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OBJECTIVE: The identification of novel autoantibodies in juvenile dermatomyositis (DM) may have etiologic and clinical implications. The aim of this study was to describe autoantibodies to a 140-kd protein in children recruited to the Juvenile DM National Registry and Repository for UK and Ireland. METHODS: Clinical data and sera were collected from children with juvenile myositis. Sera that recognized a 140-kd protein by immunoprecipitation were identified. The identity of the p140 autoantigen was investigated by immunoprecipitation/immunodepletion, using commercial monoclonal antibodies to NXP-2, reference anti-p140, and anti-p155/140, the other autoantibody recently described in juvenile DM. DNA samples from 100 Caucasian children with myositis were genotyped for HLA class II haplotype associations and compared with those from 864 randomly selected UK Caucasian control subjects. RESULTS: Sera from 37 (23%) of 162 patients with juvenile myositis were positive for anti-p140 autoantibodies, which were detected exclusively in patients with juvenile DM and not in patients with juvenile DM-overlap syndrome or control subjects. No anti-p140 antibody-positive patients were positive for other recognized autoantibodies. Immunodepletion suggested that the identity of p140 was consistent with NXP-2 (the previously identified MJ autoantigen). In children with anti-p140 antibodies, the association with calcinosis was significant compared with the rest of the cohort (corrected P < 0.005, odds ratio 7.0, 95% confidence interval 3.0-16.1). The clinical features of patients with anti-p140 autoantibodies were different from those of children with anti-p155/140 autoantibodies. The presence of HLA-DRB1*08 was a possible risk factor for anti-p140 autoantibody positivity. CONCLUSION: This study has established that anti-p140 autoantibodies represent a major autoantibody subset in juvenile DM. This specificity may identify a further immunogenetic and clinical phenotype within the juvenile myositis spectrum that includes an association with calcinosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events. [ABSTRACT FROM AUTHOR]

Objectives: Systemic sclerosis (SSc)-related autoantibodies are widely used diagnostic and prognostic biomarkers. This study aimed to develop a new assay for detecting anti-ribonucleoprotein autoantibodies in SSc based on RNA immunoprecipitation (RNA IP) coupled with massive parallel sequencing., Methods: Serum samples and clinical data were collected from 307 SSc patients. Among these, 57 samples underwent analysis using a new protocol that combines RNA IP with massive parallel sequencing (RIP-Seq). Filtering strategies and statistical outlier detection methods were applied to select RNA molecules that could represent novel ribonucleoprotein autoantigens associated with SSc., Results: Among the 30,966 different RNA molecules identified by RIP-Seq in 57 SSc patients, 197 were ultimately selected. These included all RNA molecules previously identified by RNA IP, which were found to exhibit high counts almost exclusively in samples positive for the autoantibodies associated to the corresponding RNA molecule, indicating high sensitivity and specificity of the RIP-Seq technique. C/D box snoRNAs were the most abundant RNA type identified. The immunoprecipitation patterns of the detected C/D box snoRNAs varied among patients and could be associated with different clinical phenotypes. In addition, other ribonucleoproteins were identified, which could be potential targets for previously undescribed SSc-related autoantibodies. These include H/ACA box snoRNPs, vault complexes, mitochondrial tRNA synthetases, and 7SK snRNP., Conclusion: A novel RIP-Seq assay has been developed to detect autoantibodies targeting ribonucleoprotein complexes in SSc patients. This method successfully identified RNA molecules associated with ribonucleoproteins known to be targeted by SSc-related autoantibodies, validating both the assay and the analysis strategy. Additionally, this approach uncovered RNA molecules associated with ribonucleoproteins that were not previously identified as targets of SSc patients' sera, suggesting potential new autoantibody candidates in this disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To determine the annual incidence of psoriatic arthritis (PsA) in a United Kingdom primary care population with preexisting psoriasis (PsO) followed prospectively over 2 years after excluding baseline prevalence of existing disease., Methods: Total Burden of Psoriasis (TUDOR; ISRCTN registry: ISRCTN38877516) was a multicenter, prospective, 2-arm parallel-group cluster randomized controlled trial of the early identification of PsA by annual rheumatological assessment (termed "Enhanced Surveillance") vs standard care in people with PsO identified in primary care. Incidence of PsA is reported at 12 months and 24 months using patients from the Enhanced Surveillance arm, which allows for the exclusion of patients with prevalent PsA at baseline., Results: Fourteen of 511 participants attending a 12-month screen developed PsA over that interval, giving an incidence of 2.74/100 patient-years (PYs; 95% CI 1.32-4.16). Another 7/444 participants attending the 24-month visit developed PsA, giving an incidence of 1.58/100 PYs (95% CI 0.42-2.74). The combined incidence over 2 years was 2.20/100 PYs (95% CI 1.27-3.13)., Conclusion: The estimated annual incidence of PsA over a 2-year period was 2.20/100 PYs, which is in keeping with studies including clinical assessment rather than relying on health records alone. Extended follow-up of the TUDOR cohort with accrual of larger numbers of incident cases will allow risk factors for PsA to be explored in more depth., (Copyright © 2024 by the Journal of Rheumatology.)

