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In order to identify risk factors for SARS-CoV-2 infection as well as for severe/critical COVID-19 in rheumatic and musculoskeletal diseases (RMDs) patients, we conducted a multicentre observational nationwide study of adult patients prospectively-followed in the Rheumatic Diseases Portuguese Register – Reuma.pt – during the first 6 months of the pandemic. We further evaluated the development of IgG antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 in patients with RMDs. We used multivariate logistic regression to compare patients with COVID-19 (COVID-19+) with those who did not develop the disease (COVID-19-) and patients with mild/moderate disease with those exhibiting severe/critical COVID-19. COVID-19+ patients were asked to collect a blood sample for IgG testing ≥ 3 months after infection and results were compared with age-, sex- and sampling date-matched controls. Overall, 179 cases of COVID-19 were registered in Reuma.pt in the period of interest (median age 55 (IQR 20); 76.5% females) in a total of 6404 registered appointments. We found that patients treated with TNF inhibitors had reduced odds of infection (OR=0.16, 95%CI 0.10-0.26, p

Key Points Question Is receipt of tumor necrosis factor (TNF) inhibitor monotherapy at the time of COVID-19 diagnosis associated with adverse COVID-19 outcomes compared with other treatment regimens among patients with immune-mediated inflammatory diseases (IMIDs)? Findings In this cohort study of 6077 patients with IMIDs and COVID-19, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, or Janus kinase inhibitor monotherapy were each associated with significantly higher odds of hospitalization or death compared with TNF inhibitor monotherapy. Meaning This study’s findings support the continued use of TNF inhibitor monotherapy among individuals with IMIDs during the pandemic., Importance Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19–associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures The main outcome was COVID-19–associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P, This cohort study uses data from 3 international registries to examine the association between the receipt of tumor necrosis factor monotherapy and the risk of COVID-19–associated hospitalization or death among adult patients with immune-mediated inflammatory diseases.

Copyright © 2020 Cascão, Vidal, Carvalho, Lopes, Romão, Goncalves, Moita andFonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., Objectives: To describe our experience with a coronavirus disease 2019 (COVID-19) outbreak within a large rheumatology department early in the pandemic. Methods: Symptomatic and asymptomatic healthcare workers (HCWs) had a naso-oropharyngeal swab for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were followed clinically. Reverse transcription polymerase-chain reaction (RT-PCR) was repeated to document cure, and serological response was assessed. Patients with risk contacts within the department in the 14 days preceding the outbreak were screened for COVID-19 symptoms. Results: 14/34 HCWs (41%; 40 ± 14 years, 71% female) tested positive for SARS-CoV-2, and 11/34 (32%) developed symptoms but were RT-PCR-negative. Half of RT-PCR-positive HCWs did not report fever, cough, or dyspnea before testing, which were absent in 3/14 cases (21%). Mild disease prevailed (79%), but 3 HCWs had moderate disease requiring further assessment, which excluded severe complications. Nevertheless, symptom duration (28 ± 18 days), viral shedding (31 ± 10 days post-symptom onset, range 15-51), and work absence (29 ± 28 days) were prolonged. 13/14 (93%) of RT-PCR-positive and none of the RT-PCR-negative HCWs had a positive humoral response Higher IgG indexes were observed in individuals over 50 years of age (14.5 ± 7.7 vs. 5.0 ± 4.4, p = 0.012). Of 617 rheumatic patients, 8 (1.3%) developed COVID-19 symptoms (1/8 hospitalization, 8/8 complete recovery), following a consultation/procedure with an asymptomatic (7/8) or mildly symptomatic (1/8) HCW. Conclusions: A COVID-19 outbreak can occur among HCWs and rheumatic patients, swiftly spreading over the presymptomatic stage. Mild disease without typical symptoms should be recognized and may evolve with delayed viral shedding, prolonged recovery, and adequate immune response in most individuals.

