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Objective.Tofacitinib (TOF) is the first Janus kinase (JAK) inhibitor approved for psoriatic arthritis (PsA). It has shown efficacy in patients refractory to anti–tumor necrosis factor-α in randomized controlled trials (RCTs). Our aim was to assess efficacy and safety of TOF in clinical practice.Methods.This was an observational, open-label multicenter study of PsA patients treated with TOF due to inefficacy or adverse events of previous therapies. Outcome variables were efficacy, corticosteroid dose-sparing effect, retention rate, and safety. A comparative study of clinical features between our cohort of patients and those from the OPAL Beyond trial was performed.Results.There were 87 patients (28 women/59 men), with a mean age of 52.8 ± 11.4 years. All patients were refractory to biologic disease-modifying antirheumatic drugs (DMARDs) and/or to conventional synthetic DMARDs plus apremilast. TOF was started at 5 mg twice daily after a mean follow-up of 12.3 ± 9.3 years from PsA diagnosis. At first month, Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) decreased from median 4.8 (IQR 4.1–5.4) to 3.7 (IQR 2.8–4.7,P< 0.01), Disease Activity Index for Psoriatic Arthritis from median 28 (IQR 18.4–34.1) to 15.5 (IQR 10.1–25.7,P< 0.01), and C-reactive protein from median 1.9 (IQR 0.3–5.0) to 0.5 (IQR 0.1–2.2) mg/dL (P< 0.01). Also, TOF led to a significant reduction in prednisone dose. Mild adverse effects were reported in 21 patients (24.13%), mainly gastrointestinal symptoms. TOF retention rate at Month 6 was 77% (95% CI 65.2–86.3). Patients in clinical practice were older with longer disease duration and received biologic agents more commonly than those in the OPAL Beyond trial.Conclusion.Data from clinical practice confirm that TOF seems to be effective, rapid, and relatively safe in refractory PsA despite clinical differences with patients in RCTs.

Few studies have been published focusing on the differences between juvenile idiopathic inflammatory myopathy (JIIM) and adult IIM. This study aimed to describe the characteristics of JIIM main subgroups (juvenile dermatomyositis [JDM] and juvenile polymyositis [JPM]) and to compare their differences with adult IIM subgroups (adult DM and adult PM). Methods This study reviewed the medical records of patients from the REMICAM cohort, a multicentric longitudinal study carried out in patients with IIM, followed up between 1980 and 2014 in 12 hospitals in Madrid, Spain. Patients with definite or probable JPM, JDM, adult DM, and adult PM according to the modified Bohan and Peter criteria were selected. We compared the characteristics between JDM and JPM, and between JIIM and adult IIM. Results Eighty-six juvenile patients (75 JDMs and 11 JPMs) and 283 adult patients (133 DMs and 150 PMs) were included. Compared with patients with JDM, patients with JPM were older at diagnosis, had more fever and arthritis, and were less frequently treated with disease-modifying antirheumatic drugs (these differences were not statistically significant). Compared with patients with adult DM, those with JDM presented more frequently with calcinosis (33.8% vs 6.9%, p Conclusions Our findings confirm that JIIMs are a heterogeneous group of diseases with relevant differences compared with adult IIMs.

Objectives To describe the methods of the Spanish Registry of patients with idiopathic inflammatory myopathy (IIM) (Myo-Spain), as well as its strengths and limitations. The main objective of the project is to analyse the evolution and clinical management of a cohort of patients with IIM. Methods Observational, longitudinal, ambispective and multicentre study of a cohort of patients with IIM seen in rheumatology units in Spain. All patients with a diagnosis of IMM will be included in the regular follow-up of the participating centres, regardless of age on initiation of the process. Incident cases will be all patients who at the beginning of the study have been diagnosed for less than 12 months and prevalent cases for more than 12 months. The registry will include data from the visit at baseline, one year and two years. Socio-demographic, clinical, analytical variables, complications, comorbidities, association with other rheumatic diseases, hospital admissions, mortality and treatments will be collected. In addition, indices, scales and questionnaires of activity, muscle involvement, damage, disability, and quality of life will be determined. The recruitment period will be 23 months. The purpose is to obtain a cohort of 400 patients with IMM. Conclusions Myo-Spain registry provides the opportunity to develop a cohort of incident and prevalent patients with IMM in Spain. Myo-Spain will be able to assess in detail the clinical characteristics of the disease at different times. The comprehensive information collected during the visits is expected to provide a broad source of data for future analysis.