Myositis-specific autoantibodies (MSAs) are hallmarks of idiopathic inflammatory myopathies (IIMs) and have become increasing valuable in disease diagnosis, phenotyping, and classification. In addition to their clinical utility, emerging data, including findings from several animal studies, suggest that MSAs and autoreactive T cells substantially contribute to the etiopathogenesis of IIMs. This review aims to provide an updated perspective on myositis autoantibodies by focusing on relevant clinical and translational studies.

Background: Cancer can cause mortality in systemic sclerosis (SSc). We investigated the association between cancer and SSc using the Clinical Practice Research Datalink (CPRD)., Methods: A validated case-ascertainment strategy identified SSc patients in the CPRD. A cohort study design examined cancer occurrence following SSc, with SSc patients matched to six non-SSc comparators by age, sex and GP-practice. Prevalent and incident cases of SSc were analysed separately. Descriptive statistics and Cox analyses determined hazard ratios for cancer occurrence. A case-control study (matched 1:6) examined cancer occurrence prior to SSc., Results: From 10.1 million individuals in CPRD, 1,588 of cases of SSc were identified. Two hundred and six cancers followed SSc diagnosis (116 in prevalent and 90 in incident cohort). Commonest cancers were mucocutaneous (4.5%), lung (2.1%) and breast (1.9%). The proportion of SSc patients developing cancer was significantly higher than non-SSc in both incident (11.2% vs 9.7%, p= 0.02) and prevalent cohorts (14.8% vs 12.1%, p= 0.03); particularly for lung cancer (2.6% vs 0.9% in prevalent cohort, p< 0.001). Overall incidence of cancer in the SSc groups was 17.6/1000 person years, compared with 13.9/1000 person years in non-SSc group. The adjusted hazard ratios for cancer was 1.41 (95% CI 1.14-1.75) and 1.32 (95% CI 1.04-1.67) for prevalent and incident SSc respectively. No increased risk of cancer prior to SSc diagnosis was identified in case-control study., Conclusion: We have identified an increased risk of cancer diagnosis following, but not before, SSc diagnosis. Our findings could support screening recommendations for cancer in SSc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in patients diagnosed with idiopathic ILD., Methods: 499 patient sera were analysed: 251 idiopathic pulmonary fibrosis (IPF), 206 idiopathic non-specific interstitial pneumonia (iNSIP) and 42 cryptogenic organising pneumonia (COP). Autoantibody status was determined by immunoprecipitation., Results: 2.4% of IPF sera had a CTD-autoantibody compared to 10.2% of iNSIP and 7.3% of COP. 45% of autoantibodies were anti-synthetases. A novel autoantibody targeting an unknown 56 kDa protein was found in seven IPF patients (2.8%) and two NSIP (1%) patients. This was characterised as anti-annexin A11., Conclusion: Specific guidance on autoantibody testing and interpretation in patients with ILD could improve diagnostic accuracy. Further work is required to determine the clinical significance of anti-annexin A11., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Background: The reliable detection of myositis-specific autoantibodies (MSA) provides valuable clinical information regarding prognosis, clinical progression and diagnostic confirmation., Objectives: To evaluate the reliability of a commercial ELISA immunoassay in detecting myositis-specific autoantibodies in comparison to immunoprecipitation as the reference standard., Methods: Serum samples were chosen from a biobank of more than 3000 samples. Samples with a confirmed MSA on Immunoprecipitation (n=116) were evaluated in duplicate by ELISA to detect Mi2, MDA5, Jo1, EJ, KS, PL-7 and PL-12 (Medical & Biological Laboratories Co. Ltd, Nagoya, Aichi, Japan). Healthy control samples (n=246) confirmed autoantibody negative by immunoprecipitation were similarly assessed., Results: There was a very good agreement between ELISA and immunoprecipitation for serum samples containing anti-Mi2, MDA5, Jo1, EJ, KS and PL-7 and PL-12 auto-antibodies. Cohen's κ values ranged from 0.86-1 for the measured autoantibodies on ELISA., Conclusion: ELISA was an accurate method for detecting anti-synthetase, anti-Mi2 and anti-MDA5 autoantibodies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Loganathan, McMorrow, Lu, Li, Mulhearn, McHugh and Tansley.)