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com, Objectives: To identify serum sphingolipids that could act as candidate biomarkers in RA. Methods: We performed lipidomic analyses in the serum of 82 participants: 19 established RA patients, 18 untreated early RA patients, 13 untreated early arthritis patients not fulfilling the classification criteria for RA, 12 established SpA patients and 20 controls. We compared the lipid levels from the different patient groups with the control group through multiple-regression analyses controlling for age at diagnosis, gender and medication (cDMARDs and corticoids). Results: Established RA patients had significantly increased levels of sphingosine, monohexosylceramide and ceramide compared with controls, when controlling for age and gender. Monohexosylceramide levels remained significantly increased when additionally controlling for medication. On the contrary, SpA patients had significantly decreased levels of ceramide, in both analyses. Conclusion: We observed a detectable increase in the levels of certain sphingolipids in the serum of established RA patients when compared with controls, in line with previous observations in the synovial fluid. Such findings provide further evidence that sphingolipids may play a key role in the pathophysiology of RA., This study was supported by a grant from thePortuguese Society of Rheumatology and by UID/BIM/50005/2019, a project funded by Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência,Tecnologia e Ensino Superior (MCTES) through Fundosdo Orçamento de Estado.

Background: The impact of gender on tumor necrosis factor inhibitors (TNFi) effectiveness has been poorly studied in Psoriatic Arthritis (PsA) patients. Objectives: To study gender differences in persistence and response of 1st TNFi in PsA patients. Methods: PsA patients prospectively followed at the Rheumatic Diseases Portuguese Registry (Reuma.pt), treated with a 1st TNFi, between 2001 and 2016. Drug retention assessed by Kaplan-Meier survival analysis and Cox models, adjusted for the year of starting a TNFi. Response rates measured by EULAR response, DAPSA remission, MDA and ASDAS response, applying LUNDEX method, were compared between genders. Baseline predictors of discontinuation and response were identified (Cox and logistic regression models). Results: 750 PsA patients, mean age 47.6 (± 11.6) years and 50.3% (n=377) females. PsA females showed significantly different baseline PsA disease characteristics in comparison with males and had more severe peripheral disease activity (Table 1). The overall TNFi survival rate for females was also significantly lower when compared with males (Figure 1). Additionally, females experienced lower rates of response at 3 and 6 months (Figure 2). Female gender was further identified as an independent predictor factor of worse persistence and showed a lower chance of good EULAR response. Conclusion: PsA females from Reuma.pt have distinct PsA features and worse persistence and response to a 1st TNFi in comparison with males. This might be related to gender dependent inflammatory pathways and was independent of baseline disease activity. Disclosure of Interests: Elsa Vieira-Sousa Grant/research support from: MSD, Novartis, Monica Eusebio: None declared, Pedro Avila-Ribeiro: None declared, Nikita Khmelinskii: None declared, Ana Rita Cruz-Machado: None declared, Teresa Martins-Rocha: None declared, Miguel Bernardes: None declared, Daniela Faria: None declared, Joana Silva: None declared, Helena Santos: None declared, Claudia Miguel: None declared, Pedro Carvalho: None declared, Tiago Costa: None declared, Lidia Teixeira: None declared, Tiago Meirinhos: None declared, Patricia Nero: None declared, Joao Eurico Fonseca: None declared, Maria Jose Santos: None declared

We thank Favalli et al for their comment on our letter1 regarding the effect of antimalarials for the prevention of coronavirus disease 2019 (COVID-19).2 The authors provide updated information on a cohort of 914 patients with rheumatic and musculoskeletal diseases (RMDs), 112 of whom were treated with hydroxychloroquine (HCQ). The prevalence of confirmed or suspected COVID-19 cases was similar in both groups, and a patient with systemic sclerosis-associated lung disease treated with HCQ had a fatal outcome. Notably, 87% of patients reported rigorous compliance with contagion prevention measures. These data are in accordance with accumulating evidence published over the last 2 months, indicating the occurrence of mild and severe cases of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with RMDs treated with antimalarials (table 1).1–16 Out of 869 reported patients with RMDs with confirmed COVID-19, 190 (22%) were taking long-term antimalarials prior to the infection.1–16 Of those, 99 out of 181 (55%) with available data developed severe …

