CHAPEL HILL, North Carolina—Clinicians treating rheumatoid arthritis (RA) patients are likely to find little effective difference among the conventional synthetic DMARDs methotrexate (MTX), leflunomide, and sulfasalazine, or among the anti-tumor necrosis factor (anti-TNF) drugs adalimumab, etanercept, and infliximab used as monotherapy,

However, when monotherapy fails, combining MTX with a biological works better than switching to the biologic alone, according to a systematic review by Katrina E. Donahue, MD, MPH, and colleagues published early online in Annals of Internal Medicine.¹ Dr. Donahue is in the department of family medicine at the University of North Carolina at Chapel Hill.

"Various combinations of biological DMARDs plus methotrexate had better clinical response rates and functional outcomes than monotherapy with either methotrexate or biological DMARDs. In patients previously receiving monotherapy, combination therapy with synthetic DMARDs improved response rates. Numbers of short-term adverse events were similar with biological and synthetic DMARDs," Dr. Donahue said.

Biologicals plus MTX better than conventional DMARDs as second-line treatment

The systematic review included 42 head-to-head randomized controlled trials, one head-to-head nonrandomized trial, nine placebo-controlled trials, eight systematic reviews or meta-analyses, and 58 observational studies. All studies had at least 100 participants and 12 weeks of follow-up. Meta-analyses were rated good- or fair-quality. The included studies compared benefits or harms of 11 RA drug therapies.

According to Dr. Donahue

• The 23 head-to-head trials showed no clinically significant differences in monotherapy trials either among the synthetic DMARDs or among the anti-TNF drugs.
• In patients whose first RA regimens had failed, those switching to biological DMARDs were significantly more likely than those receiving synthetic DMARDs to achieve functional independence and/or remission.
• Radiographic outcomes were better with anti-TNF monotherapy than with MTX monotherapy, but there were no important differences in clinical outcomes such as ACR20.
• Various combinations of biologicals with MTX were more effective than either alone.
• For patients whose monotherapy fails, combination therapy is more effective than switching to another monotherapy, but there is not enough evidence to support any particular combination over another.
• Adding prednisone to hydroxychloroquine, MTX, or sulfasalazine is more effective than the DMARD alone in reducing joint swelling and tenderness and improving function.
• There were no meaningful clinical differences between MTX and either leflunomide or sulfasalazine.
• For patients with early RA, combining MTX and sulfasalazine is no better than using either alone.

"In a prospective cohort study of patients whose initial RA treatment failed, those receiving biological DMARDs had, after 12 months, almost 4 times higher odds of achieving functional independence...and almost two times higher odds of achieving remission than those receiving synthetic DMARDs," Dr. Donahue reported.

The adverse effects analyses showed that

• About 17 of every 1000 people taking a biologic for 3 to 12 months have a serious infection.
• Combining two biologic DMARDs increases the risk of serious infection.
• Among the biologics, painful injection site reactions are more common for anakinra (67%) than for etanercept (22%) or adalimumab (18%).

The researchers pointed out that a number of important questions remain about how best to deploy the available RA treatments.

"Clinical decision making would benefit from examining timing of initiation of therapies, applicability of combination strategies and biological DMARD therapy in community practice, and specific head-to-head comparisons focusing on different combination strategies and different biological DMARDs," the authors write. But they warn, "The risk for rare but serious adverse events including malignant conditions, serious infections, demyelination, severe infusion reactions, or congestive heart failure, must be established in well-conducted observational studies with active harms surveillance."

This point is particularly important, since most of the studies available for this systematic review "were efficacy trials conducted in highly selected populations." Of the included studies, 48.5% were supported by pharmaceutical companies and another 10.9% by a combination of pharmaceutical and government funding.

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