Repurposing the Fibrosis-4 Score in Rheumatoid Arthritis: Data from the ESPOIR Cohort.

Background: We aimed to evaluate the value of the Fibrosis-4 (FIB-4) score as a prognostic factor in RA in the prospective ESPOIR cohort. Methods: We included patients from the ESPOIR cohort with a diagnosis of RA according to ACR/EULAR criteria. The formula for the FIB-4 score is as follows: [age (years) × aspartate transaminase level (U/L)]/[platelet count (109/L) × alanine aminotransferase level (U/L)1/2]. We used a linear mixed-effects model with a random effect of patient to account for repeated measures over time. Results: Overall, 647 of the 813 patients included met the ACR/EULAR criteria for RA, with no differential diagnosis during the first 10 years of follow-up. Of these patients, at baseline, 633 had a calculable FIB-4 score. Median FIB-4 score was 0.75 (interquartile range 0.53-0.99). On multivariate analysis, FIB-4 score was not independently associated with progression of Disease Activity Score in 28 joints over 10 years of follow-up, unlike baseline C-reactive protein level and SJC. Baseline FIB-4 score was not associated with the modified Sharp score at 5-year follow-up, unlike age and ACPAs. FIB-4 score was not associated with mortality (hazard ratio 1.1 [95% CI 0.46; 2.8], p = 0.77) or major adverse cardiovascular events (0.46 [0.13; 1.6], p = 0.22) over the 10-year follow-up. No significant change in FIB-4 score over time was related to treatments. Conclusions: The present prospective cohort study did not find a prognostic role of FIB-4 score in RA. Reassuringly, FIB-4 score was not increased with DMARD treatment after 10 years of follow-up.

Recommendations of the French Society of Rheumatology for the management in current practice of patients with polymyalgia rheumatica.

OBJECTIVE: To develop recommendations for the routine management of patients with polymyalgia rheumatica (PMR). METHODS: Following standard procedures, a systematic review of the literature by five supervised junior rheumatologists, based on the questions selected by the steering committee (5 senior rheumatologists), was used as the basis for working meetings, followed by a one-day plenary meeting with the working group (15 members), leading to the development of the wording and determination of the strength of the recommendations and the level of agreement of the experts. RESULTS: Five general principles and 19 recommendations were drawn up. Three recommendations relate to diagnosis and the use of imaging, and five to the assessment of the disease, its activity and comorbidities. Non-pharmacological therapies are the subject of one recommendation. Three recommendations concern initial treatment based on general corticosteroid therapy, five concern the reduction of corticosteroid therapy and follow-up, and two concern corticosteroid dependence and steroid-sparing treatments (anti-IL-6). CONCLUSION: These recommendations take account of current data on PMR, with the aim of reducing exposure to corticosteroid therapy and its side effects in a fragile population. They are intended to be practical, to help practitioners in the day-to-day management of patients with PMR.

Concordance and agreement between different activity scores in polymyalgia rheumatica.

OBJECTIVE: The C reactive protein polymyalgia rheumatica activity score (CRP-PMR-AS) is a composite index that includes CRP levels and was developed specifically for PMR. As treatments such as interleukin-6 antagonists can normalise CRP levels, the erythrocyte sedimentation rate (ESR) of PMR-AS, the clinical (clin)-PMR-AS and the imputed-CRP (imp-CRP)-PMR-AS have been developed to avoid such bias. Our primary objective was to measure the correlation of these activity scores. Our secondary objective was to evaluate the concordance between different cutoffs of the PMR-ASs. METHOD: Data from the Safety and Efficacy of tocilizumab versus Placebo in Polymyalgia rHeumatica With glucocORticoid dEpendence (SEMAPHORE) trial, a superiority randomised double-blind placebo-controlled trial, were subjected to post hoc analysis to compare the efficacy of tocilizumab versus placebo in patients with active PMR. The CRP-PMR-AS, ESR-PMR-AS, clin-PMR-AS and imp-CRP-PMR-AS were measured at every visit. The concordance and correlation between these scores were evaluated using kappa correlation coefficients, Bland-Altman correlations, intraclass correlation coefficients (ICCs) and scatter plots. RESULTS: A total of 101 patients were included in the SEMAPHORE trial, and 100 were analysed in this study. The correlation between the PMR-ASs was excellent, as the ICC and kappa were >0.85 from week 4 until week 24 (CRP-PMR-AS ≤10 or >10). Bland-Altman plots revealed that the differences between the CRP-PMR-AS and the other threescores were low. The cut-off values for the clin-PMR-AS were similar to those for the CRP-PMR-AS 86% of the time. CONCLUSION: The correlation between all the PMR-ASs was excellent, reflecting the low weight of CRP. In clinical trials using drugs that have an impact on CRP, the derived activity scores can be used. TRIAL REGISTRATION NUMBER: NTC02908217.