Objectives: Anti-TIF1γ is an important autoantibody in the diagnosis of cancer-associated dermatomyositis and the most common autoantibody in juvenile onset dermatomyositis. Its reliable detection is important to instigate further investigations into underlying malignancy in adults. We previously showed that commercial assays using line and dot blots do not reliably detect anti-TIF1γ. We aimed to test a new commercial ELISA and compare with previously obtained protein immunoprecipitation., Methods: Radio-labelled immunoprecipitation had previously been used to determine the autoantibody status of patients with immune-mediated inflammatory myopathies and several healthy controls. ELISA was undertaken on healthy control and anti-TIF1γ sera and compared to previous immunoprecipitation data., Results: A total of 110 serum samples were analysed: 42 myositis patients with anti- TIF1γ and 68 autoantibody negative healthy control sera. Anti-TIF1γ was detected by ELISA in 41 out of 42 of the anti-TIF1γ-positive samples by immunoprecipitation, and in none of the healthy controls, giving a sensitivity of 97.6% and specificity of 100%. The false negative rate was 2%., Conclusion: ELISA is an affordable and time-efficient method which is accurate in detecting anti-TIF1γ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mulhearn, Li, McMorrow, Lu, McHugh and Tansley.)

Objectives: To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening., Methods: A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review., Results: Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD -1189.96) or lactate dehydrogenase (WMD -336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers., Conclusion: Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: We developed and tested a robust case ascertainment strategy within the Clinical Practice Research Datalink (CPRD), with the aim of assessing the incidence, prevalence, mortality and delay in diagnosis of SSc in the UK., Methods: A two-stage case ascertainment strategy was devised and tested to establish a valid cohort of SSc cases within the CPRD. Incidence, prevalence and mortality statistics were analysed, alongside evaluation of the relationship between primary care codes for RP and SSc to examine diagnostic delay., Results: SSc Read codes were identified in 3123 patients (from a study cohort of >10.1 million individuals). Of these, 1757 cases of SSc were identified using our case ascertainment approach. The overall incidence rate of SSc over the period between 1999 and 2017 was 10.7/million/year (95% CI: 9.9-11.4), being higher in females [17.69/million/year (95% CI: 16.32-19.07)] than in males [3.59/million/year (95% CI: 2.97-4.21)]. The overall prevalence of SSc in adults was 235.5/million (95% CI: 207.2-245.7). The mean rate of mortality was 32/1000 person-years, with an overall standardized mortality ratio of 3.51 (95% CI: 3.19-3.84). Of those with an initial code of RP prior to a Read code of SSc, 191/854 (22.4%) had a lag period of >10 years., Conclusion: We have developed and tested a robust case ascertainment strategy to examine the incidence, prevalence, mortality and diagnostic delay of SSc using primary care records of over 10 million UK residents. A significant lag between coding of RP and SSc in many patients suggests diagnostic delay in SSc remains an important unmet need., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To test the addition of pain and fatigue to the Composite Psoriatic Arthritis Disease Activity (CPDAI) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) Composite Exercise (GRACE) composite measures of psoriatic arthritis (PsA)., Methods: Clinical and patient-reported outcome measures were assessed in patients with PsA at 3 consecutive follow-up visits over 6 months in a UK multicenter observational study. A pain visual analog scale and Functional Assessment of Chronic Illness Therapy Fatigue scale were added as modifications to the CPDAI and GRACE composite measures. Original and modified versions were tested against the PsA Disease Activity Score (PASDAS) and the Disease Activity Index for PsA (DAPSA). Discrimination between disease states and responsiveness were tested with t -scores, standardized response means (SRMs), and effect sizes. Data were presented to members at the 2020 annual meeting who then voted on the GRAPPA-recommended composite and treatment targets for clinical trials., Results: One hundred forty-one patients were recruited with a mean PsA disease duration of 6.1 years (range 0-41 yrs). The SRMs for the GRACE and modified GRACE (mGRACE) were 0.67 and 0.64, respectively, and 0.54 and 0.46, respectively, for the CPDAI and modified CPDAI (mCPDAI). The t -scores for the GRACE and mGRACE were unchanged at 7.8 for both, and 6.8 and 7.0 for the CPDAI and mCPDAI, respectively. The PASDAS demonstrated the best responsiveness (SRM 0.84) and discrimination ( t -scores 8.3). Most members (82%) agreed the composites should not be modified and 77% voted for the PASDAS as the GRAPPA-recommended composite for clinical trials, with 90% minimal disease activity (MDA) as the target., Conclusion: Modifying the CPDAI and GRACE with the addition of pain and fatigue does not enhance responsiveness nor the measures' ability to detect disease status in terms of requiring treatment escalation. GRAPPA members voted for the PASDAS as the composite measure in clinical trials and MDA as the target., (Copyright © 2021 by The Journal of Rheumatology.)

Objective: To test shortened versions of the psoriatic arthritis (PsA) composite measures for use in routine clinical practice., Methods: Clinical and patient-reported outcome measures (PROMs) were assessed in patients with PsA at 3 consecutive follow-up visits in a UK multicenter observational study. Shortened versions of the Composite Psoriatic Arthritis Disease Activity Index (CPDAI) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite Exercise (GRACE) measures were developed using PROMs and tested against the Disease Activity Score in 28 joints (DAS28), composite Disease Activity in Psoriatic Arthritis, and Routine Assessment of Patient Index Data (RAPID3). Discrimination between disease states and responsiveness were tested with the t -score, standardized response mean (SRM), and effect size (ES). Data were presented to members at the GRAPPA 2020 annual meeting and members voted on the recommended composite routine practice., Results: The SRM for the GRACE, 3 visual analog scale (VAS), and 4VAS were 0.67, 0.77, and 0.63, respectively, and for CPDAI and shortened CPDAI (sCPDAI) were 0.54 and 0.55, respectively. Shortened versions of the GRACE increased the t -score from 7.8 to 8.7 (3VAS) and 9.0 (4VAS), but reduced the t -score in the CPDAI/sCPDAI from 6.8 and 6.1. The 3VAS and 4VAS had superior performance characteristics to the sCPDAI, DAS28, Disease Activity in Psoriatic Arthritis, and RAPID3 in all tests. Of the members, 60% agreed that the VAS scales contained enough information to assess disease and response to treatment, 53% recommended the 4VAS for use in routine care, and 26% the 3VAS, while leaving 21% undecided. Conclusion. Shortening the GRACE to VAS scores alone enhances the ability to detect status and responsiveness and has the best performance characteristics of the tested composite measures. GRAPPA members recommend further testing of the 3VAS and 4VAS in observational and trial datasets., (Copyright © 2021 by The Journal of Rheumatology.)

