, 95% CI: 0.14\x960.92). In Caucasians, ever-smokers had a greater interstitial lung disease (ILD) frequency than never-smokers, while in African-Americans this relationship was inverted, but neither trend reached statistical significance. Pack-years of cigarette smoking showed significant positive associations with PM (adjusted OR = 1.02, 95% CI: 1.002\x961.04) and ILD (adjusted OR = 1.02, 95% CI: 1.001\x961.03) and was inversely associated with anti-p155/140 autoantibodies (adjusted OR = 0.93, 95% CI: 0.87\x960.99) in Caucasians. Caucasian heavy smokers (=20 pack-years) were more likely to have PM (adjusted OR = 2.52, 95% CI: 1.25\x965.09), ILD (adjusted OR = 2.48, 95% CI: 1.23\x965.00) and anti-Jo-1 autoantibodies (adjusted OR = 2.65, 95% CI: 1.16\x966.08) than never-smokers. In Caucasians, compared to never-smokers without HLA-DRB1*03:01 allele, ever-smokers with HLA-DRB1*03:01 allele had the highest odds of PM, ILD, ASA, and anti-Jo-1 autoantibodies. Risks for those with only one of these two factors were intermediate. An inverse pattern was observed regarding anti-p155/140 autoantibodies. CONCLUSION: Tobacco smoking was associated with clinical and autoantibody phenotypes in Caucasians. Our findings also suggest possible interactions among HLA-DRB1*03:01 and smoking on the risk of PM and ILD, as well as, anti-synthetase, anti-Jo-1, and anti-p155/140 autoantibodies in Caucasians.

Risk factors and disease mechanisms in myositis.

Autoimmune diseases develop as a result of chronic inflammation owing to interactions between genes and the environment. However, the mechanisms by which autoimmune diseases evolve remain poorly understood. Newly discovered risk factors and pathogenic processes in the various idiopathic inflammatory myopathy (IIM) phenotypes (known collectively as myositis) have illuminated innovative approaches for understanding these diseases. The HLA 8.1 ancestral haplotype is a key risk factor for major IIM phenotypes in some populations, and several genetic variants associated with other autoimmune diseases have been identified as IIM risk factors. Environmental risk factors are less well studied than genetic factors but might include viruses, bacteria, ultraviolet radiation, smoking, occupational and perinatal exposures and a growing list of drugs (including biologic agents) and dietary supplements. Disease mechanisms vary by phenotype, with evidence of shared innate and adaptive immune and metabolic pathways in some phenotypes but unique pathways in others. The heterogeneity and rarity of the IIMs make advancements in diagnosis and treatment cumbersome. Novel approaches, better-defined phenotypes, and international, multidisciplinary consensus have contributed to progress, and it is hoped that these methods will eventually enable therapeutic intervention before the onset or major progression of disease. In the future, preemptive strategies for IIM management might be possible.

2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as "possible IIM." CONCLUSION: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.