The present study was undertaken to assess mortality, causes of death, and associated prognostic factors in a large cohort of patients diagnosed with idiopathic inflammatory myositis (IIM) from Spain. A retrospective longitudinal study was carried out in 467 consecutive patients with IIM, identified from 12 medical centers. Patients were classified as primary polymyositis, primary dermatomyositis (DM), overlap myositis, cancer-associated myositis (CAM), and juvenile idiopathic inflammatory myopathies. A total of 113 deaths occurred (24%) after a median follow-up time of 9.7 years. In the overall cohort, the 2-, 5-, and 10-year survival probabilities were 91.9, 86.7, and 77%, respectively. Main causes of death were infections and cancer (24% each). Multivariate model revealed that CAM (HR = 24.06), OM (HR = 12.00), DM (HR = 7.26), higher age at diagnosis (HR = 1.02), severe infections (HR = 3.66), interstitial lung disease (HR = 1.61), and baseline elevation of acute phase reactants (HR = 3.03) were associated with a worse prognosis, while edema of the hands (HR = 0.39), female gender (HR = 0.39), and longer disease duration (HR = 0.73) were associated with a better prognosis. The standardized mortality ratio was 1.56 (95% CI 1.28-1.87) compared to the Spanish general population. Our findings indicate that IIM has a high long-term mortality, with an excess of mortality compared to the Spanish population. A more aggressive therapy may be required in IIM patients presenting with poor predictive factors. Sin financiación 1.952 JCR (2017) Q3, 24/32 Rheumatology 0.906 SJR (2017) Q2, 25/66 Rheumatology No data IDR 2017 UEM

Background: Inflammatory idiopathic myositis (IIM) comprises a heterogeneous group of systemic muscular diseases that can occur together with other connective tissue diseases (CTD), named overlap myositis (OM). The question of whether OM is a distinct entity still remains controversial. Aim: The present study was conducted to assess the clinical and prognostic differences between patients diagnosed with OM, primary polymyositis (PM) and primary dermatomyositis (DM). Method: The study consists of a retrospective longitudinal and multicenter series of IIM patients. Patients were classified as OM, PM and DM. Overlap myositis was defined as patients fulfilling criteria for IIM plus criteria for other CTD (namely systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis and primary Sjögren's syndrome). Result: A total of 342 patients were included (98 OM, 137 PM and 107 DM). Overlap myositis patients, in comparison with PM and DM, showed significant differences, with more extramuscular involvement, particularly more arthritis (66%, 34.6% and 48.1%, respectively), puffy fingers (49.5%, 11.1% and 24.3%), sclerodactyly (45.4%, 2.2% and 2%), dysphagia (41.8%, 18.2% and 26.4%), Raynaud phenomenon (65.3%, 16.9% and 19.8%), leucopenia (28.9%, 2.2% and 8.4%), thrombocytopenia (8.2%, 2.2% and 1.9%), interstitial lung disease (ILD) (48%, 35% and 30.8%), renal manifestations (13.4%, 3.7% and 1.9%), and more severe infections (41.3%, 26.7% and 21%). No significant differences were found in survival between groups in log rank test (P = 0.106). Multivariate adjusted survival analyses revealed a worse prognosis for severe infections, ILD and baseline elevation of acute phase reactants. Conclusion: Overlap myositis stands out as a distinct entity as compared to PM and DM, featuring more extramuscular involvement and more severe infections. Close monitoring is recommended in this subset for early detection and treatment of possible complications. Sin financiación 1.980 JCR (2019) Q1, 25/32 Rheumatology 0.649 SJR (2019) Q3, 33/64 Rheumatology No data IDR 2019 UEM

Objective To validate the 2013 ACR/EULAR classification criteria for systemic sclerosis (SSc) in patients from a capillaroscopy clinic. Methods All patients attended in a capillaroscopy clinic were included. Sociodemographic and SSc-related variables were collected. Using as gold standard for SSc the clinical judgement, the performance (sensitivity, specificity, predictive values, and likelihood ratios) of the 2013 ACR/EULAR criteria were analyzed. Receiver operating characteristic (ROC) curve and the area under the curve (AUC) were calculated for the global score and individual items, and the best cutoffs were obtained. Results We included 327 patients (84% women, mean age at capillaroscopy 48 years). Main reasons for capillaroscopy referral were Raynaud's phenomenon (39%) and SSc evaluation (27%). The most frequent final clinical diagnosis were SSc (32.4%) and primary Raynaud's phenomenon (25.7%). The 2013 ACR/EULAR SSc classification criteria were met by 116 patients (35.5%). Sensitivity and specificity of the new criteria were 98.1% and 94.6%, respectively, and positive and negative predictive values were 89.7% and 99.1%. The individual variables with the best sensitivity were Raynaud's phenomenon (99.1%) and abnormal nailfold capillaries (81.1%). All the individual variables, except Raynaud's phenomenon, puffy fingers and sclerodactily showed high specificity values, over 90%. The best cutoffs of the total score were ≥8, ≥9, and ≥10, and the AUC=0.993. Conclusions We validated the new ACR/EULAR classification criteria for SSc in unselected patients from a capillaroscopy clinic. Global score and individual items included in the new criteria show high diagnostic accuracy and discriminatory capacity.