Objective: To determine the risk of a diagnosis of osteoarthritis (OA) in patients with psoriatic arthritis (PsA) compared to patients with psoriasis and a general population cohort., Methods: Incident PsA patients aged 18-89 years at diagnosis were identified from the United Kingdom Clinical Practice Research Datalink between 1998 and 2014. All patients with PsA were matched to 2 cohorts of patients, both at a 1:4 ratio. The first cohort included patients with psoriasis (and no PsA) and the second was a general population cohort (with no psoriasis or PsA). The baseline prevalence of OA was calculated for each study cohort. The incidence of OA was calculated, and adjusted relative risks (RR adj ) were calculated using conditional Poisson regression., Results: We identified 6783 incident PsA patients. The baseline prevalence of OA ranged from 22.1% (95% CI 21.1-23.1) in the PsA cohort to 12.6% (95% CI 12.2-13.0) and 11.0% (95% CI 10.6-11.3) in the psoriasis and general population cohorts, respectively. The incidence of OA was significantly higher in the PsA cohort compared to the psoriasis and general population cohorts after adjusting for BMI (RR adj 1.68, 95% CI 1.46-1.93, and RR adj 1.86, 95% CI 1.62-2.14, respectively)., Conclusion: An increased risk of OA was observed in patients with PsA compared to patients with psoriasis alone and those in the general population. Further work is needed to determine whether this reflects a true increase in OA risk or misdiagnosed PsA, and the extent to which it can be explained by differences in the opportunity for OA diagnosis between cohorts., (Copyright © 2021 by the Journal of Rheumatology.)

Objectives: Uncertainty around clinical heterogeneity and outcomes for patients with JDM represents a major burden of disease and a challenge for clinical management. We sought to identify novel classes of patients having similar temporal patterns in disease activity and relate them to baseline clinical features., Methods: Data were obtained for n = 519 patients, including baseline demographic and clinical features, baseline and follow-up records of physician's global assessment of disease (PGA), and skin disease activity (modified DAS). Growth mixture models (GMMs) were fitted to identify classes of patients with similar trajectories of these variables. Baseline predictors of class membership were identified using Lasso regression., Results: GMM analysis of PGA identified two classes of patients. Patients in class 1 (89%) tended to improve, while patients in class 2 (11%) had more persistent disease. Lasso regression identified abnormal respiration, lipodystrophy and time since diagnosis as baseline predictors of class 2 membership, with estimated odds ratios, controlling for the other two variables, of 1.91 for presence of abnormal respiration, 1.92 for lipodystrophy and 1.32 for time since diagnosis. GMM analysis of modified DAS identified three classes of patients. Patients in classes 1 (16%) and 2 (12%) had higher levels of modified DAS at diagnosis that improved or remained high, respectively. Patients in class 3 (72%) began with lower DAS levels that improved more quickly. Higher proportions of patients in PGA class 2 were in DAS class 2 (19%, compared with 16 and 10%)., Conclusion: GMM analysis identified novel JDM phenotypes based on longitudinal PGA and modified DAS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: In order to address the reliability of commercial assays to identify myositis-specific and -associated autoantibodies, we aimed to compare the results of two commercial immunoassays with the results obtained by protein immunoprecipitation., Methods: Autoantibody status was determined using radio-labelled protein immunoprecipitation for patients referred to our laboratory for myositis autoantibody characterization. For each autoantibody of interest, the sera from 25 different patients were analysed by line blot (Euroline Myositis Antigen Profile 4, EuroImmun, Lübeck, Germany) and dot blot (D-Tek BlueDiver, Diagnostic Technology, Belrose, NSW, Australia). Sera from 134 adult healthy controls were analysed., Results: Overall commercial assays performed reasonably well, with high agreement (Cohen's κ >0.8). Notable exceptions were the detection of rarer anti-synthetases with κ < 0.2 and detection of anti-TIF1γ, where κ was 0.70 for the line blot and 0.31 for dot blot. Further analysis suggested that the proportion of patients with anti-TIF1γ may recognize a conformational epitope, limiting the ability of blotting-based assays that utilize denatured antigen to detect this clinically important autoantibody. A false-positive result occurred in 13.7% of samples analysed by line blot and 12.1% analysed by dot blot., Conclusion: The assays analysed do not perform well for all myositis-specific and -associated autoantibodies and overall false positives are relatively common. It is crucial that clinicians are aware of the limitations of the methods used by their local laboratory. Results must be interpreted within the clinical context and immunoprecipitation should still be considered in selected cases, such as apparently autoantibody-negative patients where anti-synthetase syndrome is suspected., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: It has been over 10 years since the first report of autoantibodies directed against phenylalanyl tRNA synthetase (anti-Zo) in a patient with features of the anti-synthetase syndrome. In that time no further cases have been published. Here we aim to characterize more fully the clinical phenotype of anti-Zo-associated myositis by describing the clinical features of nine patients., Methods: Anti-Zo was identified by protein-immunoprecipitation in patients referred for extended spectrum myositis autoantibody testing at our laboratory. Results were confirmed by immunodepletion using a reference serum. Medical records were retrospectively reviewed to provide detailed information of the associated clinical phenotype for all identified patients. Where possible, HLA genotype was imputed using Illumina protocols., Results: Nine patients with anti-Zo were identified. The median age at disease onset was 51 years, and six patients were female. Seven patients had evidence of inflammatory muscle disease, seven of interstitial lung disease and six of arthritis. The reported pattern of interstitial lung disease varied with usual interstitial pneumonia, non-specific interstitial pneumonia and organizing pneumonia all described. Other features of the anti-synthetase syndrome such as RP and mechanics hands were common. HLA data was available for three patients, all of whom had at least one copy of the HLA 8.1 ancestral haplotype., Conclusion: Patients with anti-Zo presenting with features of the anti-synthetase syndrome and interstitial lung disease is a common finding. Like other myositis autoantibodies, there is likely to be a genetic association with the HLA 8.1 ancestral haplotype., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Autoimmune connective tissue diseases are heterogeneous rheumatic diseases with the potential to affect multiple body systems. Autoantibodies are a characteristic feature of these diseases and are typically highly disease specific. In addition to aiding diagnosis, many autoantibodies have established associations with clinically important disease complications including internal organ involvement. In this chapter, we review the autoantibodies relevant to autoimmune connective tissue diseases, excluding systemic lupus erythematosus, with particular reference to the associated clinical features and how identification of such an autoantibody may inform prognosis and clinical management. We also discuss the practicalities of testing for autoantibodies along with potential difficulties and pitfalls., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To assess whether the association between psoriatic nail dystrophy and radiographic damage in the hands of patients with psoriatic arthritis (PsA) is specific to the distal interphalangeal (DIP) joints., Methods: A convenience sample of patients was collated from the Bath longitudinal PsA cohort. All patients had PsA according to the ClASsification for Psoriatic ARthritis criteria (CASPAR) criteria, scored radiographs of their hands, and documented nail scores as measured by the Psoriatic Nail Severity Score. Chi-square tests were performed to examine for association between features of nail dystrophy and radiographic damage in the DIP joints, and proximal interphalangeal or metacarpophalangeal (non-DIP) joints of the corresponding digits., Results: There were 134 patients included, with a median age of 53 years (interquartile range; IQR 44-61) and disease duration of 7 years (IQR 3-17). The presence of any form of psoriatic nail dystrophy was associated with erosion at the DIP joints of the corresponding digit (OR 1.9, 95% CI 1.23-2.83; p < 0.004) and this association was primarily driven by the presence of nail onycholysis (OR 1.72; 95% CI 1.12-2.62; p = 0.02). Nail subungual hyperkeratosis was more strongly associated with joint space narrowing, erosions, and osteoproliferation at the corresponding DIP joint compared to non-DIP joints (p < 0.001). Nail pitting was not associated with erosions or osteoproliferation., Conclusion: The presence of psoriatic nail dystrophy, particularly onycholysis, is associated with erosive disease at the DIP joints. Subungual hyperkeratosis is more strongly associated with erosive damage at the DIP than non-DIP joints. These findings support the anatomical and pathological link between nail and DIP joint disease.

