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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 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.)

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.)

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.)