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs., This work was supported by the Instituto de Salud Carlos III (ISCIII, Spain) through grants PI14/01651, PI17/01606 and RD16/0012/0014 to AG and PI12/01909 to JJG-R. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Objective: To study prognostic factors in different types of idiopathic inflammatory myopathies (IIM) associated with interstitial lung disease (ILD). Patients and methods: Multicenter retrospective study of a Spanish cohort of patients diagnosed with IIM. Patients were classified into four categories: polymyositis (PM), dermatomyositis (DM), antisynthetase syndrome (ASS), and overlap myositis (OM). Sociodemographic data, clinical characteristics, antibodies, and treatments were collected. Cox regression models were calculated to identify factors associated with mortality, the necessity for long-term oxygen therapy (LTOT), and deterioration in respiratory function tests (RFT). Results: The number of patients included was 478, of whom 112 (23.4%) suffered from ILD: 17% PM, 16% DM, 45% ASS, and 22% OM. Factors associated with mortality in the multivariate analysis were clinically meaningful progression of ILD after 3 months (CMP 3m) (hazard ratio (HR) 9.48, p = 0.005), severe infections (HR 6.41, p = 0.016), heliotrope erythema (HR 31.1, p = 0.002), delay in diagnosis (HR 1.29; p = 0.011), and Raynaud's phenomenon (HR 11.9, p = 0.007). However, being female (HR 0.19, p = 0.044) and positivity solely for ANAs (HR 0.08, p = 0.008) presented a protective effect. CMP 3m (HR 22.7, p = 0.027) was associated with the need for LTOT, while basal aldolase (HR 0.90; p = 0.049) had a protective effect. Likewise, joint manifestations (HR 0.04, p = 0.034) were shown to reduce risk of deterioration in RFT. Conclusions: CMP 3m, severe infections, delay in diagnosis, heliotrope erythema, and Raynaud's phenomenon were identified as factors of poor prognosis in different IIM associated with ILD. Sin financiación 2.394 JCR (2019) Q3, 20/32 Rheumatology 0.755 SJR (2019) Q2, 27/64 Rheumatology No data IDR 2019 UEM

Background Among the subtypes of idiopathic inflammatory myopathy (IIM), it has been recognised that primary polymyositis (PM) and primary dermatomyositis (DM) have a worse prognosis than overlap syndrome (OM). However, the benign course of OM has not been confirmed in other studies. The identification of specific characteristics that could allow a correct classification may be important for its prognosis. Objectives To analyse clinical characteristics and survival of patients diagnosed with OM, and to compare if there are differences with other IIM subgroups in a multicentric cohort. Methods Retrospective, multicentric longitudinal observational study of a cohort of patients followed between January 1980 and December 2014, with a diagnosis of MII. The patients were divided into 2 groups: OM and primary idiopathic inflammatory myositis (PIIM), which included PM and DM. Patients classified as OM had to meet IIM criteria and criteria for rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) or primary Sjogren’s syndrome (SS). Results The present study included a total of 348 patients (98 OM, 250 PIIM). The connective tissue diseases associated with OM were: MCTD in 32 (32.7%), SSc in 29 (29.6%), SLE in 21 (21.4%), RA in 8 (8.2%) and SS in 8 (8.2%). Patients with OM showed remarkable differences compared to PIIM. In general, OM exhibited more extramuscular involvement and more complications, with more serious infections (41% vs. 24%, p Conclusions In the REMICAM registry of 348 inflammatory myopathies, 98 cases of myositis with overlap syndrome have been included, presenting with more extramuscular complications, more severe infections and higher mortality than other myopathies. It would be important to identify these patients at the onset of the disease, in order to closely monitor for development of possible complications. Disclosure of Interest None declared

Background Several studies have consistently showed that the extent of skin involvement has a major impact on disease prognosis in the diffuse cutaneous subtype of systemic sclerosis. The large majority of the ongoing clinical trials aim at identifying efficient drug in this subset. By contrast, little is known about the limited cutaneous subset (LcSSc) and the translation of the data coming for DcSSc to LcSSc is uncertain. Objectives Therefore, our aim was to investigate skin and lung involvement trajectories of LcSSc patients using the large EUSTAR registry. Methods We analysed the longitudinal data extracted from the EUSTAR cohort collected before February 2017. Worsening of skin fibrosis was defined by an increase in modified Rodnan skin score (mRSS) >3.5 points from baseline to 2nd visit. Interstitial lung disease (ILD) was defined by any fibrosis on imaging (X-ray/computed tomography). Worsening of ILD was defined by a decrease of FVC >10% from baseline to 2nd visit. For predicting models, predictors with p Results 8013 LcSSc were included with a mean follow-up of about 3.3±3.7 years. At baseline, mean ±SD mRSS was 6±5 and ILD was present in 28.4% of all patients. Worsening of skin fibrosis was observed in 6.4% (19/298), 7.8% (97/1248) and 9.8% (289/2957) of LcSSc patients at 6, 12 and 24 months follow-up respectively. In multivariate analysis, variables predicting skin fibrosis progression were elevated European Scleroderma Study Group activity index (EScSG-AI) (OR [95 IC]: 1.22 [1.05–1.4], p=0.007) for 12 months progression and EScSG-AI (1.24 [1.13–1.38], p Worsening of ILD was observed in 11.7% (23/196) and 19.9% (65/326) of LcSSc patients with ILD at baseline, at 12 and 24 months follow-up respectively. In multivariate analysis, variables predicting ILD progression at 24 months were EScSG-AI >3 (OR [95 IC]: 3.8 [1.51–9.56], p=0.005), FVC (1.03 [1.01–1.04], p Conclusions It appears that only few LcSSc patients progress for skin fibrosis ; this limits the use of mRSS in this subset and the potential of anti-fibrotic drugs of skin disease. However, a substantial rate of ILD progression was identified as well as relevant predictors. These results support the inclusion of LcSSc patients in SSc-ILD trials evaluating anti-fibrotic drugs. Our predictive models will be helpful to define enriched population in future clinical trials. Acknowledgements: This work was supported by an unrestricted grant from INVENTIVA Disclosure of Interest None declared