Aim: Juvenile idiopathic inflammatory myopathies have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood., Methods: We studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b-9 complement analysis., Results: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2 and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition., Conclusion: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes., (© 2019 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies., Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups., Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10 -5 . Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10 -53  and HLA-DRB1*03:01, p=3.25×10 -9 ), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10 -26 ) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10 -11 ). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10 -13 ) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10 -6 ). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10 -64 ) and position 9 of HLA-B (p=7.03×10 -11 ). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies., Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research., Competing Interests: Competing interests: JV reports grants from Ministry of Health in the Czech Republic, grants from European Community’s FP6, AutoCure LSHB CT-2006-01866, grants from European Science Foundation, during the conduct of the study. IEL reports grants from Swedish Research Council, grants from European Science Foundation, grants from Association Francaise Contre Les Myopathies (AFM), grants from Stockholm County Council, grants from The European Union Sixth Framework Programme, during the conduct of the study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To evaluate the relationship between expression of myxovirus-resistance protein A (MxA) protein on muscle biopsies by immunohistochemistry and disease activity in juvenile dermatomyositis (JDM) patients. Also, another aim was to investigate whether the expression of MxA is related with myositis-specific autoantibodies (MSA) status in JDM patients., Methods: 103 patients (median aged 6.3, interquartile range 0.5-15.9) enrolled in the Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS). Muscle biopsies were stained with MxA and scored. Clinical data at initial presentation were collected and autoantibodies were analysed. Multiple linear regression analysis was performed to estimate the association between MxA expression on muscle fibres and muscle disease activity, and MSA status., Results: Expression of MxA protein on JDM samples was identified in 61.2%. There was a significant association between MxA scores and Childhood Myositis Assessment Scale (CMAS) (P = 0.002), and Manual Muscle Testing of Eight Muscles (MMT8) (P = 0.026). CMAS and MMT8 scores were significantly lower in the group of patients with strong MxA expression. MxA scores differed according to MSA subgroups (P = 0.002). Patients with positive nuclear matrix protein 2 autoantibodies had strong MxA expression, whereas anti-melanoma differentiation-associated gene 5 positive patients had no or weak MxA expression., Conclusions: This study reveals the significant association between level of MxA expression on muscle fibres and clinical measures of muscular disease activity in JDM patients and MSA status. This confirms type I interferonopathies in muscle fibres of JDM patients which could help with improving treatment outcome in JDM patients and underscoring the distinct pathophysiological pathways in different MSA status., (© 2018 The Authors Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Objectives: To characterize the 10 year relationship between anti-transcriptional intermediary factor 1 antibody (anti-TIF1-Ab) positivity and cancer onset in a large UK-based adult DM cohort., Methods: Data from anti-TIF1-Ab-positive/-negative adults with verified diagnoses of DM from the UK Myositis Network register were analysed. Each patient was followed up until they developed cancer. Kaplan-Meier methods and Cox proportional hazard modelling were employed to estimate the cumulative cancer incidence., Results: Data from 263 DM cases were analysed, with a total of 3252 person-years and a median 11 years of follow-up; 55 (21%) DM cases were anti-TIF1-Ab positive. After 10 years of follow-up, a higher proportion of anti-TIF1-Ab-positive cases developed cancer compared with anti-TIF1-Ab-negative cases: 38% vs 15% [hazard ratio 3.4 (95% CI 2.2, 5.4)]. All the detected malignancy cases in the anti-TIF1-Ab-positive cohort occurred between 3 years prior to and 2.5 years after DM onset. No cancer cases were detected within the following 7.5 years in this group, whereas cancers were detected during this period in the anti-TIF1-Ab-negative cases. Ovarian cancer was more common in the anti-TIF1-Ab-positive vs -negative cohort: 19% vs 2%, respectively (P < 0.05). No anti-TIF1-Ab-positive case <39 years of age developed cancer, compared with 21 (53%) of those ≥39 years of age., Conclusion: Anti-TIF1-Ab-positive-associated malignancy occurs exclusively within the 3 year period on either side of DM onset, the risk being highest in those ≥39 years of age. Cancer types differ according to anti-TIF1-Ab status, and this may warrant specific cancer screening approaches., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology.)