Objective To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. MethodsWe conducted a multicentre, international, retrospective cohort study. Results149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. ConclusionThe clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

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Supplementary table S 1. Baseline characteristics of the sample Age (years) 20-29 623 (12.7%) 30-39 957 (19.5%) 40-49 1055 (21.5%) 50-59 836 (17%) 60-69 683 (13.9%) 70-79 462 (9.4%) ≥80 300 (6.1%) Male sex 2238 (45.5%)

Background:Two antisynthetase syndrome (ASSD) diagnosis criteria sets have been proposed; both consider mandatory the presence of anti-aminoacyl transfer RNA synthetase (ARS) autoantibodies. Solomon’s criteria consider major clinical criterions (interstitial lung disease (ILD) and fulfillment of Bohan and Peter criteria for DM/PM) and minor criterions (arthritis, Raynaud’s phenomenon (RP) and mechanic’s hands (MH)) (1). In contrast, Connors criteria evaluate the presence of at least one of the previously mentioned clinical features except myositis, and includes the presence of fever without other cause (2).Objectives:1) to evaluate the performance of Solomon’s and Connors’ criteria in patients with clinical suspicion of aSSD or myositis and positive aRS. 2) to describe their clinical characteristics.Methods:We performed an observational retrospective study in two centers. All patients with clinical suspicion of aSSD or myositis, and positive aRS in the myositis immunoblot (Euroimmun assay) were included.Results:We analyzed 37 patients; 70.3% woman, with a mean age at the moment of the aRS detection of 51.4 (SD±14.0) years, median time from the first symptom to the aRS detection of 4.0 (SD±5.8) years, and time of evolution of 7.69 (SD±6.51) years. The frequency of aRS was: anti-Jo1 (n=17), anti-PL-12 (n=8), anti-PL-7 (n=4), anti-EJ (n=4), and anti-OJ (n=4).Diagnosis criteria fulfillment and clinical manifestations:1) Patients that met Solomon and Connors’ criteria (n=17, 45.9%):- at disease onset: ILD (n=6, 35.9%), muscle weakness (MW) (n=5, 29.4%), and arthritis (n=4, 23.5%).- During disease development: ILD (n=14, 82.3%); arthritis (n=13, 76.5%); MW (n=10, 58.8%); mechanic hands (n=10, 58.8%); Raynaud phenomenon (n=8, 47.0%); and fever (n=3, 17.5%).2) Patients that only met Connors’ criteria (n=17, 45.9%):- at disease onset: ILD (n=5, 29.4%), MW (n=3, 17.6%), or arthritis (n=5, 29.4%).- During disease development: arthritis (n=8, 47.0%); ILD (n=6, 35.3%); MW (n=6, 35.3%); Raynaud phenomenon (n=6, 35.3%); fever (n=5, 29.4%); and mechanic hands (n=1, 5.9%).Relative risk (RR) of the different clinical manifestation for Solomon’s criteria fulfillment:- MH RR=2.98 (95%CI 1.5-5.6; P=0.002), ILD RR=3.2 (95%CI 1.1-9.2; P=0.013); other manifestations does not presented significant RR.Conclusion:More than three quarter of all patients presented as first clinical manifestation one of those included in the aSSD classic triad (ILD, MW and arthritis). These manifestations showed increasing rates during the disease development, being more frequent in patients that met Solomon’s criteria than in those who only met Connor’s criteria; more than twice as high in for ILD, and almost twice for MW and arthritis. This suggests that patients who met Solomon’s criteria, at disease onset presented incomplete clinical forms, and their clinical progression favored the criteria fulfillment. On the other hand, we cannot predict if the patients that only met Connors’ criteria are going to fulfill Solomon’s criteria; nevertheless, our results s...