Tripterygium wilfordii Hook F versus conventional synthetic disease-modifying anti-rheumatic drugs as monotherapy for rheumatoid arthritis: a systematic review and network meta-analysis.

BACKGROUND: Tripterygium wilfordii Hook F (TwHF), a medicinal plant that has been widely used in Chinese traditional medicine, is proven effective for treating rheumatoid arthritis (RA), but its clinical efficacy and safety remain largely undefined in comparison with conventional synthetic disease modifying anti-rheumatic drugs (DMARDs). METHODS: PubMed, Embase, Cochrane Library, CNKI, VIP, CBM, and WanFang Databases. Endpoints were ACR 20, 50, and 70, and the number of withdrawals due to adverse events. Initially, traditional pairwise meta-analysis was performed by using a random-effects model. Then, we performed network meta-analysis to compare different therapies by using frequentist approach. RESULTS: A total of 22 trials (5255 participants) were identified. By direct comparison, TwHF was superior to sulphasalazine according to ACR 20, 50 and 70. TwHF was superior to placebo according to ACR 20 and 50. By indirect comparisons, TwHF was superior to methotrexate, leflunomide, sulphasalazine, tacrolimus, minocycline and placebo according to ACR 20. Ranking by the Surface under the Cumulative Ranking curve (SUCRA) values showed that TwHF had the greatest probability for being the best treatment option according to ACR 20 (92.0 %) and ACR 50 (81.3 %), and the highest probability to be in the second (57.8 %) ranking position after leflunomide (69.6 %) according to ACR 70. By both direct and indirect comparisons, TwHF caused no more significant withdrawals than the placebo. The SUCRA values showed that TwHF had the highest probability to rank sixth (26.7 %) after the placebo (45.6 %) in causing withdrawals. CONCLUSIONS: Our data suggest that TwHF is effective and safe in the treatment of RA and has better clinical efficacy in terms of ACR 20 and 50 than existing conventional synthetic DMARDs. In the absence of head-to-head treatment comparison, the confidence in these estimates is low. Future comparative efficacy studies are warranted.

A narrative review of the comparative safety of disease-modifying anti-rheumatic drugs used for the treatment of rheumatoid arthritis.

INTRODUCTION: Disease-modifying anti-rheumatic drugs (DMARDs) have improved the outcomes of patients with rheumatoid arthritis (RA). DMARDs are classified into three categories: conventional synthetic DMARDs, biological DMARDs (including biosimilars), and targeted synthetic DMARDs. DMARDs, by way of their effect on the immune system, are associated with increased risk of adverse events, including infections, malignancies, cardiovascular disease, gastrointestinal perforations, and other less common events. AREAS COVERED: In this narrative literature review performed with searches of the PubMed database from 1 January 2010 through 1 January 2023, we compare the risk of safety events between DMARDs using data from both randomized clinical trials and observational studies. EXPERT OPINION: DMARD use in RA is associated with higher rates of serious infections, tuberculosis reactivation, opportunistic infections, and possibly malignancies. Specific biologic DMARDs and higher doses are associated with elevated risks of various adverse events (gastrointestinal perforations, thromboembolism, serious infection). Shared decision-making is paramount when choosing a treatment regimen for patients based on their own comorbidities. JAKi are the newest class of medications used for RA with robust safety data provided in clinical trials. However, more real-world evidence and phase-IV pharmacovigilance data are needed to better understand comparative safety profile of DMARDs in RA.

Cause analysis of conversion to biologics in spondyloarthritis patients with poor response to conventional treatment.