Safety and efficacy of colchicine in crystal-induced arthritis flare in 54 patients with severe chronic kidney disease.

INTRODUCTION: Colchicine, commonly used in gout flare, is contraindicated in severe chronic kidney disease (CKD) (estimated glomerular filtration rate <30 mL/min). However, in this context, there are few alternatives, and colchicine use persists. We evaluated the tolerance of colchicine and its efficacy in patients with severe CKD. PATIENTS AND METHODS: All prescriptions of colchicine for managing crystal-induced arthritis flare (gout or calcium pyrophosphate deposition (CPPD) disease) in a hospitalised patient with severe CKD were screened from September 2020 to September 2021. After patient consent and treatment information, clinical and biological safety and efficacy data were prospectively collected from day 1 (D1) to D11. RESULTS: We included 54 patients (median age 75 years (IQR 67-83)) with 62 colchicine prescriptions (cases). Twelve (22%) patients were on dialysis. The main reason for hospitalisation was heart failure (31.5%), acute renal failure (22.2%), infection (18.5%) or an acute joint episode (9.3%). In total, 59.3% of patients had diabetes. The prescriptions concerned 58 cases of gout flares, 1 case of CPPD and 3 cases of both. Initial colchicine dosages were ≤0.5 mg/day in 47/62 (75.8%) cases; no dosage exceeded 1 mg/day (median duration of 6 days (IQR 3-11)). Colchicine was well tolerated in 47/61 (77%) cases. No serious adverse event was reported. Colchicine was considered completely effective by the medical team in 48/58 (83%) of cases. CONCLUSION: The use of colchicine, at reduced doses, was mostly effective to treat crystal-induced arthritis flare in 54 patients with severe CKD and was well tolerated, without any serious adverse events.

Examining the biological pathways underlying clinical heterogeneity in Sjogren's syndrome: proteomic and network analysis.

OBJECTIVES: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes. METHOD: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST. RESULTS: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6. CONCLUSIONS: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes.

Type 1 interferons: A target for immune-mediated inflammatory diseases (IMIDs).

The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of several Immune-mediated inflammatory diseases (IMIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis and Sjögren's syndrome. Here, we review the main data regarding the opportunity to target type I IFNs for the treatment of IMIDs. Type I IFNs and their downstream pathways can be targeted pharmacologically in several manners. One approach is to use monoclonal antibodies against IFNs or the IFN-receptors (IFNARs, such as with anifrolumab). The downstream signaling pathways of type I IFNs also contain several targets of interest in IMIDs, such as JAK1 and Tyk2. Of these, anifrolumab is licensed and JAK1/Tyk2 inhibitors are in phase III trials in SLE. Targeting IFN-Is for the treatment of SLE is already a reality and in the near future may prove useful in other IMIDs. IFN assays will find a role in routine clinical practice for the care of IMIDs as further validation work is completed and a greater range of targeted therapies becomes available.

Implementation of regulatory guidance for JAK inhibitors use in patients with immune-mediated inflammatory diseases: An international appropriateness study.

