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.
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).
OBJECTIVES: To assess the efficacy and safety of methotrexate (MTX) in combination with an approved biological agent compared to biological monotherapy, in the management of patients with rheumatoid arthritis (RA).
METHODS: MEDLINE, EMBASE, CENTRAL and other sources were searched for randomised trials evaluating a biological agent plus MTX versus the same biological agent in monotherapy. Co-primary outcomes were ACR50 and the number of patients who discontinued due to adverse events (AEs). Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals and the GRADE approach was used to assess confidence in the estimates.
RESULTS: The analysis comprised 16 trials (4965 patients), including all biological agents approved for RA except anakinra and certolizumab. The overall likelihood of responding to therapy (i.e. ACR50) after 6 months was 32% better when MTX was given concomitantly with biological agents (1.32 [1.20-1.45]; P < 0.001) corresponding to 11 more out of 100 patients (7-16 more); Moderate Quality Evidence. Discontinuing due to AEs from concomitant use of MTX was potentially 20% increased (1.21 [0.97-1.50]; P = 0.09) compared to biological monotherapy corresponding to 1 more out of 100 patients (0-3 more); Moderate Quality Evidence.
CONCLUSIONS: Randomised trials provide Moderate Quality Evidence for a favourable benefit-harm balance supporting concomitant use of MTX rather than monotherapy when prescribing a biological agent in patients with RA although in absolute terms only 7-16 more out of 100 patients will achieve an ACR50 response after 6 months of this combination therapy.
Objective To compare efficacy and safety of subcutaneous sarilumab 200 mg and 150 mg every 2 weeks plus conventional synthetic disease-modifying antirheumatic drugs (+csDMARDs) versus other targeted DMARDs+csDMARDs and placebo+csDMARDs, in inadequate responders to csDMARDs (csDMARD-IR) or tumour necrosis factor α inhibitors (TNFi-IR). Methods Systematic literature review and network meta-analyses (NMA) conducted on 24 week efficacy and safety outcomes: Health Assessment Questionnaire Disability Index, modified total sharp score (mTSS, including 52 weeks), American College of Rheumatology (ACR) 20/50/70, European League Against Rheumatism Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28)<2.6; serious infections/serious adverse events (including 52 weeks). Results 53 trials were selected for NMA. csDMARD-IR: Sarilumab 200 mg+csDMARDs and 150 mg+csDMARDs were superior versus placebo+csDMARDs on all outcomes. Against most targeted DMARDs, sarilumab 200 mg showed no statistically significant differences, except superiority to baricitinib 2 mg, tofacitinib and certolizumab on 24 week mTSS. Sarilumab 150 mg was similar to all targeted DMARDs. TNFi-IR: Sarilumab 200 mg was similar to abatacept, golimumab, tocilizumab 4 mg and 8 mg/kg intravenously and rituximab on ACR20/50/70, superior to baricitinib 2 mg on ACR50 and DAS28<2.6 and to abatacept, golimumab, tocilizumab 4 mg/kg intravenously and rituximab on DAS28<2.6. Sarilumab 150 mg was similar to targeted DMARDs but superior to baricitinib 2 mg and rituximab on DAS28<2.6 and inferior to tocilizumab 8 mg on ACR20 and DAS28<2.6. Serious adverse events, including serious infections, appeared similar for sarilumab versus comparators. Conclusions Results suggest that in csDMARD-IR and TNFi-IR (a smaller network), sarilumab+csDMARD had superior efficacy and similar safety versus placebo+csDMARDs and at least similar efficacy and safety versus other targeted DMARDs+csDMARDs.
Rheumatoid arthritis (RA) pharmacotherapy may impact mental health outcomes by improving pain and stiffness, potentially by targeting inflammatory processes common to RA and depression. The objectives of this review were to ascertain the frequency of mental health assessments in RA pharmacotherapy trials, quantify the efficacy of RA pharmacotherapy for mental health outcomes, and explore the clinical and demographic factors related to mental health outcomes. Effective pharmacotherapy alone is unlikely to substantially improve mental health outcomes in most patients with RA. Integrated mental health care provided within routine clinical practice is essential to optimize mental and physical health outcomes.
OBJECTIVES: Compare the benefits and harms of drug therapies for adults with early rheumatoid arthritis (RA) within 1 year of diagnosis, updating the findings on early RA from the 2012 review.
DATA SOURCES: English-language articles identified through MEDLINE®, Cochrane Library, Embase®, International Pharmaceutical Abstracts, gray literature, the previous 2012 review, expert recommendations, reference lists of published literature, and supplemental evidence data requests from January 2011 to October 5, 2017.
REVIEW METHODS: Literature was synthesized qualitatively in narrative form and summary tables within and between corticosteroids and classes of disease-modifying antirheumatic drugs (DMARDs). Additionally, combination treatment strategies were examined. We conducted network meta-analysis for five outcomes: American College of Rheumatology 50-percent improvement (ACR50), remission based on Disease Activity Score (DAS), radiographic joint damage, all discontinuations, and discontinuations due to adverse events. Eligibility for network meta-analyses required the following: (1) patients with early RA had not attempted prior treatment with methotrexate (MTX), (2) doses of treatments were within ranges approved by the Food and Drug Administration (FDA), (3) length of followup was similar, and (4) studies were double-blinded randomized controlled trials of low or medium risk of bias.
RESULTS: We analyzed 49 studies: 41 RCTs and 8 observational studies reported in 124 published articles. All included studies enrolled patients with moderate to high disease activity at baseline as measured with mean or median DAS 28 scores. A combination of corticosteroids plus MTX achieved higher remission rates than with MTX monotherapy (low strength of evidence [SOE]). Combination therapy with TNF (tumor necrosis factor) or non-TNF biologics plus MTX improved disease control, remission, and functional capacity compared with monotherapy with either MTX or a biologic (low to moderate SOE). Network meta-analyses found higher ACR50 response for combination therapy of biologics plus MTX than for MTX monotherapy (range of relative risk, 1.20 [95% confidence interval (CI), 1.04 to 1.38] to 1.57 [95% CI, 1.30 to 1.88]). In available data, consisting mostly of clinical trials, no significant differences emerged between any DMARDs for rates of discontinuation attributable to adverse events or serious adverse events (low SOE for adalimumab, certolizumab pegol, etanercept, infliximab, or abatacept with MTX, and moderate SOE for rituximab or tocilizumab with MTX). Data about subgroups (based on disease activity, prior therapy, demographics, and the presence of other serious conditions) were insufficient. No difference in findings were noted in MTX naïve and resistant populations. We found no studies of biosimilars for patients with early RA.
CONCLUSIONS: Qualitative synthesis and network meta-analyses suggest that the combination of MTX with TNF or non-TNF biologics improves disease activity and remission when compared with biologic monotherapy or a conventional synthetic DMARD (csDMARD) monotherapy in patients with moderate to high disease activity at baseline as measured with mean or median DAS 28 scores. Overall rates of adverse events and discontinuation were similar among patients given csDMARDs, TNF biologics, and non-TNF biologics. We did not find eligible studies of biosimilars.
OBJECTIVES: To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy.
METHODS: We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed-effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800.
RESULTS: The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included "DMARD-naïve", and 20 "DMARD-Inadequate responder" (DMARD-IR) patients. All agents except anakinra and infliximab were superior (p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra (p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab (p = 0.0082), anakinra (p = 0.0083), certolizumab (p = 0.037), and golimumab (p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found (p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events (p > 0.068).
CONCLUSIONS: Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients׳ preferences and values in the final treatment choice.
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.