Objective: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years’ duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets. Method: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud’s SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud’s phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31–59, and ≥ 60 years. We performed descriptive and bivariate analyses. Results: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud’s. Conclusion: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice. (Less)

Objective To analyze the performance of the 1980 ACR and new 2013 ACR/EULAR criteria for systemic sclerosis (SSc) in cutaneous SSc (lcSSc) patients, especially those affected by lcSSc and pulmonary arterial hypertension (PAH). Methods All patients with a clinical lcSSc diagnosis from a prospective observational SSc cohort were included. Sociodemographic and disease-related variables were collected, and PAH confirmed by right heart catheterization (RHC). Performance of the 2013 and 1980 SSc criteria was analyzed in terms of clinical diagnosis. Descriptive and between-group analyses were performed as to the fulfillment of criterion sets, including comparison of survival. Results Overall, 321 patients were included, 63% of whom fulfilled the 1980 ACR and 93% the 2013 ACR/EULAR criteria. Agreement between both criteria sets proved poor ( κ = 0.23). LcSSC patients fulfilling both criterion sets were significantly younger at diagnosis, whilst presenting organ involvement, calcinosis, fingertip digital ulcers, and pitting scars more frequently than those who met the 2013 criteria only. Patients who fulfilled the 2013 but not the 1980 criteria presented a higher degree of ACA positivity and PAH. Nearly 12% of patients developed PAH. Patients who did not meet the 1980 criteria were affected by a milder disease from but demonstrated higher pulmonary vascular resistance and lower cardiac index than those fulfilling both criterion sets. Whereas patients with PAH met the 2013 criteria, only 47% fulfilled the 1980 criteria. Regardless of criterion set fulfillment, high mortality was observed in PAH patients, with no significant between-patient difference based on criterion set. Conclusion The new 2013 ARC/EULAR criteria prove more accurate than the former 1980 ACR criteria in identifying and differentiating patients with lcSSc, especially those with associated PAH. Since PAH exhibits a better prognosis if treated early, all SSc patients should undergo PAH screening.

Background Inflammatory myopathies (IIM) are a heterogeneous group of autoimmune rheumatic diseases characterized by muscle inflammation and progressive weakness. They include any kind of primary inflammatory muscle disease that is not otherwise better explained by metabolic, toxic, infectious, neurologic or inherited causes. The presence of autoantibodies (AA) in IIM is variable and they can recognize nuclear and cytoplasmic cellular components. Objectives To evaluate the AA profile in patients diagnosed with IIM. Methods We evaluated 479 patients that included 12 hospitals belonging to the IIM registry of the Rheumatology Society in Madrid (SORCOM-REMICAM) with diagnosis from January 1980 to December 2014. All patients were diagnosed of IIM according to Bohan and Peter criteria. The AAs evaluated were ANA (n=476), anti-Jo1 (n=457), anti-RNP (n=427), anti-MI2 (n=159) and ACA (n=293), according to the standard techniques in the respective laboratories. The presence of ANA was considered valid with at least two positive determinations. The AAs were compared according to the classification I) as dermatomyositis (primary and secondary dermatomiositis) (DM) and polymyositis (PM) including the rest of the patients. Also, IIM were classified (II) as primary polimiositis (PPM), primary dermatomyositis (PDM), overlap syndrome (OSd), juvenile myopathies (JM), cancer-associated myopathies (CAM), autoimmune necrotizing myopathy and inclusion body myositis (these were grouped as other myositis; OM). Results In the PM and DM groups 250 and 229 (52.2% and 47.8%) patients were included respectively. Positive ANA, anti-Jo1 and anti-RNP were higher in the PM than in the DM group (67, 22 and 19% vs. 56, 11 and 6%) (p=0.21, p=0.002, p=0.0001, respectively). The presence of anti-MI2 was higher in the DM group (p=0.024), according to the classification II, we found statistically significant differences in ANA, anti-Jo1, anti-RNP and anti-ACA. The OSd group had the highest proportion of ANA, anti-RNP and ACA positive AA and the JM group had the lowest frequency of Anti-Jo1 (see Table 1). Conclusions The AA associated with the IIM subtypes is consistent with published scientific evidence on other cohorts for ANA, anti-Jo1, anti-RNP and anti-MI2, in spite of the small sample size. The OSd group showed higher ANA and anti-RNP frequencies which might be explained by the coexistence of SLE and MCTD patients. It could be interesting to follow up those PPM patients with positive AA because they could be in the future diagnosed with a connective tissue disease. Carrying out longitudinal studies that include a greater proportion of patients may help to evaluate and predict the clinical course of IIM. References Bohan A, Peter JB. N Engl J Med 1975 Feb 13;292(7):344–7. Acknowledgements . Disclosure of Interest None declared