BACKGROUND AND AIMS: The Pharmacovigilance Risk Assessment Committee (PRAC) proposed measures to address severe side effects linked to Janus kinase inhibitors (JAKi) in immune-mediated inflammatory diseases (IMID). Use of these medications in individuals aged 65 and older, those at high cardiovascular risk, active or former long-term smokers, and those with increased cancer risk should be considered only if no alternatives exist. Caution is advised when administering JAKi to patients at risk of venous thromboembolism. We aim to implement recommendations from regulatory guidelines based on areas of uncertainty identified. METHODS: A two-round modified Research and Development/University of California Los Angeles appropriateness methodology study was conducted. A panel of 21 gastroenterologists, dermatologists and rheumatologists used a 9-point Likert scale to rate the appropriateness of administering a JAKi for each proposed clinical scenario. Scores for appropriateness were categorized as appropriate, uncertain, or inappropriate. Two rounds were performed, each with online surveys and a virtual meeting to enable discussion and rating of each best practice. RESULTS: Round 1 involved participants rating JAKi appropriateness and suggesting descriptors to reduce uncertainty. Survey results were discussed in a virtual meeting, identifying areas of disagreement. In round 2, participants rated their agreement with descriptors from round 1, and the level of uncertainty and disagreement reduced. Age flexibility is recommended in the absence of other risk factors. Active counseling on modifiable risks (e.g., overweight, mild hyperlipidemia and hypertension) and smoking cessation is advised. Uncertainty persists regarding cancer risk due to various factors. CONCLUSIONS: We outlined regulatory guidance without a personalized evaluation of the patient's risk profile might lead to uncertainty and become an arid technicality. Therefore, we identified gaps and implemented PRAC recommendations to help health professionals in clinical practice.

Impact of hyperuricaemia on patients with psoriatic arthritis treated with secukinumab in the FUTURE 2-5 and MAXIMISE studies.

OBJECTIVES: Patients with psoriatic arthritis (PsA) are at a significantly increased risk of hyperuricaemia and development of gout, and those with hyperuricaemia have been found to respond poorly to PsA treatment and have more peripheral and destructive joint damage. We present a comprehensive post hoc analysis using pooled data from the FUTURE 2-5 studies and the MAXIMISE study to further evaluate the impact of hyperuricaemia on clinical presentation/disease severity and response to secukinumab in patients with PsA. METHODS: Patients were stratified into two groups based on baseline serum uric acid (SUA) level (threshold of 360 µmol/L). A sensitivity analysis was also performed based on SUA thresholds of 300 µmol/L and 420 µmol/L. Demographics, clinical, radiological characteristics and comorbidities data were collected. RESULTS: At baseline, patients with hyperuricaemia were mostly male, reported a higher prevalence of hypertension, with more clinical dactylitis, more psoriasis and more severe skin disease compared with patients with normouricaemia. A similar proportion of patients in the normouricaemic and hyperuricaemic cohorts achieved American College of Rheumatology responses, resolution of enthesitis and dactylitis, inhibition of structural damage progression and improvement in health-related quality of life across all secukinumab doses at week 52. CONCLUSION: Patients with PsA and hyperuricaemia have different clinical characteristics from patients with PsA and normouricaemia. Identification of these patients at an early stage may facilitate a personalised treatment approach and improved management of comorbidities. Furthermore, secukinumab provided a rapid and sustained response across all manifestations of PsA up to week 52, irrespective of baseline uricaemia status.

Prevalence, characteristics, and knowledge related to photosensitivity in patients with lupus erythematosus: the international PHOTOLUP study.

OBJECTIVES: To assess the prevalence, characteristics and knowledge about photosensitivity and the use of photoprotective measures in an international cohort of cutaneous and systemic lupus erythematosus patients. METHODS: We conducted an international, cross-sectional study based on a 46-question web-based survey including patients with medically confirmed LE conducted between November 2021 and April 2022. RESULTS: 600 patients with lupus erythematosus (94% female, median age: 41 years [IQR: 33-51]) from 50 countries were included. A history of photosensitivity was reported by 389/600 (64.8%) patients. Photosensitivity was associated with the presence of other cutaneous involvement (OR = 3.8; 95%CI 2.5-5.7; p < 0.001) and differed according to the area of habits and level of education (p < 0.001, for all). Photosensitivity was characterized by a wide range of clinical manifestations (both cutaneous and systemic symptoms in 56.1% and systemic symptoms only in 29.8% of patients). Fatigue was the most frequently reported systemic manifestation (82.3%). Overall, 559/600 (93%) patients were aware of the detrimental role of UV exposure in lupus erythematosus, but 160/480 (33.3%) were unaware of the importance of photoprotective measures, including 90/310 (29%) among those with photosensitivity. CONCLUSION: A high rate of self-reported photosensitivity characterize lupus erythematosus patients. Photosensitivity frequently includes subjective features, which makes it difficult to evaluate in clinical practice. As fatigue is frequent in LE, further study is needed to clarify its causal link with UV exposure. About one-third of lupus erythematosus patients are unaware of the importance of photoprotective measures. This should be improved through more frequent and targeted awareness interventions.

