AIM: To investigate different approaches to RA treatment that might lead to greater efficacy and better safety profiles. METHODS: The Search strategy was based on medical subject headings, and screening and selection were based on inclusion/exclusion criteria. RESULTS & DISCUSSION: Early therapy is critical for disease control and loss of bodily function. The most promising outcomes came from the development of disease-modifying anti-rheumatic drugs. Different foods have anti-inflammatory and antioxidant qualities that protect against the development of rheumatoid arthritis (RA). Some dietary patterns and supplements have been shown to have potential protective benefits against RA. CONCLUSION: Improvement in the quality of life of RA patients requires a tailored management approach based on the current patient medical data.
OBJECTIVES: Abatacept (Orencia) is a drug used to treat patients with rheumatoid arthritis. The agent improves patients' pain and joint inflammation through modulation of a co-stimulatory signal necessary for T cell activation. We aimed to analyse the efficacy and safety of abatacept in the management of rheumatoid arthritis using the Cochrane systematic review.
METHODS: We conducted a systematic search among PubMed, Cochrane central register of controlled trials, Web of Science, and Embase databases from the establishment of these databases to April 2022. The effectiveness and safety of abatacept in treating rheumatoid arthritis were assessed in terms of American College of Rheumatology (ACR) 20/50/70/90 responses, Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS-28-CRP), and adverse events. The Relative Risks (RRs) of relative safety and efficacy and their corresponding 95 confidence intervals (CIs) were used to compute the pooled assessments of the outcomes. We used the review manager software version 5.4 to analyse our data, and the PRISMA checklist 2020 was used to ensure that our work conforms with the specification of meta-analysis.
RESULTS: Our study included 13 randomised control trials with a total of 5978 adult patients from different geographic regions and races. Following the combined analysis of these enrolled studies, the RRs for ACR 20/50/70/90 responses were 1.57 [95%CI 1.27, 1.93], 1.84 [95%CI 1.38, 2.44], 2.36 [95%CI 1.60, 3.47], and 2.95 [95%CI 1.88, 4.63], respectively. Such findings suggest that abatacept-treated patients were 1.57, 1.84, 2.36, and 2.95 times more likely to achieve ACR 20/50/70/90 responses, respectively, than those treated with placebo, conventional synthetic disease-modifying antirheumatic drugs, and or other biologic disease-modifying anti-rheumatic drugs. An exclusive comparison of abatacept and other biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) indicated that participants who were treated with abatacept could achieve better ACR responses than those treated with other b/tsDMARDs. Adverse events were less seen in abatacept-treated patients than in those who were given other b/tsDMARDs.
CONCLUSIONS: This meta-analysis concludes that in adult with rheumatoid arthritis, abatacept can achieve better health outcomes than other biologic drugs.
OBJECTIVE: To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in rheumatoid arthritis (RA) in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar).
METHODS: The PubMed, EMBASE, Cochrane, databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the American College of Rheumatology (ACR) 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% confidence intervals (95%CI), pooled using random-effects models and then compared using a meta-regression model.
RESULTS: We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95%CI, 66-74) compared with 59% (95%CI, 55-62) in the reference-pbo group (p= 0.001). A significant difference was also found for ACR 50 [44% (95%CI, 39-50) vs 35% (95%CI, 31-39) respectively, p< 0.01].
CONCLUSION: Effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the Lessebo effect.
Background: Adalimumab, golimumab, infliximab, certolizumab, and etanercept are five anti-tumor necrosis factor (anti-TNF) medicines that have been approved for use in rheumatology. Apart from their well-established therapeutic usefulness, -it is unclear to what extent -they are linked to an increased risk of various side effects. The present meta-analysis was carried out to assess the risk of infection and other side effects after anti-TNF- α for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Methods: We searched PubMed, Cinahl (via Ebsco), Scopus, and Web of Sciences databases for trials comparing anti-TNF medications to placebo or no therapy in adult patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis from August 2006 to August 2020. A total of 23 articles were used for meta-analysis. The Cochrane Collaboration’s risk of bias tool was used to assess the methodological quality of the included studies. In addition, a random-effects model was used to calculate the pooled odds ratio, and Forest plots were constructed to determine the risk of infections and cancer following the use of anti-TNF treatment. Results: Treatment with anti-TNFα agents resulted in an increase in the risk of serious infections (OR: 1.72, 95% CI: 1.56–1.90, p < 0.00001) and an increase in cancer risk (OR: 1.36, 95% CI: 1.20–1.53, p < 0.00001) whereas the risk of developing tuberculosis was not significantly different with anti-TNFα agents versus those without treatment with anti-TNFα agents (OR: 2.55, 95% CI: 0.40–16.23, p = 0.32) although the number of studies is limited to make a definitive conclusion. The risk of bias of the included studies was unclear to high across most domains, and there was evidence of publication bias for most outcomes. Conclusion: The present meta-analysis suggests an increased risk of infectious adverse events, including overall adverse events and cancer following anti-TNFα treatment, whereas the risk of tuberculosis was not significantly different. Although anti-TNF agents have shown promise to treat inflammatory conditions, their use should be balanced by the risk-benefit ratio as suggested by the meta-analysis.
