The American College of Rheumatology White Paper: The Effects of Climate Change on Rheumatic Conditions - An Evolving Landscape and a Path Forward.

BACKGROUND: Increases in global temperatures and extreme weather events associated with climate change have complex yet poorly understood detrimental impacts on human health. We reviewed the current published literature on climate change-related effects and rheumatic conditions. METHODS: To summarize our current understanding of the likely effects of climate change, including increased air pollution, on rheumatic disease, we searched the published, peer-reviewed English-language literature from January 2000-December 2022. Articles were reviewed by a team of rheumatologists and clinical and translational science researchers. Systematic review articles were not included but informed additional literature searches. RESULTS: After extensive examination and adjudication, 88 articles met inclusion criteria and were selected for review. Much of the epidemiologic investigations assessed associations between air pollution and increased risk of development of rheumatoid arthritis, anti-citrullinated protein antibodies, flares of gout and hospitalizations for systemic lupus erythematosus. Increased heat vulnerability was associated with higher odds of recurrent hospitalizations across rheumatic conditions. Mechanisms for observed associations are poorly understood but could include the effects of epigenetic changes, oxidative stress, and inflammatory cytokines. Studies had limitations including restricted geography and populations studied without focus on historically marginalized communities at highest risk for adverse effects from pollution and climate change, the relative lack of mechanistic evaluations, and most with only indirect links to climate change. CONCLUSIONS: To date, the published literature lacks studies that directly examine effects of climate change on rheumatic diseases. Collaborative translational and epidemiologic research is needed to enhance our understanding and awareness in this area.

Performance of the 2017 EULAR/ACR Classification Criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a scoping review.

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

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.

Race/ethnicity-stratified fine-mapping of the MHC locus reveals genetic variants associated with late-onset asthma.

Introduction: Asthma is a chronic disease of the airways that impairs normal breathing. The etiology of asthma is complex and involves multiple factors, including the environment and genetics, especially the distinct genetic architecture associated with ancestry. Compared to early-onset asthma, little is known about genetic predisposition to late-onset asthma. We investigated the race/ethnicity-specific relationship among genetic variants within the major histocompatibility complex (MHC) region and late-onset asthma in a North Carolina-based multiracial cohort of adults. Methods: We stratified all analyses by self-reported race (i.e., White and Black) and adjusted all regression models for age, sex, and ancestry. We conducted association tests within the MHC region and performed fine-mapping analyses conditioned on the race/ethnicity-specific lead variant using whole-genome sequencing (WGS) data. We applied computational methods to infer human leukocyte antigen (HLA) alleles and residues at amino acid positions. We replicated findings in the UK Biobank. Results: The lead signals, rs9265901 on the 5' end of HLA-B, rs55888430 on HLA-DOB, and rs117953947 on HCG17, were significantly associated with late-onset asthma in all, White, and Black participants, respectively (OR = 1.73, 95%CI: 1.31 to 2.14, p = 3.62 × 10-5; OR = 3.05, 95%CI: 1.86 to 4.98, p = 8.85 × 10-6; OR = 19.5, 95%CI: 4.37 to 87.2, p = 9.97 × 10-5, respectively). For the HLA analysis, HLA-B*40:02 and HLA-DRB1*04:05, HLA-B*40:02, HLA-C*04:01, and HLA-DRB1*04:05, and HLA-DRB1*03:01 and HLA-DQB1 were significantly associated with late-onset asthma in all, White, and Black participants. Conclusion: Multiple genetic variants within the MHC region were significantly associated with late-onset asthma, and the associations were significantly different by race/ethnicity group.

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.

Inflammatory Bowel Disease Prevalence: Surveillance data from the U.S. National Health and Nutrition Examination Survey.