Current Pharmacological Therapies for the Management of Spondyloarthritis: Special Considerations in Older Patients.

Spondylarthritis (SpA) is generally observed in young male patients but can be diagnosed in older patients. These cases correspond to late-onset SpA (LoSpA) with two main clinical presentations, axial and peripheral SpA. Another increasingly common situation is that of older patients who have had SpA for many years. The therapeutic management of LoSpA is quite smilar to the management of patients with an early-onset disease, combining both non-pharmacological and pharmacological treatments. The treatments that can be used in LoSpA include non-steroidal anti-inflammatory drugs (NSAIDs) and biological agents targeting TNFα or IL-17A. Janus kinase inhibitors (JAKi) were recently introduced on the market for SpA. TNF inhibitors and IL-17inhibitors are very effective drugs in early-onset SpA. The effectiveness and safety of targeted therapies have not been specifically evaluated in LoSpA or older patients, and thus caution is required for these patients with comorbidities and/or polymedication. According to indirect data, biological agents seem to be less effective in LoSpA compared with early-onset disease. In parallel, a careful evaluation for the risk of infection, malignancy and cardiovascular events is recommended before initiating these drugs in this age category. JAKi may be used in LoSpA, but only in selected patients according to recent recommendations from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). When considering that the prevalence of such situations is expected to increase as ageing progresses, it is certainly time to consider this patient category as a distinct subgroup within the spectrum of SpA. Specific studies evaluating targeted agents in this age category are thus desirable.

New and future therapies: Changes in the therapeutic armamentarium for SLE.

Following better understanding of molecular pathways involved in the pathogenesis of Systemic lupus erythematosus (SLE), pharmaceutical companies have been investigating new targeted drugs for SLE. The purpose of this scoping review is to provide an updated view of the most promising targeted therapies currently in clinical development or recently approved for SLE treatment as well as of the most promising potential future therapeutic strategies in SLE. In the past several years, two new drugs have been developed for lupus treatment along with an extended indication for belimumab. Anifrolumab, the anti-interferon medication, to treat non-renal lupus; voclosporin, a calcineurin inhibitor, for the treatment of lupus nephritis; and belimumab for lupus nephritis. More than 90 investigational drugs are currently in clinical development for SLE treatment, with various targets including inflammatory cytokines and their receptors, intracellular signaling, B cells or plasma cells, co-stimulation molecules, complement fractions, T cells, plasmacytoid dendritic cells as well as various other immunological targets of interest. Researchers are also actively engaged in the development of new therapeutic strategies, including the use of monoclonal antibodies in combination with bispecific monoclonal antibodies, nanobodies and nanoparticles, therapeutic vaccines, utilizing siRNA interference techniques, autologous hematopoietic stem-cell transplantation and Chimeric Antigens Receptor (CAR)-T cells. The therapeutic management and prognosis of SLE have profoundly evolved with changes in the therapeutic armamentarium. With the broad pipeline of targeted treatments in clinical development and new treatment strategies in the future, current challenges are transitioning from the availability of new drugs to the selection of the most appropriate strategy at the patient level.

The 2023 pipeline of disease-modifying antirheumatic drugs (DMARDs) in clinical development for spondyloarthritis (including psoriatic arthritis): a systematic review of trials.