OBJECTIVE: To assess the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and the risk of cardiovascular events in patients with systemic inflammatory conditions.
METHODS: Eligible cohort studies or randomized controlled trials (RCTs) from inception to January 2021 were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for cardiovascular outcomes were calculated in the fixed- and random-effects model accordingly. Associated factors with risks of cardiovascular events were also studied in sensitivity analyses and metaregression analyses.
RESULTS: Compared with non-bDMARD users, the risks of myocardial infarction (MI) (OR = 0.74, 95% CI, 0.63 to 0.87), heart failure (OR = 0.84, 95% CI, 0.74 to 0.95), cardiovascular (CV) death (OR = 0.62, 95% CI, 0.40 to 0.95), all-cause mortality (OR = 0.64, 95% CI, 0.58 to 0.70), and 3P-MACE (composite endpoint of MI, stroke, and CV death) (OR = 0.69, 95% CI, 0.53 to 0.89) were significantly reduced in bDMARD users, which were mainly driven by the risk reduction in patients with rheumatoid arthritis (RA). TNF-α inhibitors exhibited consistent benefits in reducing the risks of MI, heart failure, CV death, all-cause mortality, and 3P-MACE. Moreover, the risks of heart failure, CV death, all-cause mortality, and 3P-MACE were significantly reduced in bDMARD users with follow-up over one year.
CONCLUSIONS: The use of bDMARDs might be associated with the reduced risks of CV events, especially in patients with RA. The CV events might be less frequent in bDMARD users with TNF-α inhibitors or follow-up over one year. More investigations are needed to validate conclusions.
Objective: To evaluate the comparative efficacy and safety of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to at least one disease-modifying antirheumatic drug (DMARD). Methods: PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to April 2020. The active drugs included three JAK inhibitors and eight bDMARDs while the control drugs included placebo or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Outcomes include American College of Rheumatology 20% response (ACR20), Disease Activity Score in 28 joints (DAS28), Health Assessment Questionnaire–Disability Index (HAQ-DI) and discontinuations for adverse events (AEs). We estimated summary odds ratios (ORs) and weighted mean differences (WMDs) using network meta-analysis with random effects. Results: Eighty-eight RCTs with 31,566 patients were included. All JAK inhibitors and bDMARDs were more effective than placebo in ACR20 (ORs ranging between 3.05 and 5.61), DAS28 (WMDs ranging between −1.91 and −0.80) and HAQ-DI (WMDs ranging between −0.34 and −0.21). Tocilizumab, certolizumab pegol and upadacitinib showed relatively good efficacy in these three outcomes according to their relative ranking. Notably, tocilizumab was more effective than other active drugs in DAS28 (WMDs ranging between −1.11 and −0.49). Compared with the lower recommended doses, increasing the doses of JAK inhibitors (baricitinib 4 mg versus 2 mg, tofacitinib 10 mg versus 5 mg and upadacitinib 30 mg versus 15 mg) cannot provide significant additional benefits. In terms of discontinuations for AEs, all active drugs showed no significant difference compared with placebo except certolizumab pegol [OR 1.65, 95% credible interval (CrI) 1.06–2.61] and rituximab (3.17, 1.11–10.80). Conclusions: Tocilizumab, certolizumab pegol and upadacitinib may have relatively good efficacy in patients with RA after treatment failure with csDMARDs. RA patients taking a JAK inhibitor may have a preference for a lower recommended dose.
WHAT IS KNOWN AND OBJECTIVE: Both biologic and Janus kinase (JAK) inhibitor therapies have demonstrated substantial effectiveness in placebo-controlled studies in patients with active rheumatoid arthritis (RA) showing inadequate responses to tumour necrosis factor (TNF) inhibitors. The purpose of this study was to determine the relative effectiveness and safety of non-TNF biologics and JAK inhibitors in patients with RA showing insufficient response to TNF inhibitors.
