Review question
We studied the effects of biologics on people with rheumtoid arthritis (RA), whose previous treatment with biologic therapy was unsuccessful, either due to lack of benefits or occurrence of side effects, or both. There were a total of 12 studies (up to June 2015) with data available for four of the tumor necrosis factor (TNF)-biologics (certolizumab pegol, etanercept, golimumab, infliximab) and three of the non-TNF biologics (abatacept, rituximab, and tocilizumab); only one study provided data for tofacitinib.
What is RA and what are biologics/tofacitinib?
In RA, your immune system, which normally fights infection, attacks the joint lining making it inflamed. If the inflammation is untreated, joint damage and disability may result. Biologics and tofacitinib are medications that can reduce joint inflammation, improve symptoms and prevent some of the joint damage.
The review shows that in people with RA:
- Biologics alone or in combination with methotrexate (MTX), a disease-modifying anti-rheumatic drug (DMARD), improve signs (tender or swollen joints) and symptoms of RA, function, and probably improve the chances of RA remission (disappearance of symptoms), based on high- and moderate-quality evidence (downgraded for imprecision).
- Tofacitinib in combination with MTX, probably improves signs and symptoms of RA (tender or swollen joints) and function, based on high- and moderate-quality evidence (downgraded for imprecision).
- We often do not have precise information about side-effects and complications. This is particularly true for rare but serious side-effects. Because of the lack of data and low-quality evidence, we are uncertain of the effect of biologics and tofacitinib on the risk of cancer, serious adverse events, and withdrawals due to adverse events.
Best estimate of what happens to people with RA when taking biologics or tofacitinib:
ACR50 (number of tender or swollen joints, pain, and disability)
Biologic monotherapy versus placebo: 18 out of 100 people on a biologic monotherapy experienced improvement in their symptoms versus 4 out of 100 on placebo (14% absolute improvement).
Biologic + MTX versus MTX/other traditional DMARDs: 21 people out of 100 on biologic + MTX experienced improvement in RA symptoms compared to 5 people out of 100 who were on MTX/DMARD (16% absolute improvement).
Tofacitinib + MTX versus MTX: 28 people out of 100 on tofacitinib + MTX experienced improvement in RA symptoms compared to 9 people out of 100 who were on MTX/DMARD (19% absolute improvement), based on one study.
Remission (DAS < 1.6 or DAS28 < 2.6)
Biologic monotherapy versus placebo: 102 people out of 1000 who were on biologic had their RA symptoms disappear compared to 8 people out of 1000 on placebo (9% absolute improvement).
Biologic + MTX versus MTX/other traditional DMARDs: 104 people out of 1000 who were on biologic + MTX had their RA symptoms disappear compared to 3 people out of 1000 who were on MTX/DMARD (10% absolute improvement).
Tofacitinib + MTX versus MTX: 56 people out of 1000 who were on tofacitinib + MTX had their RA symptoms disappear compared to 0 people out of 1000 who were on MTX/DMARD (6% absolute improvement), based on one study.
Progression of radiographic destruction
No studies were available for analysis.
Drug withdrawal due to adverse events
Biologic monotherapy versus placebo: 32 people out of 1000 on biologic reported withdrawal due to adverse events versus 42 out of 1000 on placebo (1% fewer withdrawals).
Biologic + MTX versus MTX/other traditional DMARDs: 38 people out of 1000 on biologic + MTX reported withdrawal due to adverse events compared to 8 out of 1000 people on MTX/DMARD (5% more withdrawals).
Tofacitinib + MTX versus MTX: there was no difference in withdrawals due to adverse events between people on tofacitinib + MTX and people on MTX/DMARD, both with 5 participants out of 100, based on one study.
Serious a dverse events
There was a 1% to 3% difference for fewer serious adverse events in all comparisons compared with people on MTX/DMARD.
Cancer
Biologic + MTX versus MTX/other traditional DMARDs: there was a less than 1% difference for the risk of cancer between biologic + MTX and MTX/DMARD; 5 out of 1000 of those on biologic + MTX and 0 on MTX/DMARD developed cancer, although there were very few studies available.
Biologic (with or without MTX) or tofacitinib (with MTX) use was associated with clinically meaningful and statistically significant benefits (ACR50, HAQ, remission) compared to placebo or an active comparator (MTX/other traditional DMARDs) among people with RA previously unsuccessfully treated with biologics.
No studies examined radiographic progression. Results were not clinically meaningful or statistically significant for withdrawals due to adverse events and serious adverse events, and were inconclusive for cancer.
Biologic disease-modifying anti-rheumatic drugs (DMARDs: referred to as biologics) are effective in treating rheumatoid arthritis (RA), however there are few head-to-head comparison studies. Our systematic review, standard meta-analysis and network meta-analysis (NMA) updates the 2009 Cochrane overview, 'Biologics for rheumatoid arthritis (RA)' and adds new data. This review is focused on biologic or tofacitinib therapy in people with RA who had previously been treated unsuccessfully with biologics.