Background Idiopathic inflammatory myopathies (IIM) comprise a heterogeneous group of autoimmune conditions. Joint involvement can be considered to be part of the IIM systemic manifestations, together with a possible gastrointestinal, cardiovascular and/ or pulmonary involvement. Although articular involvement in the IIM has been described as variable and non-specific with a chronic course it might be an early symptom of dermatomiositis in up to 30% of cases and in those patients with overlap syndromes. Objectives To evaluate and to identify joint manifestations in IIM patients. Methods We evaluated a cohort of 479 patients that included 12 hospitals in the Community of Madrid belonging to the IIM registry of the Society of Rheumatology of Madrid (SORCOM-REMICAM) with diagnosis from January 1980 to December 2014. All patients were diagnosed of IIM according to Bohan and Peter criteria (1). The presence of arthralgia and arthritis was considered. IIM were classified as dermatomyositis (primary and secondary dermatomiositis) (DM) and polymyositis (PM) including the rest of the patients (classification I). Also, IIM were classified (II) as primary polimiositis (PPM), primary dermatomyositis (PDM), overlap syndrome (OSd), juvenile myopathies (JM), cancer-associated myopathies (CAM), autoimmune necrotizing myopathy and inclusion body myositis (these were grouped as other myositis; OM). Results We found 70 (18%) patients with acute arthritis ( 6 weeks) and 245 (65%) patients without any joint manifestations. Using the Tanimoto et al. criteria (1), the presence of erosive arthritis was observed in 149/479 (38.3%) of the patients. When comparing the joint manifestations in the PM and DM groups (n=250, 52.2% vs. n=229, 47.8%) no statistically significant differences were observed. However, assessing joint manifestations according to classification II, we observed that the highest prevalence was found in the OSd group, followed by the PDM group (p=0.0001). The group with less joint manifestations was JM compared to OSd and PDM (Table 1. Conclusions The presence of joint manifestations associated with IIM in our cohort is higher compared to other studies described in the literature so far and emphasize the importance of an accurate joint examination in these patients. The OSd group showed more joint manifestations which might be explained by the coexistence of SLE and MCTD patients in this group. Currently, no association between the clinical subtypes of IIM, overall, these results are encouraging and suggest that joint assessment in follow up may be helpful in differentiating subtypes of IIM. References Bohan A, Peter JB. N Engl J Med 1975 Feb 13;292(7):344–7. Disclosure of Interest None declared

Background Interstitial lung disease (ILD) in idiopathic inflammatory myopathies (IIM) may appear at any time in evolution and is associated with a worse prognosis. Objectives To investigate sociodemographics data and clinical characteristics of patients with IIM and ILD from the REMICAM registry. Methods A multicenter retrospective study (1980–2014) was performed. Patients were classified as polymiosytis (PM), dermatomyositis (DM), IIM with anti-synthetase antibodies (AB) and overlap syndrome. In addition, ILD was classified according to HRCT pattern: usual interstitial pneumonia (IP), non specific IP, organizing pneumonia, and acute IP. We compared sociodemographic data, clinical characteristics, AB and treatments of patients with and without ILD, patients with ILD according to subgroup of myositis or ILD. Results 478 patients were included, of whom 129 (27%) had ILD. Patients with ILD had a higher age at diagnosis, ESR and CRP and worse initial respiratory function. They were characterized by increased frequency of arthritis, systemic and cardiac manifestations, Raynaud, cardiovascular disease, pulmonary hypertension, ischemic ulcers, sclerodactyly and anti-synthetase AB (p Conclusions We found some clinical manifestations and AB that may help for detection of patients with IIM associated to ILD, as well as clinical manifestations to better differentiate myositis subtypes in patients with ILD. Disclosure of Interest None declared

ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.ResultsWe identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.ConclusionCombining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Objective To analyze clinical characteristics, survival and causes of death of patients diagnosed with autoimmune inflammatory myositis in the REMICAM registry from the Society of Rheumatology in the Community of Madrid (SORCOM). Methods Multicenter cohort of patients diagnosed with autoimmune inflammatory myopathy with follow-up between January 1980 and December 2014. A total of 313 variables concerning demographic, clinical and morbidity data were collected, and a comparison was performed between clinical subgroups. Results A total of 479 patients were recruited from 12 centers with 14% of patients lost to follow-up. Seventy-four percent of cases were women, age at diagnosis of 44 ± 23 years and a mean follow-up period of 10 ± 8 years. The most frequent clinical subgroups were primary myositis (PM 29%, DM 22%), followed by overlap myositis (20.5%), juvenile myositis (18%), myositis associated with cancer (8%), immune-mediated necrotizing myositis (1%) and inclusion body myositis (1%). During the follow-up period, a total of 114 deaths (28%) were registered, the main causes being cancer (24%), infections (23%) and cardiovascular events (21%). Conclusions A total of 479 patients were recruited in the REMICAM registry of inflammatory myopathies. Including sociodemographic, clinical and prognostic information, it represents the largest Spanish multicenter registry to date in rheumatology, and constitutes an important source for conducting further substudies.

