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Objectives: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases., Methods: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019., Results: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10). Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years). Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued., Conclusion: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs., Competing Interests: Competing interests: XM received consulting fees from BMS, Novartis, Sanofi, Pfizer, UCB, Janssen, GSK, Galapagos and BMS and is RMD Open associate editor. JE-G received grants from BMS, Lilly, Pfizer (payments made to University of Strasbourg Foundation; no access to TATA data) and consulting fees from BMS, Galapagos, Abbvie, Janssen, Novartis, Pfizer, Sanofi, Gilead, Roche, Chugai and Lilly., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica., Objective: To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica., Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day., Interventions: Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone., Main Outcomes and Measures: The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone., Results: Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group., Conclusions and Relevance: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms., Trial Registration: ClinicalTrials.gov Identifier: NCT02908217.

Objectives: To describe new-onset IBD (new IBD) in patients treated with IL-17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life., Methods: A French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case-control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease., Results: Thirty-one cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and four patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5-7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). Two patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 patient-years [PY] (7/1010) in 2016 to 0.08/100 PY (6/7951) in 2019. No previous treatment with etanercept (odds ratio [OR] = 0.33, 95% CI: 0.14-0.80, P = 0.014) and low number of previous biologic therapies (OR = 0.67, 95% CI: 0.47, 0.94, P = 0.021) were significantly associated with new IBD., Conclusion: The incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The management of psoriatic arthritis (PsA) has long been equated with that of rheumatoid arthritis (RA), particularly because methotrexate (MTX) was found efficient in RA in the 1990s. However, results of collective evidence-based medicine, included and argued in this narrative review, do not currently support the use of MTX as first-line therapy in severe PsA. A recent Cochrane systematic review examining the efficacy of MTX in PsA concluded that low-dose MTX was only slightly more effective than placebo. Questions about a structural effect of MTX in PsA remains non-elucidated. Even if tolerance data on MTX are more consensual and adverse events generally non-severe, subjective side effects such as fatigue might lead to MTX withdrawal based on the patient's decision. PsA patients with axial disease, radiographic lesions, and extensive and disabling skin or joint involvement should receive early treatment with targeted therapy and no longer with MTX. Finally, the usefulness of MTX combined with targeted therapies is limited. MTX does not affect efficacy but only seems to increase the therapeutic maintenance of monoclonal TNF inhibitors. This narrative review may help clarify the place of MTX in PsA management. It allows for reflection on the evolution of current concepts and practices., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.F. has received speaker and consultant fees from Abbvie, BMS, Janssen, Lilly, Nordic, Novartis, Medac, MSD, Pfizer, Sanofi, and UCB. G.L.C. declare no conflict of interest. E.L. has received speaker and consultant fees from Celgene, Lilly, MSD, Novartis, and Pfizer., (© The Author(s), 2022.)

The coronavirus disease 2019 (COVID-19) pandemic has accelerated changes to rheumatology daily clinical practice. The main goal of the 12th International Immunology Summit, held 25-26 June, 2021 (virtual meeting), was to provide direction for these active changes rather than undergoing change reactively in order to improve patient outcomes. This review describes and explores the concept of change in rheumatology clinical practice based on presentations from the Immunology Summit. Many of the changes to rheumatology practice brought about by the COVID-19 pandemic may be considered as having a positive impact on disease management and may help with the long-term development of more patient-focused treatment. Rheumatologists can contribute key knowledge regarding the use of immunosuppressive agents in the context of the pandemic, and according to the European League Against Rheumatism, they should be involved in any multidisciplinary COVID-19 guideline committees. New technologies, including telemedicine and artificial intelligence, represent an opportunity for physicians to individualise patient treatment and improve disease management. Despite major advances in the treatment of rheumatic diseases, the efficacy of available disease-modifying anti-rheumatic drugs (DMARDs) remains suboptimal and data regarding serological biomarkers are limited. Synovial tissue biomarkers, such as CD68 + macrophages, have shown promise in elucidating pathogenesis and targeting treatment to the individual patient. In spondyloarthritis (SpA) or psoriatic arthritis (PsA), information regarding the effectiveness of the available agents with different mechanisms of action may be integrated to manage patients using a treat-to-target approach. Early diagnosis of SpA and PsA is important for optimisation of treatment response and long-term outcomes. Improving our understanding of disease pathogenesis and practice methods may help reduce diagnostic delays, thereby optimising disease outcomes in patients with rheumatic diseases., (© 2022. The Author(s).)

Competing Interests: LA reports consulting fees and honoraria from Pfizer and AstraZeneca, outside this work. All other authors declare no competing interests. NZ, LEK, IH, and MM designed the study and were part of the steering committee that wrote the study protocol, included participants from their respective countries, and supervised the recruitment of participants in all the countries. LA and RF provided the original questionnaire from the VAXICOV study and participated in the questionnaire adaptation and in the finalisation of the protocol. NZ, LEK, MM, and IH drafted the manuscript and handled the comments of the authors. NA, HH, ME, MER, BM, FA, WH, AA, and AAN participated in the study design and protocol, included participants from their respective countries, and helped in addressing logistical issues during recruitment. NZ and IH analysed the results of the survey and designed the tables and figures. All authors made substantial contributions to work and participated in the discussion of the study results, the draft of the manuscript, and revised the final submitted document for intellectual content. All the authors approved the version to be published and agreed to be accountable for all aspects of the work. RF and LA contributed equally.

