Biologics or tofacitinib for rheumatoid arthritis not improved by treatment with methotrexate or other disease-modifying anti-rheumatic drugs

What is rheumatoid arthritis and what are biologics?

When people have rheumatoid arthritis (RA), their immune system, which normally fights infection, attacks the joint lining. This makes their joints swollen, stiff and painful. If the inflammation goes on without treatment, joint damage and disability may result. Biologics and tofacitinib are medications that work by blocking different types of immune cells in the body that cause swelling and joint damage in people who have RA.

This is an update of a review published in 2009. We have split the original review into four reviews based on patient population. We looked at trials done until June 2015 on the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab) and tofacitinib on people with RA who had not improved with treatment of methotrexate or other DMARDs.

The review shows that in people with rheumatoid arthritis:

Biologics in combination with methotrexate (MTX) or other DMARDs:

- probably improve signs and symptoms of RA (tender or swollen joints), function, the chances of RA remission (disappearance of symptoms) and slow down X-ray disease progression. However, we are not sure of the importance of the amount of slowing of disease progression as seen on X-rays. We downgraded our confidence in the results because of concerns about the inconsistency of some results.

- probably slightly increase the number of serious adverse events, though there are few events.

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, we are uncertain of the effect of biologics on the risk of cancer and withdrawals due to adverse events.

Best estimate of what happens to people with RA taking biologics

ACR50 (number of tender or swollen joints and other doctor/patient assessed aspects)

Twenty-four more people out of 100 experienced improvement in the symptoms of their rheumatoid arthritis with biologics + MTX/DMARD (24% absolute improvement).

Thirty-eight people out of 100 who were on biologic+ MTX experienced improvement compared to 14 people out of 100 who were on MTX/DMARD/placebo.

Function improvement by Health Assessment Questionnaire (0 to 3 scale, lower score or more reduction = better function)

People who took biologics + MTX/DMARDs rated their improvement in function to be 0.25 points more on a scale of 0 to 3 (-8% absolute improvement).

People who took biologics + MTX/DMARDs rated their function improved by 0.39 points on a scale of 0 to 3.

People who took a MTX/DMARD/placebo rated their function improved by 0.14 points on a scale of 0 to 3.

Remission

Eighteen more people out of 100 experienced no symptoms of their rheumatoid arthritis with biologics + MTX/DMARDs (18% absolute improvement).

Twenty-eight patients out of 100 who were on biologic+ MTX experienced no symptoms compared to 10 people out of 100 who were on MTX/DMARD/placebo.

Progression of disease damage as measured on X-rays (on a scale of 0 to 448)

The damage to joints of people who took biologics + MTX/DMARDs was 2.6 points lower (-0.58% absolute improvement).

The damage to joints of people who took a MTX/DMARD/placebo was 3.7 points.

Withdrawal from study due to adverse events

Ten more people out of 1000 who took biologics + MTX/DMARD withdrew from the study due to adverse events (1% more withdrawals).

Fifty-five patients out of 1000 who took biologics + MTX/DMARD withdrew from the study compared to 45 people out of 1000 who were on MTX/DMARD/placebo.

Serious Adverse Events

Ten more people out of 1000 who took biologics + MTX/DMARD had serious adverse events (1% more serious adverse events).

Seventy-eight patients out of 1000 who took biologics + MTX/DMARD had serious adverse events compared to 68 people out of 1000 who were on MTX/DMARD/placebo; most common were infections.

Cancer

The same number of people (14 out of 1000) who took biologics + MTX/DMARDs compared to those on MTX/DMARD/placebo had cancer. However, we are cautious about this estimate as there were few events of cancer in the studies.

Results for tofacitinib are provided in the results section.

Authors' conclusions: 

Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.

Read the full abstract...
Background: 

This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA).

Objectives: 

To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR).

Methods: 

We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation.

Main results: 

This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).

Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.

Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.

Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.

Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.

Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.

Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics + MTX/DMARD: 1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).

Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.

Main results text shows the results for tofacitinib and differences between medications.

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