Background:Hepatitis B virus (HBV) vaccination is recommended for rheumatic patients starting biologic therapy. There is some evidence that HBV vaccination is effective in patients under conventional disease modifying anti-rheumatic drugs (DMARDs), but it is currently unclear whether this also applies to biologics.Objectives:To assess the efficacy and safety of HBV vaccination in patients with rheumatic diseases treated with biologics.Methods:We included patients with any inflammatory rheumatic diseases treated with any biologic, who were negative for anti-HBs and anti-HBc and had never been vaccinated for HBV. Engerix B® was administered at 0, 1 and 6 months and anti-HBs was re-assessed ≥1 month after last dose. Response was defined as anti-HBs>10IU/L and compared against healthy controls (HC) undergoing Occupational Health immunization. Disease flare was evaluated before and until at least 1 month post-vaccination. We recorded serious adverse events (SAE) and immune-related disorders not previously present.Results:We included 67 patients, most treated with TNF inhibitors (TNFi), and 70 HC (Table 1). Most patients were taking concomitant DMARDs (69%) and were in remission/low disease activity (59%). Only 20 patients (30%) had a positive response to vaccination, in comparison to 68 HC (97%, pst/2nddose, deemed not to be related to vaccination. One RA patient on infliximab had bilateral uveitis 2 months after the 1stvaccine dose, which resolved with topical therapy.Table 1.Baseline characteristics of study participants.Patients (n=67)Controls (n=70)pAge (years)56 ± 946 ± 9Female (%)40 (60)62 (89)Diagnosis (%)RA32 (48)PsA / AS18 (27) / 13 (19)Other4 (6)Disease duration (years)17 ± 10Biologic (%)TNF-inhibitor53 (79)Tocilizumab / Abatacept6 (9) / 1 (1)Rituximab / Belimumab2 (3) / 4 (6)Anakinra1 (1)Conventional DMARDs (%)MTX / LEF39 (58) / 1 (1)SSZ / Other6 (9) / 3 (4)None21 (31)Prednisolone (%) / Dose (mg)29 (43) / 5.6 ± 2.1DAS283.1 ± 1.4ASDAS2.2 ± 1.4Conclusion:In this study, HBV vaccination response was poor and lower in rheumatic patients treated with biologic therapy than in healthy adults. Vaccination was overall safe but there were 4 severe flares and 3 SAE that lead to treatment switch/interruption, although causal association is difficult to establish. Our data reinforce the recommendation for HBV vaccination prior to starting biologic therapy, possibly even as soon as the diagnosis is established. Alternative HBV vaccination strategies should be investigated in patients already treated with biologics.Disclosure of Interests:Vasco C Romão: None declared, Pedro Ávila-Ribeiro Grant/research support from: Novartis, Maria João Gonçalves: None declared, Ana Rita Cruz-Machado: None declared, André Guerreiro: None declared, Vítor Teixeira: None declared, Ana Valido: None declared, Joana Silva-Dinis: None declared, Elsa Vieira-Sousa: None declared, Maria João Saavedra: None declared, Ema Leite: None declared, Rui Tato Marinho: None declared, Joao Eurico Fonseca: None declared