The antimalarial hydroxychloroquine (HCQ) has demonstrated several crucial properties for the treatment of systemic lupus erythematosus (SLE). Herein, we reviewed the main HCQ pharmacologic features, detailed its mechanism of action, and summarized the existing guidelines and recommendations for HCQ use in rheumatology with a systematic literature search for the randomized controlled trials focused on lupus. HCQ has been shown to decrease SLE activity, especially in mild and moderate disease, to prevent disease flare and to lower the long-term glucocorticoid need. The numerous benefits of HCQ are extended to pregnancy and breastfeeding period. Based on cohort studies, antithrombotic and metabolic HCQ's effects were shown, including lipid-lowering properties, which might contribute to an improved cardiovascular risk. Moreover, early HCQ use in antinuclear antibodies positive individuals might delay the progression to SLE. Finally, HCQ has a significant favorable impact on long-term outcomes such as damage accrual and mortality in SLE. Based on these multiple benefits, HCQ is now the mainstay long-term treatment in SLE, recommended by current guidelines in all patients unless contraindications or side effects. The daily dose associated with the best compromise between efficacy and safety is matter of debate. The concern regarding retinal toxicity rather than proper efficacy data is the one that dictated the daily dosage of ⩽5 mg/kg/day actual body weight currently agreed upon., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Objective: We recently recorded a high prevalence of inclusion body myositis (IBM) in patients with Sjögren's syndrome (SS). Whether myositis patients with SS differ from myositis patients without SS in terms of the characteristics of the myositis is currently unknown. Anti-cytosolic 5'-nucleotidase 1 A (cN1A) has recently been proposed as a biomarker for IBM but is also frequent in SS. Whether anti-cN1A is independently associated with IBM is still an open question. We aimed to assess the significance of SS and anti-cN1A in myositis patients., Methods: Cumulative data on all myositis patients (EULAR/ACR 2017 criteria) screened for SS (ACR/EULAR 2016 criteria) in a single centre were analysed. Ninety-nine patients were included, covering the whole spectrum of EULAR/ACR 2017 myositis subgroups and with a median follow-up of 6 years (range 1.0-37.5). The 34 myositis patients with SS (myositis/SS+) were compared with the 65 myositis patients without SS (myositis/SS-)., Results: . IBM was present in 24% of the myositis/SS+ patients vs 6% of the myositis/SS- group (P = 0.020). None of the IBM patients responded to treatment, whether they had SS or not. Anti-cN1A was more frequent in myositis/SS+ patients (38% vs 6%, P = 0.0005), independently of the higher prevalence of IBM in this group (multivariate P value: 0.02). Anti-cN1A antibody specificity for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group., Interpretation: In myositis patients, SS is associated with IBM and with anti-cN1A antibodies, independently of the IBM diagnosis. As a consequence, anti-cN1A has limited specificity for IBM in myositis patients with SS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: There was no funding for this study. LA declares consulting fees from AstraZeneca, Janssen, and BMS, unrelated to the current work. All other authors declare no competing interests. RF and FG contributed equally and have directly accessed and verified the underlying data. All authors contributed to the concept, design and drafting of the study and have approved the final version.

Competing Interests: RS has received consulting fees from GSK, BMS, Fresenius Kabi, Boerhinger, Jansen, Amgen, Pfizer, and Roche. AB has received honoraria from AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Biogen, and UCB. M-ET has received honoraria or participated on advisory boards for Galapagos, Eli Lilly, SOBI, Boehringer Ingelheim, Fresenius Kabi, MSD, and AbbVie and had received research support from Gilead. AR has received honoraria from AbbVie and Pfizer. J-EG has received honoraria or participated on advisory boards for AbbVie, BMS, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, Sanofi, Novartis, MSD, CSL-Behrin,g and Genzyme and received research support from BMS. RF has received honoraria or participated on advisory boards for AbbVie, Eli Lilly, and Pfizer. AC has received honoraria from Chugai and Pfizer. JA has received consultancy fees from AbbVie, Sanofi, and Nordic Pharma; honoraria from Galapagos, AbbVie, BMS, Sanofi, Roche-Chugai, Nordic Pharma, Biogen, Fresenius Kabi, and MSD; and research support from Pfizer, BMS, and Novartis. XM has received consulting fees from BMS, Galapagos, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, Sanofi, and UCB and research support from Ose Pharmaceutical and Pfizer. CP has received honoraria from UCB, Eli Lilly, AbbVie, Sandoz, Pfizer, and Novartis; support for attending meetings from Chugai, AbbVie, Sandoz, and Amgen; and a research grant from Pfizer. J-HS has received consulting fees or honoraria from Eli Lilly, Pfizer, AbbVie, and Galapagos. ED has received honoraria from AbbVie, Amgen, Celgene, BMS, UCB, Eli Lilly, Janssen, MSD, and Novartis. All other authors declare no competing interests. We thank the French Society of Rheumatology, the sponsor of this study. We also thank the MAJIK scientific committee and the group of MAJIK Registry investigators and Pascale Thevenot for her great help. Funding of the MAJIK Registry is supported by the French Rheumatology Society. The French Rheumatology Society received unrestricted institutional grants for conducting the MAJIK Registry from AbbVie, Galapagos, Eli Lilly, and Pfizer. The French Rheumatology Society, AbbVie, Galapagos, Eli Lilly, and Pfizer were not involved in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. RS and MC contributed to study conception, study design, data collection, statistical analysis, interpretation of data and writing - original draft. RS and MC had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. J-HS, CR, ED, AB, VG, CL, SB, M-ET, AR, J-EG, RF, FC, AC, CP, XM, and JA contributed to interpretation of data and writing - critical review for intellectual concept and editing.

Introduction: Few data are available concerning the effect of SARS-CoV-2 vaccination on the persistent symptoms associated with COVID-19, also called long-COVID or post-acute sequelae of COVID-19 (PASC)., Patients and Methods: We conducted a nationwide online study among adult patients with PASC as defined by symptoms persisting over 4 weeks following a confirmed or probable COVID-19, without any identified alternative diagnosis. Information concerning PASC symptoms, vaccine type and scheme and its effect on PASC symptoms were studied., Results: 620 questionnaires were completed and 567 satisfied the inclusion criteria and were analyzed. The respondents' median age was 44 (IQR 25-75: 37-50) and 83.4% were women. The initial infection was proven in 365 patients (64%) and 5.1% had been hospitalized to receive oxygen. A total of 396 patients had received at least one injection of SARS-CoV-2 vaccine at the time of the survey, after a median of 357 (198-431) days following the initially-reported SARS-CoV-2 infection. Among the 380 patients who reported persistent symptoms at the time of SARS-CoV-2 vaccination, 201 (52.8%) reported a global effect on symptoms following the injection, corresponding to an improvement in 21.8% and a worsening in 31%. There were no differences based on the type of vaccine used. After a complete vaccination scheme, 93.3% (28/30) of initially seronegative patients reported a positive anti-SARS-CoV-2 IgG. A total of 170 PASC patients had not been vaccinated. The most common reasons for postponing the SARS-CoV-2 vaccine were fear of worsening PASC symptoms (55.9%) and the belief that vaccination was contraindicated because of PASC (15.6%)., Conclusion: Our study suggests that SARS-CoV-2 vaccination is well tolerated in the majority of PASC patients and has good immunogenicity. Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with PASC.

