Biologics for rheumatoid arthritis (RA) in people not previously treated with methotrexate (MTX)

Review question

We studied the benefits and harms of biologics or tofacitinib on people with rheumatoid arthritis (RA) who have not previously been treated with methotrexate (MTX), in trials done until June 2015. Data was available for four TNF biologics (adalimumab, etanercept, golimumab, infliximab) and two non-TNF biologics (abatacept, rituximab).

What is RA and what are biologics/tofacitinib?

In RA, the immune system, which normally fights infection, attacks the joint lining making it inflamed. Without treatment, the inflammation can lead to joint damage and disability. Biologics or tofacitinib are medications that can reduce joint inflammation/damage and improve symptoms.

The review shows that in people with RA:

- Biologics (abatacept, adalimumab, etanercept, golimumab, infliximab, rituximab) in combination with MTX probably improve signs and symptoms of RA (tender or swollen joints), the chances of RA remission (disappearance of symptoms) and probably slightly improve functional ability. We downgraded our confidence in the results because of concerns about the inconsistency of some results.

- Biologics in combination with MTX may make little or no difference in the risk of serious adverse events or withdrawals due to adverse events. We downgraded our confidence in the results because of concerns about the inconsistency of some results and the lack of data.

- We often do not have precise information about side effects and complications. Because of the lack of data, we are uncertain of the effect of biologics on the risk of cancer.

-TNF biologics (adalimumab, etanercept, golimumab) alone (not in combination with MTX) probably make little or no difference in signs and symptoms of RA or chances of RA remission (no data for non-TNF biologics alone).

Best estimate of what happens to people with RA when taking biologics:

ACR50 (American College of Rheumatology 50: number of tender or swollen joints, pain and disability) :

Biologic + MTX versus MTX: 56 people out of 100 who were on a biologic (in combination with MTX) experienced improvement in RA compared to 40 people out of 100 who were on MTX (16% improvement).

Biologic monotherapy (TNF biologics) versus MTX: 35 people out of 100 who were on a biologic experienced improvement in RA compared to 37 people out of 100 who were on MTX (2% reduction)

Remission (DAS <1.6 or DAS28 < 2.6)

Biologic + MTX versus MTX: 37 people out of 100 who took a biologic (in combination with MTX) had their RA symptoms disappear compared to 22 people out of 100 who were on MTX (15% improvement).

Biologic monotherapy (TNF biologics) versus MTX: 22 people out of 100 who took a biologic had their RA symptoms disappear compared to 20 people out of 100 who were on MTX (2% improvement).

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

Biologic + MTX versus MTX: people who took a biologic (in combination with MTX) showed radiographic progression of 0.45 points compared to those on MTX who showed progression of 3 points (0.5% reduction).

There were no studies for biologic monotherapy.

Drug withdrawal due to adverse events

Biologic + MTX versus MTX: 7 people out of 100 who took a biologic (in combination with MTX) withdrew from the study due to adverse events compared to 5 out of 100 participants who took MTX (2% more).

Biologic monotherapy (TNF biologics) versus MTX: 6 people out of 100 who took a biologic withdrew from the study due to adverse events compared to 6 out of 100 participants who took MTX (0% difference).

Serious adverse events

Biologic + MTX versus MTX: 11 participants out of 100 who took a biologic (in combination with MTX) reported serious adverse events compared to 10 participants out of 100 on MTX (1% more serious adverse events).

Biologic monotherapy (TNF biologics) versus MTX: 3 participants out of 100 who took a biologic reported serious adverse events compared to 7 participants out of 100 on MTX (4% fewer serious adverse events).

Cancer

The same number of people (1 out of 100) reported cancer for biologic (both alone and in combination with MTX) and the comparator MTX. However, there were few events of cancer so caution in this interpretation is needed.

Authors' conclusions: 

In MTX-naive RA participants, there was moderate-quality evidence that, compared with MTX alone, biologics with MTX was associated with absolute and relative clinically meaningful benefits in three of the efficacy outcomes (ACR50, HAQ scores, and RA remission rates). A benefit regarding less radiographic progression with biologics with MTX was not evident (low-quality evidence). We found moderate- to low-quality evidence that biologic therapy with MTX was not associated with any higher risk of serious adverse events compared with MTX, but results were inconclusive for withdrawals due to adverse events and cancer to 24 months.

TNF biologic monotherapy did not differ statistically significantly or clinically meaningfully from MTX for any of the outcomes (moderate-quality evidence), and no data were available for non-TNF biologic monotherapy.