Background:Pregnant women with rheumatic diseases (RD) represent a population at a higher risk for adverse pregnancy outcomes (APO). At our unit, these patients (pts) are surveilled at a high-risk pregnancy clinic, by both rheumatologists and obstetricians.Objectives:To assess pregnancy outcomes in pts with RD surveilled at our unit over the last decade.Methods:Single-centre observational retrospective study of pregnant women with RD followed at a portuguese tertiary centre between 2009 to 2019.Results:Overall, 353 pregnancies (preg) in 295 pts with RD were managed at our unit. Table 1 summarizes clinical data and the main APO recorded. Systemic lupus erythematous (SLE) was the leading diagnosis followed by spondyloarthritis (SpA) and rheumatoid arthritis (RA). Antiphospholipid syndrome (APS) was diagnosed in 49 (13.9%) preg. We documented 284 (78%) live births (9 twin preg), 32 (10%) miscarriages, 7 (2%) elective abortions, 2 stillbirths (0.6%) and 2 ectopic preg; 35 (10%) of the overall preg were lost to follow up before delivery. Miscarriages occurred predominantly in pts with APS (34%). Fetal growth restriction (FGR) was recorded in 6% of preg, more than 1/3 of those in pts with APS. Preeclampsia (PE) complicated a total of 10 (4%) preg, 3 of those with superimposed HELLP syndrome, with SLE and APS accounting for 60% of the cases. Preterm births (15.5%) occurred mainly in APS, SLE and juvenile idiopathic arthritis (JIA) pts. Neonatal lupus ensued in 3 (3.8%) preg positive for anti-Ro/La antibodies. No neonatal deaths were recorded. SpA and RA represented the diseases which flared the most considering both pregnancy and the postpartum period.Table 1.Pregnancy outcomes by diseaseMain diagnosisN, %Gest age at delivery(weeks)MiscarrFGRPEPreterm birthsFlares in pregFlares in PPSLE116,32.938±2.313/110,11.86/82,7.35/78,6.415/76,21.116/92,17.45/79,6.3SpA60,1739±2.62/55,3.65/44,11.41/45,2.25/40,12.518/40,455/23,21.7RA51,14.439±1.26/49,12.21/35,2.91/33,31/29,3.410/37,277/30,23.3Vasculitis25,7.138±1.81/24,4.21/21,4.80/19,04/21,197/23,30.42/17,11.8Primary APS22,6.238±1.63/22,13.61/17,5.91/16,6.32/16,12.5NANAJIA17,4.838±2.51/17,5.90/12,00/11,04/12,33.32/13,15.41/8,12.5UCTD15,4.239±1.52/15,13.30/11,01/10,101/11,9.10/15,00/15,0Primary Sjögren Syndrome12,3.439±1.40/11,00/9,00/10,01/9,11.11/8,12.50/6,0Others35,9.938±2.34/31,12.92/20,101/18,5.63/18,16.74/27,14.81/22,4.5Total353,10038±2.232/334,9.616/251,6.410/240,4.236/232,15.558/255,22.721/200,10.5Secondary diagnosisAPS2737±2.78/26,30.85/16,31.32/12,16.75/15,33.3NANASjögren Syndrome937±2.51/9,11.11/7,14.30/7,03/6,50NANALegend - gest: gestational; miscarr: miscarriages; NA – not applicable; PP: postpartum; preg: pregnancy; UCTD - Undifferentiated connective tissue disease. Continuous variables are presented as mean±SD. Categorical variables as n/mN, % - modified(m)N stands for total N – (not applicable+missing data); “Others” accounts for diagnosis with N≤6, such as APS non criteria, mixed connective tissue disease, myositis, overlap syndromes, Still’s disease and systemic sclerosis.Conclusion:In pregnant women with RD, it is of vital importance to be aware of the increased risk for APO. In our cohort, APS and SLE were the conditions most associated with APO, while SpA and RA were responsible for most maternal flares. Nevertheless, the majority of these pts, surveilled by a multidisciplinary team, had successful gestations.Disclosure of Interests:None declared

Background:Disease activity (DA) at conception is one of the main predictors of pregnancy outcomes in women of childbearing age (WoCBA) with rheumatic diseases. Teratogenicity and unawareness about pregnancy compatibility of some disease-modifying anti-rheumatic drugs might limit the choice of treatment in WoCBA.Objectives:To assess differences in prescription patterns between WoCBA with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and juvenile idiopathic arthritis (JIA) and comparator groups, namely postmenopausal women (PMW) and age-matched men. Evaluate DA in WoCBA comparing to the aforementioned groups.Methods:Observational transversal study, using data from the portuguese registry of rheumatic diseases (Reuma.pt) from 3 portuguese centers. Adult patients (pts) with the diagnosis of RA, PsA, AS or JIA were allocated to the following groups: WoCBA (aged 18–44y), young men (YM) (18–44y), PMW (≥ 45y) and matched men (≥45y). Demographic and clinical variables are described as means or frequencies. Differences between groups regarding therapy and DA were assessed with Chi-square and ANOVA tests. Linear and logistic regression models were used to find predictors of DA and prescription patterns.Results:2133 pts were included, 69.9% female with a mean age of 55.96±15.85 y. 1437 pts were diagnosed with RA, 305 with PsA, 254 with AS and 137 with JIA. Patterns of prescription are detailed in table 1. WoCBA were less likely to be treated with glucocorticoids than PMW (OR 0.66 95%CI 0.44-0.99). WoCBA were 1.76 times more likely to be treated with MTX than YM (95%CI 1.04-2.97). Certolizumab was specially prescribed in WoCBA (OR 13.8, 95%CI 1.4-132.8). WoCBA had significantly higher DA scores than YM (DAS28 3.03±1.39 vs 2.32±1.18 and BASDAI 3.55±2.0 vs 2.43±1.66).Table 1.Prescription patternsMedications, n (%)A -WoCBA(N=256)B - Young Men(N=161)C - Post menopausal Women(N=927)D - MenN=340Chi-square testNSAIDs143 (55.9)111(68.9)472 (50.9)169 (49.7)pGlucocorticoids106 (41.4)31 (19.3)625 (67.4)154 (45.3)pcsDMARDs- Methotrexate149 (58.2)60 (37.3)663 (71.5)197 (57.9)p- Leflunomide12 (4.7)4 (2.5)45 (4.9)2 (0.6)p=0.003- Sulfassalazine9 (3.5)5 (3.1)39 (4.2)9 (2.7)NS- Hydroxychloroquine36 (14.1)4 (2.5)117 (12.6)18 (5.3)pbDMARDs- Etanercept48 (18.8)29 (18.0)140 (15.1)66 (19.4)NS- Infliximab9 (3.5)11 (6.8)36 (3.9)30 (8.8)p=0.002- Adalimumab17 (6.6)15 (9.3)47 (5.1)27 (7.9)NS- Golimumab15 (5.9)18 (11.2)37 (4.0)30 (8.8)p- Certolizumab10 (3.9)0 (0)2 (0.3)2 (0.6)p- Tocilizumab12 (4.7)2 (1.2)71 (7.7)10 (2.9)p- Rituximab5 (1.9)0 (0)50 (5.4)4 (1.2)p- Abatacept0 (0)0 (0)9 (1)0 (0)NS- Secukinumab1 (0.4)4 (3.5)8 (0.9)2 (0.6)NS- Ustekinumab1 (0.4)3 (1.9)5 (0.5)0 (0)NStsDMARDs4 (1.6)1 (0.6)9 (0.9)0 (0)NSbDMARDs – biologic disease modifying antirheumatic drugs, csDMARDs – conventional synthetic disease modifying antirheumatic drugs, NSAIDs – non-steroidal anti-inflammatory drugs, tsDMARD – targeted synthetic disease modifying antirheumatic drugs, WoCBA – women of childbearing ageConclusion:Certolizumab was prescribed preferentially in WoCBA, who alsoreceived more MTX than YM. Nevertheless, DA in this group was not well controlled, which may influence future pregnancy outcomes. Ensuring tight DA control in WoCBA through proper and ideally no teratogenic medication remains an unmet clinical need.Disclosure of Interests:None declared