B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor that is expressed by lymphoid cells and regulates the immune response. Consistent with an inhibitory role for BTLA, the disease is exacerbated in BTLA-deficient lupus mice. We recently demonstrated that the BTLA pathway is altered in CD4 + T cells from lupus patients. In the present work, we aimed at delineating the expression pattern of BTLA on CD4 + T cell subsets suspected to play a key role in lupus pathogenesis, such as circulating follicular helper T cells (cT FH ) and regulatory T cells (Tregs). We did not detect significant ex vivo variations of BTLA expression on total CD4 + T cells (naive and memory), cT FH or T FH subsets between lupus patients and healthy controls. However, we interestingly observed that BTLA expression is significantly increased on activated Tregs, but not resting Tregs, from lupus patients, especially those displaying an active disease. Moreover, it correlates with the diminution of the Tregs frequency observed in these patients. We also showed that both BTLA mRNA and protein expression remain low after TCR stimulation of activated Tregs sorted from healthy donors and evidenced a similar dynamic of BTLA and HVEM expression profile by human Tregs and effector CD4 + T cells upon T cell activation than the one previously described in mice. Finally, we observed that the HVEM/BTLA ratio is significantly lower in Tregs from lupus patients compared to healthy controls, whereas ex vivo effector CD4 + T cells express higher BTLA levels. Our data suggest that an altered expression of BTLA and HVEM could be involved in an impaired regulation of autoreactive T cells in lupus. These results provide a better understanding of the BTLA involvement in lupus pathogenesis and confirm that BTLA should be considered as an interesting target for the development of new therapeutic strategies., 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 © 2021 Aubergeon, Sawaf, Felten, Gottenberg, Dumortier and Monneaux.)

Introduction: Given the COVID-19 pandemic, it is crucial to understand the underlying behavioural determinants of SARS-CoV-2 vaccine hesitancy in patients with autoimmune or inflammatory rheumatic diseases (AIIRDs). We aimed to analyse patterns of beliefs and intention regarding SARS-CoV-2 vaccination in AIIRD patients, as a mean of identifying pragmatic actions that could be taken to increase vaccine coverage in this population., Methods: Data relating to 1258 AIIRD patients were analysed using univariate and multivariate logistic regression models, to identify variables associated independently with willingness to get vaccinated against SARS-CoV-2. Subsets of patients showing similar beliefs and intention about SARS-CoV-2 vaccination were characterized using cluster analysis., Results: Hierarchical cluster analysis identified three distinct clusters of AIIRD patients. Three predominant patient attitudes to SARS-COV-2 vaccination were identified: voluntary, hesitant and suspicious. While vaccine willingness differed significantly across the three clusters (P < 0.0001), there was no significant difference regarding fear of getting COVID-19 (P = 0.11), the presence of comorbidities (P = 0.23), the use of glucocorticoids (P = 0.21), or immunocompromised status (P = 0.63). However, patients from cluster #2 (hesitant) and #3 (suspicious) were significantly more concerned about vaccination, the use of a new vaccine technology, lack of long-term data in relation to COVID-19 vaccination, and potential financial links with pharmaceutical companies (P < 0.0001 in all) than patients from cluster #1 (voluntary)., Discussion: Importantly, the differences between clusters in terms of patient beliefs and intention was not related to the fear of getting COVID-19 or to any state of frailty, but was related to specific concerns about vaccination. This study may serve as a basis for improved communication and thus help increase COVID-19 vaccine coverage among AIIRD patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Clinical practice needs the identification of the patient disease. The physician has to rationalize symptoms allowing the recognition of a realistic entity and its classification in a reference nosology. Unlike other practices, the biomedical model uses scientific census methodology, from a tabular perspective to the definition of diseases. Due to its simplification process, it therefore neglects transitional or complex cases. In Rheumatology, this reasoning is challenged by the lack of objectivity and specificity of the items supporting the clinician when he builds the diagnosis, but also by the physiopathological complexity. Sometimes, diseases may be confused or superposed, possibly leading to the description of novel entities. The authors describe herein the difficulties encountered in practical clinical medicine. They show, from a concrete and real personal situation, how it can possibly lead to the justification of a new entity., (© 2021 médecine/sciences – Inserm.)

Introduction: COVID-19 long-haulers, also decribed as having "long-COVID" or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied., Methods: In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group., Results: The median age was 40 [interquartile range: 35-54] years and 18 (60%) were female. At a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5-8] and 5 [2-6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively., Conclusions: Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress., (© 2021. The Author(s).)