Objective To analyze the causes of death, survival, and risk factors for mortality in a large series of Spanish systemic sclerosis (SSc) patients followed over the last 25 years in a tertiary care university hospital. Methods Demographic, clinical, and outcome data from all SSc patients followed in the rheumatology department were included in a database created in 1989. ANOVA, Kruskal-Wallis, or χ 2 tests were used to identify differences among groups; Kaplan-Meier analysis was used to estimate survival, and Cox proportional hazards regression analysis was used to identify factors associated with mortality. Results A total of 204 patients were included, of whom 182 (89%) were women. Mean age at diagnosis was 49 ± 17 years, and mean follow-up was 8 years. Over 1635 patient-years, 36 of 44 deaths were attributable to SSc: 28 related to cardiorespiratory involvement, 4 to peripheral vascular disease, 3 to gastrointestinal, and 1 to renal involvement. The main SSc-unrelated causes of death were malignancy (3 cases) and infections (2 cases). Survival rates from disease onset were 85, 75, and 55% at 5, 10, and 20 years, respectively, with poorer survival in patients with renal disease and pulmonary hypertension (PH). Independent prognostic factors for mortality were older age at diagnosis, diffuse skin involvement, proteinuria, PH, and elevated erythrocyte sedimentation rate. Conclusions Ten-year survival is over 70% in Spanish SSc patients. The main causes of death are lung and cardiac involvement, and to a lesser extent, peripheral vascular disease and coexisting malignancy. Diffuse subset, proteinuria, PH, elevated erythrocyte sedimentation rate and older age at diagnosis are the main risk factors for mortality.

Montes, Ariana et al., [Introduction] We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA)., [Methods] The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria., [Results] An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication., [Conclusions] Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA., Funding was provided by grants PI11/01048, PI12/01909 and by RETICS Program, RD08/0075/0019 and RD12/0009/0008 (RIER) of the Instituto de Salud Carlos III (Spain) that are partially financed by the European Regional Development Fund of the European Union.

Objectives We aimed to assess a functional polymorphism in FCGR2A H131R, for association with the treatment response to Fc-containing inhibitors of tumor necrosis factor (TNF). Methods A total of 429 biologic-naive patients with rheumatoid arthritis collected in two sets (299 and 130) were treated during standard care with infliximab (INX), etanercept, or adalimumab. Response to the treatment was evaluated at 3, 6, and 12 months of follow-up as the change in the Disease Activity Score (DAS) 28 from baseline and as the response by the European League Against Rheumatism (EULAR) criteria. These variables were analyzed for association with linear and logistic regression models that included sex, inhibitors of TNF, and baseline DAS28 as covariates. Results Significant association was found between the FCGR2A H131R polymorphism and the response to treatment with INX, but not with the other two TNF inhibitors. The 131R allele was associated with a lower change in DAS28 (P=0.04-0.008 at different times) in the first set of patients and confirmed in the second group of patients (P=0.026 at 3 months of follow-up). Association was also found in the comparison between nonresponders and responders to INX by the EULAR criteria. Conclusion We found an association of the FCGR2A 131R allele with poor response to INX. This finding could be of utility to understand the mechanisms behind treatment failure and contribute to biomarker panels for INX response prediction.

[Introduction] In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations., [Methods] The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients., [Results] None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis., [Conclusion] Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes., The work done at Consejo Superior de Investigaciones Científicas (CSIC) was supported by AbbVie Pharmaceuticals and partially by Cooperative Research Thematic Network (RETICS) programs RD08/0075/0011, RD12/0009/0004, RD12/0009/0012 and RD12/0009/0016 (RIER); “Instituto de Salud Carlos III” (ISCIII, Health Ministry, Madrid, Spain); and grants from the European Innovative Medicines Initiative (IMI) Be the Cure for Arthritis (BTCure) program. The work done in Santiago de Compostela was funded by Fondo de Investigación Sanitaria from ISCIII, (Health Ministry, Madrid, Spain), grants PI11/01048, PI12/01909, RD08/0075/0019 and RD12/0009/0008, which are partially financed by the European Regional Development Fund of the European Union. The sponsors had no role in the design of the study; in the collection, analysis or interpretation of data; or in the preparation, review or approval of the manuscript.