Background The treat-to-target concept is currently recommended in axSpA management and remission is the main objective of treatment. Although consensual definitions of remission are lacking, most authors assume remission as a state of inactive disease or, alternatively, of low disease activity, as a near concept. In current practice, ASAS-Partial Remission (ASAS-PR) and ASDAS-Inactive Disease (ASDAS-ID) scores have gained wide acceptance as clinical remission-like definitions. Objectives In this review we assessed the efficacy of different biologic disease-modifying anti-rheumatic drugs (bDMARD) in achieving ASAS-PR or/and ASDAS-ID as remission-like primary outcomes. Data from randomised controlled trials (RCT) conducted in radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) patients were included. Methods A systematic literature review was performed using the MEDLINE database (August 17 2017) with the filters “published in the last 10 years” and “humans”. The PICO (P, population; I, intervention; C, comparison; O, outcome) concept was used to perform the analysis according to: Patients – adults (>18 years old) with r-axSpA or nr-axSpA; Intervention – any bDMARD regardless of formulation or duration; Comparison – placebo and/or any different drug; Outcomes: ASAS-PR and ASDAS-ID. Results After screening 557 references (after de-duplication), 7 RCTs fulfilled the inclusion criteria, all concerning tumour necrosis factor inhibitors (TNFi) bDMARDs – table 1. ASAS-PR was the most commonly used remission-like definition- in 6 of the 7 trials, 1 of those as a composed measure with a magnetic resonance score. Despite different baseline populations (including r-axSpA and nr-axSpA), all these trials provide evidence of TNFi efficacy in achieving remission. The proportion of patients achieving ASAS-PR and ASDAS-ID varied between 33%–61.9% and 27.3%–55%, respectively, with a minimum and maximum follow-up periods of 28 to 254 weeks for ASAS-PR and 24 weeks to 5 years for ASDAS-ID. Conclusions Clinical trials addressing remission-like concepts as primary outcomes are scarce. ASAS-PR score was the most commonly used remission outcome. Depending on the studies, between one third to one half of patients treated with TNFi achieved ASAS-PR or ASDAS-ID. Considering nowadays aimed treatment targets, these data raise the unmet need for improved treatment options and strategies, that favour optimised remissions rates in axSpA patients. References [1] Braun2008. [2] Davis2008. [3] Sieper2011. [4] Sieper2012. [5] Song2012. [6] Sieper2013. [7] van Heijde2014. [8] van Heijde2016. [9] Smolen2017. Disclosure of Interest None declared