Background: Recent randomised controlled trials (RCTs) in primary Sjögren's syndrome used the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjögren's syndrome, it might be more appropriate to also assess other clinically relevant disease features. We aimed to develop a novel composite endpoint for assessing treatment efficacy in patients with primary Sjögren's syndrome: the Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS)., Methods: A multidisciplinary expert team selected clinically relevant items and candidate measurements for inclusion in the composite score. For each measurement, cutoff points for response to treatment were chosen based on expert opinion, previously published data on minimal clinically important improvements, and trial data, primarily the week-24 data of the single-centre ASAP-III trial of abatacept versus placebo. CRESS was validated using data from three independent RCTs: one trial of rituximab (TRACTISS), one of abatacept (multinational trial), and one of tocilizumab (ETAP). We calculated the number and percentage of patients who were responders in the separate CRESS items, and the percentage of responders based on the total CRESS at the primary endpoint visits (week 48 for TRACTISS, week 24 for the other two trials). Patients with fewer than three items available for evaluating CRESS response were imputed as non-responders., Findings: Based on expert opinion, five complementary items were selected to assess response: (1) systemic disease activity by Clinical ESSDAI (less than 5 points); (2) patient-reported symptoms by EULAR Sjögren's Syndrome Patient Reported Index, assessed by a decrease of at least 1 point or at least 15% from baseline; (3) tear gland item by Schirmer's test and ocular staining score, assessed by an increase of at least 5 mm or decrease of at least 2 points, respectively, in patients with abnormal Schirmer's test or ocular staining score findings at baseline, or, in patients with normal baseline values, assessed by no change to abnormal for both; (4) salivary gland item, assessed by unstimulated whole saliva secretion (increase of at least 25%) and salivary gland ultrasonography (decrease of at least 25%); and (5) serology, assessed by rheumatoid factor (decrease of at least 25%) and IgG (decrease of at least 10%). Total CRESS response is defined as response on at least three of five items. Post-hoc assessment of phase 3 trial data showed that CRESS response rates at the primary endpoint visits were 60% (24 of 40) for abatacept versus 18% (seven of 39) for placebo (p<0·0001) in ASAP-III, 49% (33 of 67) for rituximab versus 30% (20 of 66) for placebo (p=0·026) in the TRACTISS trial, 45% (41 of 92) for abatacept versus 32% (30 of 95) for placebo (p=0·067) in the multinational abatacept trial, and 18% (10 of 55) for tocilizumab versus 24% (13 of 55) for placebo (p=0·48) in the ETAP trial., Interpretation: The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjögren's syndrome. As a next step, the CRESS will require validation in a prospective RCT., Funding: None., Translation: For the Dutch translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests ANB reports personal fees from Bristol-Myers Squibb and Sanofi-Aventis, outside the submitted work. MB reports grants and personal fees from Amgen/Medimmune, Janssen, and GSK, and personal fees from UCB, outside the submitted work. HB reports grants and personal fees from Bristol Myers Squibb and Roche, and personal fees from Novartis, Medimmune, personal fees and Union Chimique Belge, outside the submitted work. SJB reports consulting fees from Novartis, AstraZeneca, and Abbvie/Galapagos, outside the submitted work. J-EG reports grants and personal fees from Bristol Myers Squibb and Pfizer, and personal fees from CSL Behring, Lilly, Janssen, UCB, and Roche, outside the submitted work. FGMK reports grants and personal fees from Bristol Myers Squibb and Roche, and personal fees from Janssen-Cilag, outside the submitted work. MN and NR are employees and shareholders of Bristol-Myers Squibb. JFvN reports personal fees from Bristol Myers Squibb, outside the submitted work. JV reports personal fees from Santen and Tramedico, outside the submitted work. AV reports grants from Bristol Myers Squibb and Roche, during the conduct of the study. SA, LdW, GMPJV, EP, and RF declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The risk of severe COVID-19 and its determinants remain largely unknown in patients with autoimmune and inflammatory rheumatic diseases. The objective of this study was to assess the prevalence of COVID-19 infection in patients followed for rare autoimmune diseases as well as the predictors of COVID-19 and disease flare-ups., Methods: Cross-sectional phone survey from April 9, 2020, to July 2, 2020, during which patients with autoimmune diseases followed at the National Reference Center for Rare Autoimmune diseases of Strasbourg were systematically contacted by phone and sent a prescription for a SARS-CoV-2 serology., Results: One thousand two hundred thirty-two patients were contacted. One thousand fifty-five patients with a confirmed diagnosis of systemic autoimmune disease were included (4 unreachable, 4 moves abroad, 5 deaths before pandemic, 50 without consent, and 114 without autoimmune disease). Among them, 469 (44.5%) patients were tested for SARS-CoV-2 serology. Thirty-nine patients (7.9%) had SARS-CoV-2 infection (either through chest CT-scan [n = 5], RT-PCR on nasopharyngeal swab [n = 14], or serology [n = 31]) among the 496 who underwent at least one of those 3 diagnosis modalities. Of the 39 proven cases, 33 had clinical manifestations (6 asymptomatic patients were diagnosed through systematic serology testing), 31 were managed by home care, 3 were hospitalized due to a need for oxygenation, two required admission to an intensive care unit, and one died. Among patients with confirmed SARS-CoV-2 infection, reported flares were more frequent than in uninfected patients (26.3% [10/38] vs. 7.0% [32/457], p < 0.0001). Preventive sick leave had no significant impact on the prevalence of SARS-CoV-2 infection (5.8% [3/53]) compared to work continuation (7.6% [30/397], p = 0.64). Overall, the seroprevalence of SARS-CoV-2 was 6.6% (31/469) which was numerically lower to the Grand-Est general population estimated to be 9.0%., Conclusions: This systematic survey of more than 1000 patients with rare systemic autoimmune diseases reports a low prevalence of proven SARS-CoV-2 infection and very rare severe infections, probably related to good compliance with prophylactic measures in these patients., (© 2021. The Author(s).)

