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.
BACKGROUND: Treat to target (TTT) is a broad concept for treating patients with rheumatoid arthritis (RA). It involves setting a treatment target, usually remission or low disease activity (LDA). This is often combined with frequent patient assessment and intensive and rapidly adjusted drug treatment, sometimes based on a formal protocol.
OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of TTT compared with routine care.
DATA SOURCES: Databases including EMBASE and MEDLINE were searched from 2008 to August 2016.
REVIEW METHODS: A systematic review of clinical effectiveness was conducted. Studies were grouped according to comparisons made: (1) TTT compared with usual care, (2) different targets and (3) different treatment protocols. Trials were subgrouped by early or established disease populations. Study heterogeneity precluded meta-analyses. Narrative synthesis was undertaken for the first two comparisons, but was not feasible for the third. A systematic review of cost-effectiveness was also undertaken. No model was constructed as a result of the heterogeneity among studies identified in the clinical effectiveness review. Instead, conclusions were drawn on the cost-effectiveness of TTT from papers relating to these studies.
RESULTS: Sixteen clinical effectiveness studies were included. They differed in terms of treatment target, treatment protocol (where one existed) and patient visit frequency. For several outcomes, mixed results or evidence of no difference between TTT and conventional care was found. In early disease, two studies found that TTT resulted in favourable remission rates, although the findings of one study were not statistically significant. In established disease, two studies showed that TTT may be beneficial in terms of LDA at 6 months, although, again, in one case the finding was not statistically significant. The TICORA (TIght COntrol for RA) trial found evidence of lower remission rates for TTT in a mixed population. Two studies reported cost-effectiveness: in one, TTT dominated usual care; in the other, step-up combination treatments were shown to be cost-effective. In 5 of the 16 studies included the clinical effectiveness review, no cost-effectiveness conclusion could be reached, and in one study no conclusion could be drawn in the case of patients denoted low risk. In the remaining 10 studies, and among patients denoted high risk in one study, cost-effectiveness was inferred. In most cases TTT is likely to be cost-effective, except where biological treatment in early disease is used initially. No conclusions could be drawn for established disease.
LIMITATIONS: TTT refers not to a single concept, but to a range of broad approaches. Evidence reflects this. Studies exhibit substantial heterogeneity, which hinders evidence synthesis. Many included studies are at risk of bias.
FUTURE WORK: Future studies comparing TTT with usual care must link to existing evidence. A consistent definition of remission in studies is required. There may be value in studies to establish the importance of different elements of TTT (the setting of a target, the intensive use of drug treatments and protocols pertaining to those drugs and the frequent assessment of patients).
CONCLUSION: In early RA and studies of mixed early and established RA populations, evidence suggests that TTT improves remission rates. In established disease, TTT may lead to improved rates of LDA. It remains unclear which element(s) of TTT (the target, treatment protocols or increased frequency of patient visits) drive these outcomes. Future trials comparing TTT with usual care and/or different TTT targets should use outcomes comparable with existing literature. Remission, defined in a consistent manner, should be the target of choice of future studies.
STUDY REGISTRATION: This study is registered as PROSPERO CRD42015017336.
FUNDING: The National Institute for Health Research Health Technology Assessment programme.
OBJECTIVES: To perform a systematic literature review (SLR) informing the 2016 update of the recommendations for the management of rheumatoid arthritis (RA).
METHODS: An SLR for the period between 2013 and 2016 was undertaken to assess the efficacy of glucocorticoids (GCs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and targeted synthetic DMARDs (tsDMARDs) (tofacitinib and baricitinib) in randomised clinical trials.
RESULTS: For GCs, four studies were included in the SLR. Patients without poor prognostic factors experienced benefit when GCs were added to methotrexate (MTX). Lower doses of GCs were similar to higher doses. For csDMARDs, two new studies comparing MTX monotherapy with combination csDMARD were included in the SLR. In the tREACH trial at the end of 12 months no difference between the groups in disease activity, functional ability and radiographic progression was seen, using principles of tight control (treat-to-target). In the CareRA trial, combination therapy with csDMARDs was not superior to MTX monotherapy and monotherapy was better tolerated.For tsDMARDs, tofacitinib and baricitinib were shown to be more effective than placebo (MTX) in different patient populations.
CONCLUSIONS: Addition of GCs to csDMARD therapy may be beneficial but the benefits should be balanced against the risk of toxicity. Under tight control conditions MTX monotherapy is not less effective than combination csDMARDs, but better tolerated. Tofacitinib and baricitinib are efficacious in patients with RA, including those with refractory disease.
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.