METHODS: A Bayesian network meta-analysis incorporating direct and indirect data from randomized controlled trials (RCTs) was used to investigate the effectiveness and safety of non-TNF biologics (abatacept, rituximab, tocilizumab, salirumab and sirukumab) and JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) in patients with RA showing insufficient response to TNF inhibitors.
RESULTS: Nine RCTs, evaluating 3577 patients for 12 weeks fulfilled the inclusion requirements. JAK inhibitors and non-TNF biologics achieved a significant American College of Rheumatology 20% (ACR20) response relative to the placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) showed that JAK inhibitor treatment was most likely to achieve the highest ACR20 response rate, followed by non-TNF biologics and placebo. The ACR50 rate displayed similar patterns as the ACR20 response rate, but non-TNF biologics have a higher value than JAK inhibitors based on the ACR70 response rate. Adverse events did not reach statistical significance nor did serious adverse events when looking at safety over 12 weeks. The confidence intervals overlap, and there is no clinical significance to these safety data, even compared with placebo.
WHAT IS NEW AND CONCLUSION: Both non-TNF biologics and JAK inhibitors have similar effects in patients with active RA that are refractory to anti-TNF treatment, and there were no differences with regard to safety among the treatments.
Background/Objectives: This article compares the effectiveness of baricitinib (BARI) 4 mg (oral, Janus kinase [JAK] 1/2 inhibitor) versus other targeted synthetic/biologic disease-modifying antirheumatic drugs, in combination with methotrexate (MTX), in moderate-to-severe rheumatoid arthritis patients with inadequate response (IR) to MTX. Methods: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of the interventions of interest. Bayesian network meta-analyses (NMA) were used to compare American College of Rheumatology (ACR) responses at 24 weeks. A series of prespecified sensitivity analyses addressed the potential impact of, among others, baseline risk, treatment effect modifiers, and trial design on treatment response. Results: Nineteen RCTs were included in the NMA (primary analysis). For ACR20, BARI 4 mg + MTX was found to be more effective than adalimumab (ADA) 40 mg + MTX (Odds Ratio [OR] 1.33), abatacept (ABA) 10 mg + MTX (IV/4 weeks) (OR 1.45), infliximab (IFX) 3 mg + MTX (IV/8 wks) (OR 1.63), and rituximab (RTX) 1000 mg + MTX (OR 1.63). No differences were found on ACR50. For ACR70, BARI 4 mg + MTX was more effective than ADA 40 mg + MTX (OR 1.37), ABA 10 mg + MTX (OR 1.86), and RTX 1000 mg + MTX (OR 2.26). Sensitivity analysis including 10 additional RCTs with up to 20% of patients with prior biologic use showed BARI 4 mg + MTX to be more effective than tocilizumab (TCZ) 8 mg + MTX on ACR20 (OR 1.44). Results for all sensitivity analyses were consistent with the direction and magnitude of the primary results. Key limitations include the time span in which trials were conducted (1999-2017), during which patient characteristics and treatment approaches might have changed. Conclusion: This NMA suggests that BARI 4 mg + MTX is an efficacious treatment option in the MTX-IR population as evidenced by the robustness of results.
Background: With a 'treat to target' approach in RA, guidelines recommend tailored monitoring of disease activity using validated composite instruments, such as the disease activity score (DAS) 28. While response assessment at 24 weeks is the standard in clinical trials, assessment as early as 12 weeks is recommended. There is limited evidence assessing the relative efficacy of TIMs following a 'treat to target' strategy. Objectives: To evaluate the relative efficacy of intravenous (IV) and subcutaneous (SC) tocilizumab plus a conventional disease modifying antirheumatic drug (cDMARD) to other TIMs plus a cDMARD in TIM-naïve or mixed (<20% TIM-experienced) adults with moderate to severe RA. Efficacy was defined as achieving remission according to a DAS28 score <2.6 at 12 and 24 weeks. Methods: Randomized controlled trials (RCTs) were selected from a recent systematic literature review conducted by the Institute for Clinical and Economic Review (ICER), as well as from trials for upadacitinib (SELECT-NEXT, SELECT-COMPARE), which were not included in the ICER 2017 report. RCTs that compared TIMs to each other or placebo were included. Treatments included Janus kinase (JAK) inhibitors (upadacitinib, baricitinib, and tofacitinib), tumor necrosis factor alpha inhibitors (TNFi; adalimumab, certolizumab pegol, golimumab, and infliximab), and other non-TNFis (rituximab, sarilumab, tocilizumab, and abatacept). A Bayesian NMA