Background: Antimalarial agents (AMs), mainly hydroxychloroquine (HCQ) and chloroquine, are the cornerstone of treatment of cutaneous and systemic lupus erythematosus. However, many aspects of AM prescription remain empirical. The aim of this study was to assess the modalities of AM prescription among physicians treating patients with lupus and to verify the assumption that AM use is heterogeneous and frequently at variance with international guidelines., Methods: We performed an international cross-sectional study among physicians involved in lupus care, using a web-based survey (from September 2019 to July 2020) addressing the main controversial aspects of AM prescription., Results: A total of 298 physicians [median age: 42 (interquartile range: 17) years, mainly internists and rheumatologists] from 35 countries participated to the study. A total of 93% used HCQ as the first-line AM, 69.5% used fixed doses of AMs (mainly 400 mg/day for HCQ) and only 37.9% adjusted the dose in case of renal failure. The main reasons for measuring HCQ blood levels were suspected non-adherence (55.7%) and failure of AM treatment (34.1%). In case of AM failure, 58.0% added an immunosuppressive agent. In case of remission, 49.7% maintained the same dose of AM, whereas 48.3% reduced the dose. One-third of respondents reported not following the American screening guidelines on AM retinal toxicity and 40.9% started retinal screening from the first year of treatment., Conclusion: This study highlights the strong heterogeneity of AM prescription in lupus, as well as several key unmet needs regarding AMs. This may be improved by developing more comprehensive recommendations and favoring dissemination among physicians., Competing Interests: Conflict of interest statement: Arthur Petitdemange declares no competing interest. Renaud Felten has participated to Advisory Boards for Abbvie, Novartis and received invitations or performed interventions for Abbvie, BMS, Lilly, Nordic, Novartis, MEDAC, MSD, Pfizer, Sanofi and UCB. Jean Sibilia has acted as a consultant for Roche, Chugai, Bristol-Myers Squibb, UCB, GSK, LFB, Actelion, Pfizer, MSD, Novartis, Amgen, Abbvie, Sandoz, Gilead, Lilly, Sanofi Genzyme, Janssen and Mylan. Thierry Martin declares no competing interest. Laurent Arnaud has acted as a consultant for Alexion, Amgen, Astra-Zeneca, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Novartis, Pfizer, Roche-Chugaï and UCB., (© The Author(s), 2021.)

Objectives: No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications., Methods: Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment., Results: 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14)., Conclusion: Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo., Trial Registration Number: NCT01782235., Competing Interests: Competing interests: J-EG received honoraries and research grants from BMS and Pfizer, and honoraries from CSL Behring, Lilly, Janssen, UCB, Roche. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To refine the prevalence, characteristics and response to treatment of myositis in primary SS (pSS)., Methods: The multicentre prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort of 395 pSS patients with ≥60 months' follow-up was screened by the 2017 EULAR/ACR criteria for myositis. Extra-muscular complications, disease activity and patient-reported scores were analysed., Results: Before enrolment and during the 5-year follow-up, myositis was suspected in 38 pSS patients and confirmed in 4 [1.0% (95% CI: 0.40, 2.6)]. Patients with suspected but not confirmed myositis had higher patient-reported scores and more frequent articular and peripheral nervous involvement than others. By contrast, disease duration in patients with confirmed myositis was 3-fold longer than without myositis. Two of the four myositis patients fulfilled criteria for sporadic IBM. Despite receiving three or more lines of treatment, they showed no muscle improvement, which further supported the sporadic IBM diagnosis. The two other patients did not feature characteristics of a myositis subtype, which suggested 'pure' pSS myositis. Steroids plus MTX was then efficient in achieving remission., Conclusions: Myositis, frequently suspected, occurs in 1% of pSS patients. Especially when there is resistance to treatment, sporadic IBM should be considered and might be regarded as a late complication of this disease., (© 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.)

Aims: With the arrival of conventional synthetic (csDMARDs), biological (bDMARDS) and then targeted synthetic (tsDMARDs) disease-modifying anti-rheumatic drugs, the therapeutic arsenal against rheumatoid arthritis (RA) has recently expanded. However, there are still some unmet needs for patients who do not achieve remission and continue to worsen despite treatments. Of note, most randomized controlled trials show that, for methotrexate-inadequate responders, only 20% of patients are ACR70 responders. With our better understanding of RA pathogenesis, finding new treatments is a necessary challenge. The objective of our study was to analyse the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development., Methods: We conducted a systematic review of all drugs in clinical development in RA, in 17 online registries of clinical trials., Results: The search yielded 4652 trials, from which we identified 243 molecules. Those molecules belong to csDMARDs ( n  = 22), bDMARDs ( n  = 118), tsDMARDs ( n  = 103). Twenty-four molecules are already marketed in RA in at least one country: eight csDMARDs, 10 bDMARDs and six tsDMARDs. Molecules under current development are mainly bDMARDs ( n  = 34) and tsDMARDs ( n  = 33). Seven of those have reached phase III. A large number of molecules (150/243, 61.7%) have been withdrawn., Conclusion: Despite the availability of 24 marketed molecules, the development of new targeted molecules is ongoing with a total of 243 molecules in RA. With seven molecules currently reaching phase III, we can expect an increase in the armamentarium in the years to come., (© The Author(s), 2020.)

Background: Pathogenic inflammatory pathways are largely shared between different autoimmune and inflammatory diseases (AIDs). This offers the potential to develop a given targeted therapy in several AIDs., Methods: We analyzed two clinical trials registries (ClinicalTrials.gov and EU Clinical Trials Register) to identify the targeted therapies whose development is shared between at least two of the most common AIDs [rheumatoid arthritis (RA), spondyloarthritis (SpA), cutaneous psoriasis (cPso), inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), giant cell arteritis (GCA), and multiple sclerosis (MS)] using an in-depth repurposing analysis., Results: We identified 142 shared targeted therapies. The four diseases in which shared targeted therapies were the most numerous were RA ( n  = 92), cPso ( n  = 67), IBD ( n  = 58), and SLE ( n  = 56). The two clusters of diseases between which the overlap of targeted therapies was the most important were RA and SLE as well as RA, SpA, cPso, and IBD. The targeted therapies which were shared by five diseases or more were abatacept, ustekinumab, rituximab, anakinra, etanercept, infliximab, secukinumab, tofacitinib, alemtuzumab, tocilizumab, adalimumab, apremilast, baricitinib, belimumab, brodalumab, filgotinib, and upadacitinib. The most frequently targeted molecules and pathways were (by descending frequency): JAK-STAT pathways, Th17 axis, TNF-α, IL-6, costimulation molecules, BAFF, CD20, BTK, chemokines and integrins, IL-1, and type I interferon., Conclusion: Many targeted therapies are developed in several AIDs, reflecting the overlap of pathogenic pathways and potential of drug repurposing. This suggests that a revision of the current, clinically based classification of AIDs towards a more mechanistic-based taxonomy might be relevant., Competing Interests: Conflict of interest statement: Arthur PETITDEMANGE: no competing interest. Julien BLAESS: no competing interest. Jean SIBILIA has acted as a consultant for Roche, Chugai, Bristol-Myers Squibb, UCB, GSK, LFB, Actelion, Pfizer, MSD, Novartis, Amgen, Abbvie, Sandoz, Gilead, Lilly, Sanofi Genzyme, Janssen, Mylan. Renaud FELTEN has participated to Advisory Boards for AbbVie, Novartis and received invitations or performed interventions for Abbvie, BMS, Lilly, Novartis, MSD, Pfizer, Sanofi, UCB. Laurent ARNAUD has acted as a consultant for Alexion, Amgen, Astra-Zeneca, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Novartis, Pfizer, Roche-Chugaï, UCB., (© The Author(s), 2020.)