Background Some studies suggest that clinical subgroups of idiopathic inflammatory myopathies (IIM) and several myositis-specific antibodies (MSAs) could influence the prognosis of IIM with interstitial lung disease (ILD). Objectives To investigate the prognosis value of different clinical subgroups and of MSAs in a cohort of patients with IIM -associated ILD. Methods We analyzed patients with IIM-associated ILD included in the multicenter registry REMICAM (1980–2014). We compared prognosis between a) subgroups of IIM: dermatomyositis (DM) vs. polymiosytis (PM) (primary, juvenile, cancer-associated myositis or overlap myositis); and b) absence (−) or presence (+) of anti-Jo1 vs. anti-RO vs. anti-Jo1 and anti-RO. In this preliminary analysis, outcomes were mortality and change between final and initial visit in FVC and DLCO. Results 478 patients were included in the registry, of which 143 had ILD, 66% PM and 34% DM. The distribution by MSAs was: 56% anti-Jo1-/RO-, 20% anti-Jo1+, 9% anti-RO+ and 15% anti-Jo1+/RO+. There were 52 deaths; the main causes were 32.6% cardiovascular events and 22.4% infections without difference between subgroups of IIM. The probability of survival was 50% to 18.8 years and the mortality rate was 37.7/1000 patient-ys. We did not find differences when we compared survival between subgroups of IIM or we compared by MSAs. FVC seemed to improve more in DM than in PM patients (1.2±5.2vs. 0.5±4.7;p=0.059), but there were no significant changes in DLCO of DM patients or in FVC and DLCO according to MSAs. Conclusions We did not find prognostic differences in the causes of mortality, mortality rate between subgroups of IIM, or in mortality rate according to MSAs in patients with ILD. In DM patients there was a trend towards a greater improvement of FVC than in PM patients. Disclosure of Interest None declared

Background Classically the prognosis of idiopathic inflammatory myopathies (IIM) has improved in recent decades, but can still be poor in certain subgroups or in the presence of some clinical factors. Objectives To analyze survival, causes of death and poor prognosis factors in a cohort of patients diagnosed with IIM. Methods A multicenter retrospective study from REMICAM 1 myositis study group was performed. All patients were diagnosed with IIM according to Bohan and Peter 2 criteria and were classified into 5 different clinical subgroups: primary dermatomyositis (DM), primary polymyositis (PM), juvenile dermatomyositis (JuvM), cancer associated myositis (CAM) and overlap myositis (OM). Results 478 IIM cases were included. 74% of the cases were women, with an age at diagnosis of 43.7±22.6 ys. and a mean follow-up of 9.7±8.3 ys. During the follow-up period there were a total of 114 deaths (24%), the main causes were infections (24%), cancer (24%), and cardiovascular events (22%). Factors associated with poor prognosis were CAM (HR 15.4) and OM subgroups (HR 4.55), older age at diagnosis (HR 1.05), shorter time of disease (HR 1.30), serious infections (HR 4.57), cancer (HR 3.07), systemic symptoms (HR 1.64), heart (HR 2.52) and haematological manifestations (HR 1.53), ESR/CRP elevation at baseline (HR 3.05) and chronic renal failure (HR 2.41). The clinical characteristics that showed a protective effect were arthralgia (HR 0.68), typical skin lesions (HR 0.62), drug use (HR 0.53) and female sex (HR 0.5). In multivariate analysis the independent variables associated with mortality were CAM (HR 8.83) and OM (HR 5.17) subgroups, severe infections (HR 3.42), older age at diagnosis (HR 1.03), shorter course of the disease (HR 1.34), thrombocytopenia (HR 2.93) and elevated ESR/CRP (HR 2.47). Conclusions In our REMICAM registry on inflammatory myopathies 24% of patients died, mainly due to infections, cancer and cardiovascular events. The independent predictors of mortality were belonging to the subgroups of paraneoplastic myopathies or overlap syndrome, the presence of severe infections, thrombocytopenia, elevated ESR/CRP at baseline, shorter course of the disease and older age at onset. References REMICAM: Registry on inflammatory myopathies in Madrid Bohan A, Peter JB. N Engl J Med 1975 Feb 13;292(7):344–7. Disclosure of Interest L. Nuno Grant/research support from: SORCOM-MSD grant for myositis study, M. J. Garcia: None declared, B. Joven: None declared, V. Maldonado: None declared, I. Llorente: None declared, C. Barbadillo: None declared, P. Garcia de la Pena: None declared, L. Ruiz: None declared, H. Moruno: None declared, T. Cobo: None declared, R. Almodovar: None declared, L. Lojo: None declared, F. J. Lόpez Longo: None declared