OBJECTIVES: The objective of this systematic review was to provide an overview of current developments and potentially available therapeutic options for spondyloarthritis (SpA) in the coming years. METHODS: We conducted a systematic review of 17 national and international clinical trial databases for all disease-modifying antirheumatic drugs (DMARDs) for SpA that are already marketed, in clinical development or withdrawn. The search was performed on February 2023 with the keywords "spondyloarthritis", "ankylosing spondylitis" and "psoriatic arthritis". For each molecule, we only considered the study at the most advanced stage of clinical development. RESULTS: Concerning axial SpA (axSpA), a total of 44 DMARDs were identified: 6 conventional synthetic DMARDs (csDMARDs), 27 biological DMARDs (bDMARDs) and 11 targeted synthetic DMARDs (tsDMARDs). Among the 18 targeted treatments (b+tsDMARDs) in current development, corresponding trials reached phase I (n=1), II (n=10) and III (n=7). Ten molecules are IL-17 inhibitors, two Janus kinase (JAK) inhibitors and two granulocyte-macrophage colony-stimulating factor inhibitors; four have another mode of action. Concerning psoriatic arthritis (PsA), 44 DMARDs were identified: 5 csDMARDs, 27 bDMARDs and 12 tsDMARDs. Among the 15 molecules in current development, corresponding trials reached phase II (n=8) and III (n=7). Six molecules are JAK inhibitors, six IL-17 inhibitors and one an IL-23 inhibitor; two have another mode of action. CONCLUSION: This systematic review identified 18 and 15 molecules in clinical development for axSpA and PsA, respectively, which suggests a strengthening of the therapeutic arsenal in the coming years. However, with so many DMARDs but low target diversity, we will need to develop strategies or biomarkers to help clinicians make informed treatment decisions.

Novel therapeutic strategies for autoimmune and inflammatory rheumatic diseases.

Drugs of unknown mechanisms of action are no longer being developed because we have largely capitalized on our improved understanding of the immunopathogenesis of immune-mediated inflammatory diseases (IMIDs) to develop therapeutic monoclonal antibodies (mAbs) and targeted treatments. These therapies have profoundly revolutionized the care of IMIDs. However, because of the heterogeneity of IMIDs and the redundancy of the targeted molecular pathways, some patients with IMIDs might not respond to a specific targeted drug or their disease might relapse secondarily. Therefore, there is much at stake in the development of new therapeutic strategies, which include combinations of mAbs or bispecific mAbs (BsMAbs), nanobodies and nanoparticles (NPs), therapeutic vaccines, small interfering RNA (siRNA) interference, autologous hematopoietic stem cell transplantation (aHSCT), or chimeric antigen receptor (CAR)-T cells. With the broad pipeline of targeted treatments in clinical development, the therapeutic paradigm is rapidly evolving from whether new drugs will be available to the complex selection of the most adequate targeted treatment (or treatment combination) at the patient level. This paradigm change highlights the need to better characterize the heterogeneous immunological spectrum of these diseases. Only then will these novel therapeutic strategies be able to fully demonstrate their potential to treat IMIDs.

Alteration of innate lymphoid cell homeostasis mainly concerns salivary glands in primary Sjögren's syndrome.

OBJECTIVE: Innate lymphoid cells (ILCs) are a cell population implicated in the pathogenesis of various chronic inflammatory diseases, but little is known about their role in primary Sjögren's syndrome (pSS). The aim of this study was to assess the frequency of ILC subsets in peripheral blood (PB) and their quantity and location in minor salivary glands (MSGs) in pSS. METHODS: The frequency of ILC subsets was analysed in the PB of patients with pSS and healthy controls (HCs) by flow cytometry. The amount and location of ILC subsets in MSGs were studied in patients with pSS and sicca controls by immunofluorescence assay. RESULTS: In PB, the frequency of ILC subsets did not differ between patients with pSS and HCs. The circulating frequency of the ILC1 subset was increased in patients with pSS with positive anti-SSA antibodies and that of the ILC3 subset was reduced in patients with pSS with glandular swelling. In MSGs, the ILC3 number was higher in lymphocytic-infiltrated than non-infiltrated tissue in patients with pSS and normal glandular tissues in sicca controls. The ILC3 subset was preferentially located at the periphery of infiltrates and was more abundant in small infiltrates of recently diagnosed pSS. CONCLUSION: Altered ILC homeostasis mainly concerns salivary glands in pSS. Most ILCs in MSGs consist of the ILC3 subset, located at the periphery of lymphocytic infiltrates. The ILC3 subset is more abundant in smaller infiltrates and in recently diagnosed pSS. It might play a pathogenic role in the development of T and B lymphocyte infiltrates in the early stages of pSS.