Objectives: To assess the efficacy and tolerance profile of rituximab in rheumatoid arthritis (RA)-associated large granular lymphocyte leukemia (LGLL)., Methods: Multicenter retrospective case series. Inclusion criteria were RA defined by the ACR/EULAR 2010 criteria and LGLL defined by absolute LGL count ≥ 0.3 × 10 9 /L with evidence of an expanded clonal LGL population (flow cytometry, TCR-γ polymerase chain reaction, or Stat3 mutation)., Results: Fourteen patients (10 women, mean age 55.2 ± 14.2 years) included; 13 were seropositive for anti-cyclic citrullinated peptides (n = 11) or rheumatoid factor (n = 10). LGLL diagnosis was made 9.5 [IQR: 3.25;15.5] years after RA diagnosis. Thirteen patients had T-LGLL. Rituximab was the first-line therapy for LGLL for 4 patients. Previous treatment lines included methotrexate (n = 7), cyclophosphamide (n = 2), cyclosporin A (n = 1), or granulocyte colony-stimulating factor (n = 4). Rituximab was used in monotherapy (n = 8) or associated to methotrexate (n = 3), granulocyte colony-stimulating factor (n = 2), or alkylating agents (n = 1). The number of rituximab cycles ranged from 1 to 11 (median 6), with high heterogeneity in dosing regimens. Median duration response after rituximab initiation was 35 [IQR: 23.5;41] months. The overall response rate was 100%: 8 patients experienced complete response (normalization of blood count and LGL ≤ 0.3 × 10 9 /L) and 6 experienced partial responses (improvement in blood counts without complete normalization). The tolerance profile was good, with no infectious complications., Conclusion: rituximab appears as a valuable therapeutic option for RA-associated LGLL., Competing Interests: Declaration of Competing Interest The authors reports no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To describe changes in the 2001-2014 mortality of 6 autoimmune systemic diseases (AISDs), namely Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Idiopathic Inflammatory Myopathies (IIM), Sjögren's Syndrome (SS), Mixed Connective Tissue Disease (MCTD) and ANCA-associated vasculitis (AAV) at the country-, continent-, and world-levels., Methods: Mortality data were retrieved from the World Health Organization (WHO) mortality database for each disease, based on ICD-10 codes. We computed age-standardized mortality rate (ASMR) as the estimated number of deaths per million inhabitants and its 95% confidence interval (95%CI). The association between gender, geographical areas and disease-specific mortality was analyzed using multivariate Poisson regression. The 2001-2014 temporal trends were analyzed using Jointpoint software., Results: In 2014, the worldwide ASMR for SLE was 2.68 (95%CI: 2.62-2.75) deaths/millions inhabitants, 1.46 (1.42-1.51) for SSc, 0.47 (0.44-0.49) for IIM, 0.17 (0.15-0.18) for SS, 0.11 (0.10-0.13) for MCTD and 0.53 (0.50-0.56) for AAV, with ASMRs generally lower in Europe than in North America, Latin America and Asia. Between 2001 and 2014, the worldwide ASMR decreased significantly for SSc (-0.71%/year), IIM (-1.65%/year) and AAV (-1.01%/year; p < .001 for all) and increased for SS (+1.53%/year, p = .01). The worldwide ASMR of SLE decreased significantly between 2001 and 2003 (-6.37%, p < .05) before increasing slightly between 2004 and 2014 (+0.58%, p < .01)., Conclusions: We observed a strong heterogeneity of standardized mortality rates across all countries analyzed for 6 autoimmune diseases. Those results further highlight the impact of world-wide inequities and major gaps in access to care and strategies for diagnosis and management of rare diseases, a crucial finding for world-wide physicians, patient associations and policy makers., (Copyright © 2020. Published by Elsevier B.V.)

Psoriatic arthritis and gout are frequently encountered conditions sharing a number of common risk factors, which render their independent study difficult. Epidemiological studies have demonstrated a strong link between these diseases, suggesting the presence of underlying, intertwined pathophysiological mechanisms that currently remain unknown. Indeed, sodium urate crystals could play a pathogenic role in psoriasis and psoriatic arthritis. In daily practice, the distinction between psoriatic arthritis associated with hyperuricemia and a gouty arthropathy with psoriasis is complex. Several common pathogenic features suggest a more intricate relationship than their mere coexistence in the same patient. Thus, the concurrence of these two diseases should be seen as a novel overlap syndrome, at the boundary between inflammatory and metabolic rheumatism. The present update aims to clarify the determinants of the link and to define this new nosological entity. Its recognition could have therapeutic implications that appear essential for treatment optimization in a personalized setting.Key Points• What is already known about this subject? Psoriatic arthritis (PsA) and gout have strong interconnections, including comorbidities and pathophysiology. One must note that confounding clinical symptoms and radiological signs of PsA and gout are similar and difficult to differentiate in patients whose radiological lesions become too advanced to be differentiated or with less clearly defined phenotypes.• What does this study add? The pathogenic role of chronic hyperuricemia in the development and maintenance of PsA is based on epidemiological, clinical, and fundamental arguments and hence does not appear fortuitous. These two pathological processes can influence each other.• How might this impact on clinical practice? This new line of thinking regarding the convergence of gout and PsA, involving the role of urate crystals, could prompt a potential new approach to treatment (urate-lowering therapy) among patients with active/refractory PsA.