To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (placebo or methotrexate (MTX)/other DMARDs) in people with RA, previously unsuccessfully treated with biologics.
On 22 June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, and Embase; and trials registries (WHO trials register, Clinicaltrials.gov). We carried out article selection, data extraction, and risk of bias and GRADE assessments in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparison (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We have also presented results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Outcomes measured included four benefits (ACR50, function measured by Health Assessment Questionnaire (HAQ) score, remission defined as DAS < 1.6 or DAS28 < 2.6, slowing of radiographic progression) and three harms (withdrawals due to adverse events, serious adverse events, and cancer).
This update includes nine new RCTs for a total of 12 RCTs that included 3364 participants. The comparator was placebo only in three RCTs (548 participants), MTX or other traditional DMARD in six RCTs (2468 participants), and another biologic in three RCTs (348 participants). Data were available for four tumor necrosis factor (TNF)-biologics: (certolizumab pegol (1 study; 37 participants), etanercept (3 studies; 348 participants), golimumab (1 study; 461 participants), infliximab (1 study; 27 participants)), three non-TNF biologics (abatacept (3 studies; 632 participants), rituximab (2 studies; 1019 participants), and tocilizumab (2 studies; 589 participants)); there was only one study for tofacitinib (399 participants). The majority of the trials (10/12) lasted less than 12 months.
We judged 33% of the studies at low risk of bias for allocation sequence generation, allocation concealment and blinding, 25% had low risk of bias for attrition, 92% were at unclear risk for selective reporting; and 92% had low risk of bias for major baseline imbalance. We downgraded the quality of the evidence for most outcomes to moderate or low due to study limitations, heterogeneity, or rarity of direct comparator trials.
Biologic monotherapy versus placebo
Compared to placebo, biologics were associated with clinically meaningful and statistically significant improvement in RA as demonstrated by higher ACR50 and RA remission rates. RR was 4.10 for ACR50 (95% CI 1.97 to 8.55; moderate-quality evidence); absolute benefit RD 14% (95% CI 6% to 21%); and NNTB = 8 (95% CI 4 to 23). RR for RA remission was 13.51 (95% CI 1.85 to 98.45, one study available; moderate-quality evidence); absolute benefit RD 9% (95% CI 5% to 13%); and NNTB = 11 (95% CI 3 to 136). Results for withdrawals due to adverse events and serious adverse events did not show any statistically significant or clinically meaningful differences. There were no studies available for analysis for function measured by HAQ, radiographic progression, or cancer outcomes. There were not enough data for any of the outcomes to look at subgroups.
Biologic + MTX versus active comparator (MTX/other traditional DMARDs)
Compared to MTX/other traditional DMARDs, biologic + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50, function measured by HAQ, and RA remission rates in direct comparisons. RR for ACR50 was 4.07 (95% CI 2.76 to 5.99; high-quality evidence); absolute benefit RD 16% (10% to 21%); NNTB = 7 (95% CI 5 to 11). HAQ scores showed an improvement with a mean difference (MD) of 0.29 (95% CI 0.21 to 0.36; high-quality evidence); absolute benefit RD 9.7% improvement (95% CI 7% to 12%); and NNTB = 5 (95% CI 4 to 7). Remission rates showed an improved RR of 20.73 (95% CI 4.13 to 104.16; moderate-quality evidence); absolute benefit RD 10% (95% CI 8% to 13%); and NNTB = 17 (95% CI 4 to 96), among the biologic + MTX group compared to MTX/other DMARDs. There were no studies for radiographic progression. Results were not clinically meaningful or statistically significantly different for withdrawals due to adverse events or serious adverse events, and were inconclusive for cancer.
Tofacitinib monotherapy versus placebo
There were no published data.
Tofacitinib + MTX versus active comparator (MTX)
In one study, compared to MTX, tofacitinib + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50 (RR 3.24; 95% CI 1.78 to 5.89; absolute benefit RD 19% (95% CI 12% to 26%); NNTB = 6 (95% CI 3 to 14); moderate-quality evidence), and function measured by HAQ, MD 0.27 improvement (95% CI 0.14 to 0.39); absolute benefit RD 9% (95% CI 4.7% to 13%), NNTB = 5 (95% CI 4 to 10); high-quality evidence). RA remission rates were not statistically significantly different but the observed difference may be clinically meaningful (RR 15.44 (95% CI 0.93 to 256.1; high-quality evidence); absolute benefit RD 6% (95% CI 3% to 9%); NNTB could not be calculated. There were no studies for radiographic progression. There were no statistically significant or clinically meaningful differences for withdrawals due to adverse events and serious adverse events, and results were inconclusive for cancer.