Identification of new candidate drugs for primary Sjögren's syndrome using a drug repurposing transcriptomic approach.

OBJECTIVES: To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes. METHODS: Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database. RESULTS: We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated. CONCLUSION: This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.

COVID-19 presentation and outcomes in patients with inflammatory rheumatic and musculoskeletal diseases receiving IL6-receptor antagonists prior to SARS-CoV-2 infection.

Objective: COVID-19 outcome may be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases (RMD) receiving immunosuppressive therapy. We aimed to investigate whether RMD patients on anti-IL6 therapy prior to SARS-CoV-2 infection have less severe disease and better outcomes of COVID-19. Methods: We conducted a retrospective national, multicentre cohort study using data from the French RMD COVID-19 cohort. We compared the severity and outcome of highly suspected or confirmed COVID-19 infection in RMD patients previously treated with tocilizumab or sarilumab (anti-IL6 group) with patients who did not receive anti-IL6 therapy (no anti-IL6 group). Results: Data were collected for 1883 patients with mean age of 55.2 years [SD 16.7] and 1256 (66.7%) female. Two hundred ten (11.1%) developed severe COVID-19 and 115 (6.4%) died. After adjusting for potential confounding factors, severe COVID-19 was less frequent in the anti-IL6 group compared with the no anti-IL6 group (aOR for moderate vs. mild severity, 0.23 [95% CI, 0.10 to 0.54], p ≤ 0.01 and aOR for severe vs. mild, 0.29 [95% CI, 0.10 to 0.81], p ≤ 0.01). No significant differences were found for the evolution of COVID-19 between the anti-IL6 group and the no anti-IL6 group (aOR for recovery with sequelae vs recovery without sequelae, 0.78 [95% CI, 0.41 to 1.48] and aOR for death vs recovery without sequelae, 0.29 [95% CI, 0.07 to 1.30]). Conclusion: RMD patients receiving anti-IL6 therapy prior to SARS-CoV-2 infection have less severe forms of COVID-19. No difference was observed in COVID-19 evolution, i.e., sequelae or death, between the groups.

New biologics and targeted therapies in systemic lupus: From new molecular targets to new indications. A systematic review.

INTRODUCTION: Despite available therapies, persistently active and corticosteroid-dependent Systemic Lupus Erythematosus (SLE) represent a significant therapeutic challenge. The purpose of this systematic review was to provide an updated view of targeted therapies currently in clinical development in SLE, with a special focus on the most promising ones. METHODS: We performed a systematic review of targeted therapies in clinical development in SLE in clinicaltrials.gov (search date: 28th of August 2022). Targeted therapies (defined as drugs specifically designed to block certain molecules, receptors, or pathways involved in the development of SLE) were extracted. For each investigational drug, we considered only the study at the most advanced stage of clinical development. RESULTS: The systematic review yielded a total of 92 targeted therapies (58 biological DMARDs [bDMARDs] and 34 targeted synthetic [ts]DMARDs) assessed in a total of 203 clinical trials. The candidate drugs reached phase I (n=20), Ia/IIb (n=6), phase II (n=51), phase II/III (n=1), phase III (n=13) and phase IV (n=1). These trials were reported as recruiting (n=31), active but not recruiting (n=8), not yet recruiting (n=4), enrolling by invitation (n=2), completed (n=31), prematurely terminated (n=12) and withdrawn in 1 (status unknown in 3). The main investigational drugs for SLE target inflammatory cytokines, chemokines or their receptors (n=19), intracellular signaling pathways (n=18), B cells (n=14) or plasma cells (n=7),T/B cells co-stimulation molecules (n=10), complement molecules (n=5),T lymphocytes (n=2), plasmacytoid dendritic cells (n=2), as well as various other immune targets (n=15). CONCLUSION: The pipeline of investigational drugs in SLE is highly diversified and will hopefully enable more optimal Treat-To-Target with the goal of disease modification. Companion biomarkers will be needed to better characterized SLE heterogeneity and optimize treatment selection at the individual-patient level.