Auto-immune diseases, including auto-immune hepatitis may be associated with the use of drugs, such as anti-TNF-α inhibitors. The aim of the study was to analyze the characteristics of anti-TNF-α inhibitor-associated auto-immune hepatitis (ATIAIH) in a large international pharmacovigilance database. We analyzed all ICSRs classified as "Autoimmune hepatitis" according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase, the World Health Organization global pharmacovigilance database of adverse drug reactions collected by national drug authorities in >130 countries (>90% of the world population). Bayesian disproportionality analysis was used to compute IC 025 , which is the lower end of the 95% credibility interval for the association between a suspected treatment and an adverse event. IC 025  > 0 are considered statistically significant. A total of 389 ATIAIH ICSRs were identified. The median age at ATIAIH onset was 44 years and the female to male sex ratio was 3.72. Infliximab (IC025 = 2.98), adalimumab (IC025 = 0.32) and etanercept (IC025 = 0.19) yielded a statistically significant signal in disproportionality analysis. Infliximab was the most frequently involved drug (50.1%). The median treatment duration before ATIAH occurrence was 4.9 months. ATIAIH was reported as serious adverse event in 91%. Death (directly linked to AIH or not) occurred in 10 cases (2.9% of ICSRs). The most frequent reported indication for anti-TNF-α agent was rheumatoid arthritis (31.9%). This study enables the identification and a detailed study of 389 new cases of ATIAIH and confirms a significant association of ATIAIH with infliximab, adalimumab and etanercept., (Copyright © 2020. Published by Elsevier B.V.)

Avascular necrosis is an ischemic or cytotoxic necrosis of epiphyseal bone, responsible for joint pain, altered life quality and frequently affecting young patients. Avascular necrosis can be unifocal or multifocal, underlining the possibility of a systemic origin. Avascular necrosis involves the femoral head in more than 75% of cases. Although avascular necrosis is irreversible, many risk factors must be sought, including corticosteroid treatment, hypercholesterolemia, sickle cell disease or alcohol abuse. MRI imaging is the main exploration for the diagnostic and staging of the disease, and should be performed in unexplained hip pain in young patients with normal X-rays. In the earlier stages of the disease (stage I and II of the Arlet and Ficat classification), joint surface is preserved, and conservative treatment is recommended. In the more advanced stages (III and IV of the Arlet and Ficat classification), the articular surface collapses and joint arthroplasty is the main treatment. However, there are some recent therapeutic advances, based on mesenchymal stem cells, which may contribute, in the future, to improve the bad functional prognosis of the disease., (Copyright © 2019. Published by Elsevier Masson SAS.)

There have been many advances in the diagnosis and therapeutic management of systemic lupus erythematosus (SLE) over the past decades. Following more than eleven centuries of therapeutic uncertainty, the discovery of the therapeutic properties of glucocorticoids is without any doubt one of the most significant advance in the field of autoimmune diseases. The many progresses made by rapidly growing chemical industry of the 19th century chemistry have allowed the identification of valuable therapeutic compounds such as anti-malarials, cyclophosphamide, azathioprine, cyclosporine and later mycophenolate mofetil, which have all profoundly changed the face of the disease. A very visible consequence of this is the profound improvement in the prognosis of the disease, with 10-year survival rates of more than 90% in most dedicated centres. Following the development of biotherapies in rheumatoid arthritis, the late 20th century has slowly opened a new era for the treatment of SLE, that of targeted therapies. With the approval of belimumab in 2011 and 74 targeted therapies in clinical development, we may expect great changes in the therapeutic management of SLE. Those molecules target inflammatory cytokines or chemokines and their receptors, B cells or plasma cells, intracellular signalling pathways, B/T cells co-stimulation molecules, interferons, plasmacytoid dendritic cells, as well as various other targets of interest. Current challenges are now slowly shifting from whether some new drugs will be available to how to select the most adequate drug (or drug combination) at the patient-level., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Musculoskeletal (MSK) diseases are expected to have a growing impact worldwide., Objective: To analyse the worldwide burden of MSK diseases from 2000 to 2015., Methods: Disability-adjusted life years (DALYs), which combines the years of life lost (YLLs) and the years lived with disability (YLDs), were extracted for 183 countries from the WHO Global Health Estimates Database. We analysed the median proportion of DALYS, YLLs and YLDs for MSK diseases (ICD-10: M00-M99) among the 23 WHO categories of diseases. Mixed models were built to assess temporal changes., Results: Worldwide, the total number of MSK DALYs increased significantly from 80,225,634.6 in 2000 to 107,885,832.6 in 2015 (p < 0.001), with the total number of MSK YLDs increasing from 77,377,709.4 to 103,817,908.4 (p = 0.0008) and MSK diseases being the second cause of YLDs worldwide. YLLs due to MSK diseases increased from 2,847,925.2 to 4,067,924.2 (p = 0.03). In 2015, the median proportion of DALYs attributed to MSK diseases was 6.66% (IQR: 5.30 - 7.88) in Europe versus 4.66% (3.98 - 5.59) in the Americas (p < 0.0001 vs Europe), 4.17% (3.14 - 6.25) in Asia (p < 0.0001), 4.14% (2.65 - 5.57) in Oceania (p = 0.0008) and 1.33% (1.03 - 1.92) in Africa (p < 0.0001). We observed a significant correlation (r = 0.85, p < 0.0001) between the proportion of MSK DALYs and the gross domestic product per capita for the year 2015., Conclusions: The burden of MSK diseases increased significantly between 2000 and 2015 and is high in Europe. These results are crucial to health professionals and policy makers to implement future health plan adjustments for MSK diseases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