Determining the overall US prevalence of Inflammatory Bowel Disease (IBD) is essential to national level prevention programs and population risk assessment; however currently US IBD prevalence remains uncertain. We used US National Health and Nutrition Examination Survey (NHANES) data to estimate the population-based prevalence of a self-reported history of medically diagnosed IBD, comparing to prior reports. Lifetime IBD prevalence for adults aged 20 + years was estimated in the independently conducted NHANES II (1976-80) and NHANES 2009-10 surveys. Participants were considered to have IBD if they reported being told by a physician they had Crohn's Disease (CD) or ulcerative colitis (UC). Clinically relevant NHANES data were analyzed to assess the self-reports. Survey design variables and sample weights were used to account for the complex survey design. The NHANES 2009-10 US IBD diagnosed prevalence was 1.2% (95% CI 0.8,1.6%), or an estimated 2.3 million persons. UC prevalence was 1.0% (95% CI 0.5,1.4%; 1.9 million persons) and CD prevalence was 0.3% (95% CI 0.1,0.4%; 578,000 persons). NHANES II UC prevalence was 1.0 (95% CI 0.8,1.2%), similar to 2009-10. UC prevalence was higher for ages ≥ 50 years in both surveys. NHANES 2009-10 data showed no UC sex differences, but women had higher UC prevalence in NHANES II. Remarkably, UC prevalence was similar between the two NHANES surveys fielded 30 years apart. The NHANES data are consistent with IBD prevalences reported in previous US nationally representative surveys, indicating that diagnosed IBD may affect approximately 1% of the US adult population.

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.

Performance of the 2016 ACR-EULAR myositis response criteria in juvenile dermatomyositis therapeutic trials and consensus profiles.

OBJECTIVES: The 2016 ACR-EULAR Response Criteria for JDM was developed as a composite measure with differential weights of six core set measures (CSMs) to calculate a Total Improvement Score (TIS). We assessed the contribution of each CSM, representation of muscle-related and patient-reported CSMs towards improvement, and frequency of CSM worsening across myositis response criteria (MRC) categories in validation of MRC. METHODS: Data from JDM patients in the Rituximab in Myositis trial (n = 48), PRINTO JDM trial (n = 139), and consensus patient profiles (n = 273) were included. Observed vs expected CSM contributions were compared using Sign test. Characteristics of MRC categories were compared by Wilcoxon tests with Bonferroni adjustment. Spearman correlation of changes in TIS and individual CSMs were examined. Agreement between physician-assessed change and MRC categories was evaluated by weighted Cohen's kappa. RESULTS: Of 457 JDM patients with IMACS CSMs and 380 with PRINTO CSMs, 9-13% had minimal, 19-23% had moderate and 41-50% had major improvement. The number of improved and absolute percentage change of CSMs increased by MRC improvement level. Patients with minimal improvement by MRC had a median of 0-1 CSM worsened, and those with moderate/major improvement had a median of zero worsening CSMs. Of patients improved by MRC, 94-95% had improvement in muscle strength and 93-95% had improvement in ≥1 patient-reported CSM. IMACS and PRINTO CSMs performed similarly. Physician-rated change and MRC improvement categories had moderate-to-substantial agreement (Kappa 0.5-0.7). CONCLUSION: The ACR-EULAR MRC perform consistently across multiple studies, supporting its further use as an efficacy end point in JDM trials.

Performance of the 2016 ACR-EULAR Myositis Response Criteria in adult dermatomyositis/polymyositis therapeutic trials and consensus profiles.

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

The increasing prevalence of autoimmunity and autoimmune diseases: an urgent call to action for improved understanding, diagnosis, treatment, and prevention.

Autoimmunity is characterized by self-reactive immune components and autoimmune disease by autoimmunity plus pathology. Both autoimmunity and autoimmune diseases are dramatically increasing in many parts of the world, likely as a result of changes in our exposures to environmental factors. Current evidence implicates the momentous alterations in our foods, xenobiotics, air pollution, infections, personal lifestyles, stress, and climate change as causes for these increases. Autoimmune diseases have a major impact on the individuals and families they affect, as well as on our society and healthcare costs, and current projections suggest they may soon take their place among the predominant medical disorders. This necessitates that we increase the scope and scale of our efforts, and coordinate our resources and studies, to understand autoimmune disease risk factors and pathogeneses and improve our diagnostic, therapeutic, and preventive approaches, as the costs of inaction will be profound and far greater without such investments.

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation.

OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

Association of distance to swine concentrated animal feeding operations with immune-mediated diseases: An exploratory gene-environment study.

BACKGROUND: Concentrated animal feeding operations (CAFOs) are a source of environmental pollution and have been associated with a variety of health outcomes. Immune-mediated diseases (IMD) are characterized by dysregulation of the normal immune response and, while they may be affected by gene and environmental factors, their association with living in proximity to a CAFO is unknown. OBJECTIVES: We explored gene, environment, and gene-environment (GxE) relationships between IMD, CAFOs, and single nucleotide polymorphisms (SNPs) of prototypical xenobiotic response genes AHR, ARNT, and AHRR and prototypical immune response gene PTPN22. METHODS: The exposure analysis cohort consisted of 6,464 participants who completed the Personalized Environment and Genes Study Health and Exposure Survey and a subset of 1,541 participants who were genotyped. We assessed the association between participants' residential proximity to a CAFO in gene, environment, and GxE models. We recombined individual associations in a transethnic model using METAL meta-analysis. RESULTS: In White participants, ARNT SNP rs11204735 was associated with autoimmune diseases and rheumatoid arthritis (RA), and ARNT SNP rs1889740 was associated with RA. In a transethnic genetic analysis, ARNT SNPs rs11204735 and rs1889740 and PTPN22 SNP rs2476601 were associated with autoimmune diseases and RA. In participants living closer than one mile to a CAFO, the log-distance to a CAFO was associated with autoimmune diseases and RA. In a GxE interaction model, White participants with ARNT SNPs rs11204735 and rs1889740 living closer than eight miles to a CAFO had increased odds of RA and autoimmune diseases, respectively. The transethnic model revealed similar GxE interactions. CONCLUSIONS: Our results suggest increased risk of autoimmune diseases and RA in those living in proximity to a CAFO and a potential role of the AHR-ARNT pathway in conferring risk. We also report the first association of ARNT SNPs rs11204735 and rs1889740 with RA. Our findings, if confirmed, could allow for novel genetically-targeted or other preventive approaches for certain IMD.

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.

Anti-FHL1 autoantibodies in juvenile myositis are associated with anti-Ro52 autoantibodies but not with severe disease features.

OBJECTIVES: Four-and-a-half LIM domains 1 (FHL1) is a muscle-specific protein. Autoantibodies against FHL1 were recently discovered in adults with idiopathic inflammatory myopathies (IIMs) and were found to be associated with clinical features and outcomes indicative of increased disease severity. Anti-FHL1 autoantibodies have not been described in children. Here, the prevalence and clinical features associated with anti-FHL1 autoantibodies were examined in a large North American cohort of juvenile patients with IIM. METHODS: Sera from 338 juvenile IIM patients and 91 juvenile healthy controls were screened for anti-FHL1 autoantibodies by ELISA. Clinical characteristics and HLA alleles of those with and without anti-FHL1 autoantibodies were compared among those with juvenile IIM. RESULTS: Anti-FHL1 autoantibodies were present in 10.9% of juvenile IIM patients and 1.1% of controls. The frequency of anti-FHL1 autoantibodies among clinical and serologic subgroups did not differ. A higher percentage of Asian patients had anti-FHL1 autoantibodies (11% vs 0.7%; P = 0.002). Myositis-associated autoantibodies (MAAs) [odds ratio (OR) 2.09 (CI 1.03, 4.32)], anti-Ro52 autoantibodies specifically [OR 4.17 (CI 1.83, 9.37)] and V-sign rash [OR 2.59 (CI 1.22, 5.40)] were associated with anti-FHL1 autoantibodies. There were no differences in other features or markers of disease severity. No HLA associations with anti-FHL1 autoantibodies in Caucasian myositis patients were identified. CONCLUSION: Anti-FHL1 autoantibodies are present in ∼11% of juvenile IIM patients and commonly co-occur with MAAs, including anti-Ro52 autoantibodies. In contrast to adult IIM, anti-FHL1 autoantibodies in juvenile myositis are associated with V-sign rash but not with other distinctive clinical features or worse outcomes.

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.