We conclude that biologic with MTX use in MTX-naive populations is beneficial and that there is little/inconclusive evidence of harms. More data are needed for tofacitinib, radiographic progression and harms in this patient population to fully assess comparative efficacy and safety.

Read the full abstract...
Background: 

Biologic disease-modifying anti-rheumatic drugs (biologics) are highly effective in treating rheumatoid arthritis (RA), however there are few head-to-head biologic comparison studies. We performed a systematic review, a standard meta-analysis and a network meta-analysis (NMA) to update the 2009 Cochrane Overview. This review is focused on the adults with RA who are naive to methotrexate (MTX) that is, receiving their first disease-modifying agent.

Objectives: 

To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (methotrexate (MTX)/other DMARDs) in people with RA who are naive to methotrexate.

Methods: 

In June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE and Embase; and trials registers. We used standard Cochrane methods. We calculated odds ratios (OR) and mean differences (MD) along with 95% confidence intervals (CI) for traditional meta-analyses and 95% credible intervals (CrI) using a Bayesian mixed treatment comparisons approach for network meta-analysis (NMA). We converted OR to risk ratios (RR) for ease of interpretation. We also present results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial or harmful outcome (NNTB/H).

Main results: 

Nineteen RCTs with 6485 participants met inclusion criteria (including five studies from the original 2009 review), and data were available for four TNF biologics (adalimumab (six studies; 1851 participants), etanercept (three studies; 678 participants), golimumab (one study; 637 participants) and infliximab (seven studies; 1363 participants)) and two non-TNF biologics (abatacept (one study; 509 participants) and rituximab (one study; 748 participants)).

Less than 50% of the studies were judged to be at low risk of bias for allocation sequence generation, allocation concealment and blinding, 21% were at low risk for selective reporting, 53% had low risk of bias for attrition and 89% had low risk of bias for major baseline imbalance. Three trials used biologic monotherapy, that is, without MTX. There were no trials with placebo-only comparators and no trials of tofacitinib. Trial duration ranged from 6 to 24 months. Half of the trials contained participants with early RA (less than two years' duration) and the other half included participants with established RA (2 to 10 years).

Biologic + MTX versus active comparator (MTX (17 trials (6344 participants)/MTX + methylprednisolone 2 trials (141 participants))

In traditional meta-analyses, there was moderate-quality evidence downgraded for inconsistency that biologics with MTX were associated with statistically significant and clinically meaningful benefit versus comparator as demonstrated by ACR50 (American College of Rheumatology scale) and RA remission rates. For ACR50, biologics with MTX showed a risk ratio (RR) of 1.40 (95% CI 1.30 to 1.49), absolute difference of 16% (95% CI 13% to 20%) and NNTB = 7 (95% CI 6 to 8). For RA remission rates, biologics with MTX showed a RR of 1.62 (95% CI 1.33 to 1.98), absolute difference of 15% (95% CI 11% to 19%) and NNTB = 5 (95% CI 6 to 7). Biologics with MTX were also associated with a statistically significant, but not clinically meaningful, benefit in physical function (moderate-quality evidence downgraded for inconsistency), with an improvement of HAQ scores of -0.10 (95% CI -0.16 to -0.04 on a 0 to 3 scale), absolute difference -3.3% (95% CI -5.3% to -1.3%) and NNTB = 4 (95% CI 2 to 15).

We did not observe evidence of differences between biologics with MTX compared to MTX for radiographic progression (low-quality evidence, downgraded for imprecision and inconsistency) or serious adverse events (moderate-quality evidence, downgraded for imprecision). Based on low-quality evidence, results were inconclusive for withdrawals due to adverse events (RR of 1.32, but 95% confidence interval included possibility of important harm, 0.89 to 1.97). Results for cancer were also inconclusive (Peto OR 0.71, 95% CI 0.38 to 1.33) and downgraded to low-quality evidence for serious imprecision.

Biologic without MTX versus active comparator (MTX 3 trials (866 participants)

There was no evidence of statistically significant or clinically important differences for ACR50, HAQ, remission, (moderate-quality evidence for these benefits, downgraded for imprecision), withdrawals due to adverse events,and serious adverse events (low-quality evidence for these harms, downgraded for serious imprecision). All studies were for TNF biologic monotherapy and none for non-TNF biologic monotherapy. Radiographic progression was not measured.

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