Background Three large GWAs (1-3) examining the response to TNF inhibitors have provided evidence suggesting 16 SNP associations, but none of them reached the GWAS significance threshold. Objectives We aim to replicate association of the 16 SNPs with TNFi response in an independent sample collection. Methods A total of 755 European RA patients receiving TNFi (397 infliximab, 155 etanercept, and 203 adalimumab) were included. Response was evaluated either as change in the disease activity score using 28 joints (ΔDAS28) between baseline and 3, 6 and 12 months of treatment, or as classification according to the EULAR response criteria (good + moderate responders vs. non responders) at the same time points. The genotypes of the 16 SNPs were obtained with a single-base extension methodology. We considered the SNPs according to an additive model in linear and logistic regression analyses, for ΔDAS28 and EULAR criteria, respectively. Baseline DAS28, gender and treatment were considered as covariates. Results All the SNPs were successfully genotyped (call rate=99.5%; HWE>0.05). None of them was associated with response to TNFi at any time of follow-up. However, NUBPL rs2378945 minor allele (A) showed the same trend as the reported by Mirkov et al. (B = -0.14, 95% CI -0.31-0.03, P=0.10 for ΔDAS28 at 3 months as reported). This trend became a significant association after stratifying by drug, in the subgroup treated with etanercept (B = -0.50, 95% CI (-0.82, -0.17), P=0.003), but no association or trend was identified with the other drugs. Conclusions We have found a specific association with response to etanercept of NUBPL rs2378945, which is an analysis not reported in the original GWAS and, therefore, not amounting to replication. None of the other 15 associations was replicated, indicating that none of the results from these GWAS could still be taken as validated. References Mirkov et al. Ann Rheum Dis. 2013 Aug;72(8):1375-81 Plant et al. Arthritis Rheum. 2011 Mar;63(3):645-53 Cui et al. Rheum Dis Clin North Am. 2009 Nov;35(4):745-57 Acknowledgements Instituto de Salud Carlos III (Spain), grants PI11/01048, PI12/01909 and RD12/0009/0008 that are partially financed by the European Regional Development Fund Disclosure of Interest None declared

Background Clinical manifestations and prognosis of idiopathic inflammatory myopathies (IIM) are extremely heterogeneous which, combined with its low prevalence, makes difficult the study of the disease in the absence of multicenter studies. Objectives To analyze the clinical characteristics and mortality in a cohort of patients diagnosed with IIM in rheumatology units from several hospitals in Madrid. Methods A multicenter retrospective longitudinal descriptive study from REMICAM myositis study group was performed. All patients diagnosed with IIM according to Bohan and Peter1 criteria for myositis and in follow-up sometime between January 1980 and December 2014 in rheumatology units were included. Patients were classified into clinical subgroups: primary dermatomyositis (DM), primary polymyositis (PM), juvenile dermatomyositis (JDM), paraneoplasic myositis, overlap myositis (OM), inclusion body myositis (IBM) and necrotizing myositis (NM). Main causes of death and influence of age and sex were studied. Results 485 cases were included in this study, with a medium age at diagnosis of 43,3±23,2 years and mean follow-up time of 11,3±19 years. Most cases were Caucasian (93%), and women (74,4%). The most frequent form of classification were primary myopathies (28,8% PM; 21% DM; 20,6% OM; 19,4% JDM; 8,3% paraneoplasic myositis; 1% IBM and 0.8% NM) and the most frequent myositis specific antibodies detected were anti-Jo-1 (16,3% anti-Jo-1; 4,1% anti-Mi-2; 2,7% anti-PM-Scl; 0,6% anti-SRP; 0,2% anti-Ku). 25,4% of patients died, with a higher mortality rate in men (32,5% vs. 22,9; p=0,04) and older age at onset (54,1±24,8 years vs. 37,2±26,4 years, p Conclusions In our cohort of IIM 25,4% of patients died, with a worse prognosis in men and older age at onset, mainly due to cancer and cardiovascular events. Cardiovascular events are the most important cause of death in PM and MCTD, and infections in DM. References Bohan A, Peter JB. N Engl J Med 1975 Feb 13;292(7):344-7. Disclosure of Interest None declared

Tumour necrosis factor α (TNFα) has a key role in chronic arthritis,1 but it also participates in the defence against infection. TNFα, together with interferon γ, contributes to the immune response against mycobacteria.2 This can explain the higher incidence of tuberculosis seen in patients receiving anti-TNFα treatment.3 Therefore, a tuberculin purified protein derivative (PPD) test has been recommended before starting anti-TNFα treatment to better identify patients at risk for tuberculosis reactivation requiring isoniazid treatment.4 However, patients with chronic arthritis can be anergic to delayed-type hypersensitivity (DTH) tests, owing to either active disease or to immunosuppressive treatment.5 Some authors have previously shown that the DTH response in patients given second line treatment improves, but the effect of anti-TNFα treatment is not known.6 We have studied, …

Supporting information:S1 Text. Information on selected previous studies and compatibility with the current study. It includes two tables. Table A: List of SNPs selected for this study with references and the corresponding quality control results in the current study. Table B: Characteristics of the patients included in previous studies compared with the current study. https://doi.org/10.1371/journal.pone.0196793.s001 (DOCX) S1 Dataset. Raw data with all the variables and patients considered in this study. https://doi.org/10.1371/journal.pone.0196793.s002 (XLSX), Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi., Funding: This work was supported by the Instituto de Salud Carlos III (Spain) through grants [PI14/01651 and RD16/0012/0014 to AG; and PI12/01909 to JJG-R]. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). R. L.-R. was supported by Instituto de Salud Carlos III (Spain) through a Postdoctoral Contract “Sara Borrell” [CD14/00186]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.