To date, no immunomodulatory drug has proved efficacious in primary Sjögren's syndrome (pSS). In pSS, difficulties in drug efficacy assessment is related to the large spectrum of clinical involvements (glandular/extraglandular involvement), to the lack of correlation between symptoms of dryness and glandular function assessed by objective measurements, as well as between symptoms and systemic complications of the disease. Severe organ manifestations are generally treated by off-label therapies in accordance with current practice and guidelines for Systemic Lupus Erythematosus or other connective-tissue diseases. Despite a much greater understanding of the pathogenesis of pSS, modern drug development has resulted in no approval of therapy so far. In this study, we performed a systematic review of all targeted therapies under clinical development in pSS, in 17 main online registries of clinical trials. Our search identified 264 trials, from which 25 targeted therapies for pSS were included. The molecules under current clinical development for pSS target B cells (n = 4), T cells or T/B cells costimulation (n = 5), inflammatory cytokines or chemokines and their receptors (n = 5), intracellular signalling pathways (n = 7) and various other targets identified in pSS (n = 4). The current drug development pipeline in pSS may lead to valuable strategies for the treatment of this currently difficult-to-treat disease., (Copyright © 2019. Published by Elsevier B.V.)

Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-β and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab., Competing Interests: The authors report no conflicts of interest in this work.

Avascular osteonecrosis (AVN) is a bone complication that indicates poor functional prognosis. Modern immunosuppressive and steroid-sparing drugs have significantly lowered the occurrence of AVN after kidney transplantation (KT). However, recent data on its incidence rates and risk factors are lacking. Using a large, recent cohort, we sought to investigate AVN incidence and risk factors, with a special focus on mineral and bone disorders. We conducted a cohort study in 805 patients who underwent KT between 2004 and 2014. AVN was identified in 32 patients (4%): before KT in 15 (1.8%) and after KT in 18 (2.2%) cases, including one patient with both. In the group with post-KT AVN, the median time intervals from KT to 1) first symptoms and 2) AVN diagnosis were 12 months [1-99] and 20 months [4-100], respectively. Being overweight/obese, having pre-transplant diabetes or hyperparathyroidism at transplantation, developing acute rejection, and receiving higher cumulative corticosteroid doses were associated with AVN occurrence. Multivariate analysis revealed that BMI ≥ 26 kg/m2 and higher cumulative corticosteroid doses were predictive of AVN. In conclusion, overweight/obesity is a strong risk factor for AVN. Despite a low maintenance dose, the use of corticosteroids-mostly for treatment of acute rejection-remains an independent risk factor., Competing Interests: The authors have declared that no competing interests exist.

From a 1-year survival of less than 50% before the discovery of glucocorticoids to over 90% at 10 years in most dedicated centres, the spectrum of SLE has profoundly evolved. Despite this improvement, several major challenges currently remain. The aim of this review is to analyse what are, according to us, the 10 most important contemporary challenges in the management of SLE. Among those are the need to treat to target to favour disease remission (or low disease activity), limit the use of glucocorticoids, derive more comprehensive tools for the evaluation of disease activity, develop more effective drugs (yielding successful trials), dissect the heterogeneity of the disease both at the molecular and genetic levels, identify relevant biomarkers for individualised treatment, manage fertility and pregnancy, tackle comorbidities such as cardiovascular risk, the prevention of infections and osteoporosis, improve the network of care (from the patients' perspective), and favour a holistic approach (integrating fatigue, adherence to treatment, physical activity). Altogether, these 10 contemporary challenges in SLE may be considered as a roadmap for those involved in the daily care of patients with SLE, as well as for researchers who may wish to contribute to an improved management of this rare and complex disease., Competing Interests: Competing interests: LA has received honoraria and/or funding from Amgen, AstraZeneca, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Novartis, Pfizer, Roche-Chugaï and UCB. RF has received honoraria from AbbVie, BMS and Pfizer. MR has received funding from GSK and Boehringer Ingelheim. TM has received honoraria and/or funding from Amgen, GSK, CSL Behring, Janssen-Cilag, Lilly, Novartis, Pfizer, Roche-Chugaï and Sanofi-Genzyme.

Currently, Systemic Lupus Erythematosus (SLE) therapies range from antimalarials to glucocorticoids, in addition to immunosupressive agents or biologics such as rituximab or belimumab, when needed. Several unmet needs remain in the treatment SLE and more targeted drugs with improved safety profiles are expected. Based on recent advances in the understanding of the complex pathogenesis of SLE, several targeted treatments are currently assessed in clinical trials. In this study, we performed a systematic review of all targeted therapies under clinical development in SLE in 17 online registries of clinical trials. The search yielded a total of 1140 trials, from which we identified 74 targeted therapies for SLE. Those treatments target inflammatory cytokines, chemokines, or their receptors (n = 17), B cells or plasma cells (n = 17), intracellular signalling pathways (n = 10), T/B cells costimulation molecules (n = 8), interferons (n = 7), plasmacytoid dendritic cells (pDC) (n = 3), as well as various other targets (n = 12). Not all these candidate drugs will reach phase III, but the broad spectrum of drugs being investigated may satisfy the urgent need for improved lupus medications. The identification of biomarkers that would allow adequate prediction of response-to-therapy remains high, but when solved will allow a more rationale selection of the optimal pharmacological agent at the patient level., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Coinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls. However, the enhancement of BTLA expression after activation was significantly lower in SLE patients compared with that in healthy controls. Furthermore, we found an impaired capacity of BTLA to inhibit T cell activation in SLE due to a poor BTLA recruitment to the immunological synapse following T cell stimulation. Finally, we demonstrated that defective BTLA function can be corrected by restoring intracellular trafficking and by normalizing the lipid metabolism in lupus CD4+ T cells. Collectively, our results evidence that the BTLA signaling pathway is altered in SLE T cells and highlight the potential of targeting this pathway for the development of new therapeutic strategies in lupus.