was performed in OpenBUGS and R using a fixed effects model. Model selection was based on deviance information criterion. Forest plots of odds ratios (OR) are presented. Results: In the 12-week analysis, 15 trials were included with a pooled study population of 9,154 patients. Populations were similar across trials and predominantly female (mean 78%, range 39-87%), with a baseline mean age of 52 years (range 47-56), mean disease duration of 8 years (range 2-11), and mean DAS28 score of 6 (range 5-7). In the 12-week analysis, compared to cDMARD, all TIMs were more likely to achieve remission (statistically significant), but tocilizumab IV showed a substantially greater magnitude of effect (OR=19.3, 95% Crl=10.99, 37.22) which was consistent with raw trial results (Figure 1). In pair-wise comparison, tocilizumab IV was associated with a greater likelihood of achieving remission compared to abatacept IV (OR=7.47, Crl=2.53, 20.89), abatacept SC (OR=4.29, Crl=1.96, 9.94), baricitinib (OR=3.39, Crl=1.74, 7.09), adalimumab (OR=5.10, Crl=2.68,10.42), tofacitinib (OR=5.44, Crl=1.26, 20.57), upadacitinib 15mg (OR=3.23, Crl=1.72, 6.54), and upadacitinib 30mg (OR=4.05, Crl=1.97, 8.85). In the 24-week analysis, 21 trials were included in the analysis with a pooled study population of 12,180 patients. Patient characteristics were the same as the 12 week analysis. Compared to cDMARD, all TIMs were more likely to achieve remission (statistically significant), with tocilizumab IV and SC showing a greater magnitude of effect (OR=12.08, Crl=8.09-18.30 and OR=11.98, Crl=5.17-35.86, respectively) (Figure 2). In pair-wise comparison, tocilizumab IV and SC were associated with a greater likelihood of achieving remission compared to abatacept IV, adalimumab, baricitinib, infliximab, upadacitinib 15 mg, and sarilumab. Conclusion: Results of this NMA demonstrate that tocilizumab is associated with a greater likelihood of remission (DAS28 <2.6) at 12 and 24 weeks compared to most other TIMs including new JAK inhibitors, when used in combination with a cDMARD among TIM-naïve/mixed patient populations. (Figure Presented).
Introduction: Biologics and traditional disease-modifying anti-rheumatic drugs (DMARDs) are generally used in treating patients with rheumatoid arthritis (RA). Previous studies have presented abundant data and information about the efficacy of such treatments, but the results were incomplete and inconclusive. This network meta-analysis was conducted to compare and assess the efficacy and safety of 15 therapies employing biologics and DMARDs for RA patients. Material and methods: Six outcomes (American College of Rheumatology 20% response rate (ACR20), ACR50, ACR70, remission, adverse events (AEs) and serious adverse events (SAEs)) were used to evaluate the efficacy and safety of different treatments. The node-splitting method was used to assess the inconsistency, and the rank probabilities of the therapies were estimated by surface under the cumulative ranking curve. Besides, Jadad scale was used to evaluate the methodological quality of eligible studies. Results: A total of 67 randomized controlled trials with 20,898 patients met the inclusion criteria. Most of the therapies presented better performance than conventional DMARDs (cDMARDs) and placebo in ACR20, ACR50 and ACR70. Conversely, the safety of cDMARDs and placebo seemed to be superior in AEs and SAEs. Also, tocilizumab (TCZ) and TCZ + methotrexate (MTX) showed better remission in pain compared to other treatments. Overall, certolizumab pegol (CZP) + MTX and TCZ + MTX had higher probability than the other treatments in efficacy outcomes. Conclusions: We recommend CZP + MTX as the optimal drug therapy because it has the highest ranking in efficacy outcomes and relatively low risk of adverse events. TCZ + MTX is recommended as an alternative. Abatacept (ABT) and cDMARDs are not recommended due to their low efficacy.
To investigate different approaches to RA treatment that might lead to greater efficacy and better safety profiles.
METHODS:
The Search strategy was based on medical subject headings, and screening and selection were based on inclusion/exclusion criteria.
RESULTS & DISCUSSION:
Early therapy is critical for disease control and loss of bodily function. The most promising outcomes came from the development of disease-modifying anti-rheumatic drugs. Different foods have anti-inflammatory and antioxidant qualities that protect against the development of rheumatoid arthritis (RA). Some dietary patterns and supplements have been shown to have potential protective benefits against RA.
CONCLUSION:
Improvement in the quality of life of RA patients requires a tailored management approach based on the current patient medical data.