OBJECTIVE: We sought to investigate the reasons why spondyloarthritis (SpA) patients failed to respond to non-steroidal anti-inflammatory drugs (NSAIDs) and conventional synthetic disease-modifying antirheumatic drugs (cDMARDs) and the influences of different initial cDMARDs on the likelihood of a switch to biologics. METHODS: SpA patients were divided into a conventional drug maintenance group and a biologics conversion group to determine the causes of conversion to biologics. Then, we divided all patients into three groups according to different initial cDMARDs, NSAID monotherapy, NSAID + (sulfasalazine or thalidomide) double combination, and NSAID + sulfasalazine + thalidomide triple combination therapy groups, to clarify the influence of initial treatment on later conversion to biologics. RESULTS: This study includes 202 patients, including 97 patients in the conventional drug maintenance group and 105 patients in the biologics conversion group. The mean age of the conventional drug maintenance group was higher than that of the biologics conversion group (40.8 ± 14.3 vs. 33.8 ± 12.3 years, P < 0.05). Uveitis (OR 5.356, P < 0.05) is positively correlated with conversion to biological therapy, while age (OR 0.940, P < 0.05) is negatively correlated. The proportion of NSAID monotherapy, double combination, and triple combination groups converted to biological agents was 80%, 51.1%, and 23.2%, respectively (P < 0.05). CONCLUSION: Age and uveitis are related to conversion to biologics therapy. The early combination of sulfasalazine and thalidomide with NSAIDs may lower the probability of conversion to biologics therapy in the later stage and offer a new option for patients with limited use of biologics in SpA patients. Key Points • Patients' move to biologics may be caused mostly by inadequate disease control by conventional oral medications. • Regardless of axial vs. peripheral joint involvement, combination drug therapy was superior to single drug therapy in controlling SpA and decreasing the probability of conversion to a biological agent. • For SpA patients who are not candidates for biologics due to contraindications or other reasons, early combination application of NSAIDs, sulfasalazine, and thalidomide may be a new choice.

Should We Use bDMARDs as an Induction Therapy in Early and Severe Rheumatoid Arthritis? Results at 5 years from the ERA UCLouvain Brussels Cohort.

INTRODUCTION: This study sought to analyze the benefit of an early induction therapy with a biological disease-modifying anti-rheumatic drugs (bDMARD) during the first year of treatment with a 5-year follow-up in early rheumatoid arthritis (ERA). METHODS: We included ERA patients from the UCLouvain Brussels cohort who met the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria and were naïve to DMARDs. ERA patients were divided into two groups according to whether they received an induction bDMARD therapy or a standard therapy with methotrexate (MTX). Clinical response after the induction treatment at 6 and 12 months followed by a MTX maintenance therapy at 36 and 60 months was evaluated. RESULTS: Data from 470 ERA patients were collected, 189 received a bDMARD and 281 initiated MTX alone. In the bDMARD group, disease activity and HAQ were higher at baseline. A total of 391 patients were followed up to 5 years. We then divided each group into two subgroups according to the last treatment they received at 5 years: bDMARD > MTX (n = 95), bDMARD > bDMARD (n = 59); MTX > MTX (n = 134), MTX > bDMARD (n = 103). During the induction, we observed a clinical response with a large number of patients achieving DAS28-CRP remission. According to a treat-to-target (T2T) approach, remission rate was stable on MTX monotherapy or rescued by the addition or prolongation of a bDMARD. Interestingly, bDMARD followed by a MTX maintenance therapy experienced a stable and sustained DAS28-CRP remission rate in 53% of the ERA patients at year 5. CONCLUSIONS: Long-term remission is an achievable goal in ERA. Our results suggest that a bDMARD induction therapy followed by MTX maintenance therapy could be an interesting option.

Perspectives on the use of non-biological pharmacotherapy for adult-onset Still's disease.

INTRODUCTION: The treatment of the patients with adult-onset Still's disease (AOSD) remains largely empirical and it is based on the administration of immunosuppressive drugs. In this work, we described the use of non-biological pharmacotherapies for AOSD. AREA COVERED: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are employed during the diagnostic phase, glucocorticoids (GCs) are the first-line therapy, administered at the beginning of the disease. As second-line therapy, conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) are used when GCs do not fully control the disease and/or to reduce the dosage of concomitant GCs. Methotrexate (MTX) is the most commonly administered csDMARDs whereas calcineurin inhibitors (CNIs) are used in severe patients. The lack of achievement of clinical response may lead to the administration of biologic DMARDs, with or without csDMARDs. EXPERT OPINION: The management of AOSD may benefit from the administration of non-biological pharmacotherapies, including GCs, MTX, and CNIs. These therapies showed efficacy in inducing a clinical response, in managing life-threatening complications, and may be well tolerated in combination with biologic DMARDs. However, further specific studies are needed to fully clarify the specific role of such drugs in clinical practice to improve the management of AOSD and to provide a more tailored treatment.

Efficacy and safety of subcutaneous tocilizumab in rheumatoid arthritis over 1 year: a UK real-world, open-label study.

OBJECTIVE: The ACT-MOVE study assessed the real-world efficacy and safety of s.c. tocilizumab (TCZ-SC), provided as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) over 1 year, in patients with RA and an inadequate response to csDMARD therapy and/or first TNF inhibitor. METHODS: In this UK multicentre, open-label phase IIIb study, patients received TCZ-SC 162 mg once weekly for 52 weeks as monotherapy or with csDMARDs. Efficacy and safety were evaluated at baseline, weeks 2 and 4 and every 4 weeks thereafter up to week 52. RESULTS: Of 161 patients who received at least one dose of TCZ-SC, 21 (13.0%) received TCZ-SC alone and 140 (87.0%) TCZ-SC with a csDMARD(s). From baseline to week 52, there was a mean decrease in DAS28-ESR score among all patients (-3.68), and within monotherapy (-3.75) and combination therapy (-3.67) groups. The proportion of patients who achieved DAS28 clinical remission (DAS28-ESR <2.6) at week 52 was 75.4% (95% CI 66.8, 82.8). At the same time point, ≥80% of patients who remained on TCZ-SC achieved DAS28 clinical remission or had low disease activity (DAS28-ESR ≥2.6 and ≤3.2). Overall, 6.2% of patients had at least one serious adverse event (10.2/100 patient-years), and there was one death; 11.2% of patients discontinued owing to adverse events. CONCLUSION: TCZ-SC was effective and tolerated in a real-world setting over 1 year. The efficacy of TCZ-SC was similar whether given as monotherapy or with csDMARDs; its safety profile was consistent with that previously established. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT02046603.

Comparative effectiveness of first-line biological monotherapy use in rheumatoid arthritis: a retrospective analysis of the RECord-linkage On Rheumatic Diseases study on health care administrative databases.

OBJECTIVE: These analyses aim to comparatively evaluate the persistence on treatment of different biological disease-modifying antirheumatic drugs (bDMARDs) when administered in monotherapy compared with combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA) patients receiving first-line biologics. DESIGN: This is a retrospective observational study on Administrative Healthcare Databases. METHODS: Data were extracted from healthcare databases of the Lombardy Region, Italy (2004-2013), as a part of the RECord-linkage On Rheumatic Diseases study, on behalf of the Italian Society for Rheumatology. Analyses included patients with RA starting first-line approved course of bDMARDs and evaluated drug survival by using Cox proportional hazard models. Results are presented as HRs and 95% CI, crude and adjusted for prespecified confounders (age, sex, disease duration, Charlson Comorbidity Index (CCI), previous infections, use of concomitant glucocorticoids or non-steroidal anti-inflammatory drugs (NSAIDs)). RESULTS: 4478 patients with RA were included (17.84% monotherapy). Etanercept, adalimumab and infliximab were the most prescribed first-line biologics. bDMARD monotherapy was associated with longer disease duration, higher CCI, lower glucocorticoids and NSAIDs use. Compared with monotherapy, combination associated with a lower risk of failure (adjusted HR 0.79, 95% CI 0.72 to 0.88). Among monotherapies, considering etanercept as reference, adalimumab (1.28, 95% CI 1.03 to 1.59) and infliximab (2.41, 95% CI 1.85 to 3.15) had higher risk of failure. Concomitant methotrexate (0.78, 95% CI 0.70 to 0.87), leflunomide (0.80, 95% CI 0.65 to 0.98) or csDMARD combinations (0.77, 95% CI 0.68 to 0.87) reduced the risk of bDMARD withdrawal. CONCLUSION: Adalimumab and infliximab monotherapies show lower retention rate compared with etanercept. The relatively small number of therapeutic courses different from tumour necrosis factor (TNF) inhibitors makes more difficult to achieve conclusive results with other biologics. Concomitant methotrexate, leflunomide and csDMARDs combination associate with longer survival on bDMARD. Our data confirm the effectiveness of the current practices in the choice of etanercept as first-line anti-TNF monotherapy and strengthen the currently recommended use of bDMARDs in combination with csDMARDs.