No RA Benefit With Remicade Addition

Published: Oct 16, 2014

By Nancy Walsh, Senior Staff Writer, MedPage Today

Adding infliximab (Remicade) to triple therapy with conventional disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) did not provide additional benefit, a Finnish study showed.

At 5 years, 60% of patients in the triple therapy plus infliximab group were in strict remission according to the criteria of the American College of Rheumatology (ACR), as were 61% of those given triple therapy plus placebo (P=0.93), according to Vappu Rantalaiho, MD, of Tampere University, and colleagues.

In addition, radiographic erosion scores at 5 years were 3.7 among patients receiving infliximab along with conventional therapy and 4 among those not receiving the tumor necrosis factor (TNF) inhibitor (P=0.80), the researchers reported in the November Annals of the Rheumatic Diseases.

The goal of treatment for RA today is "early and sustained remission," which is possible for many patients using combination therapies. However, the optimal combination has not been established, and guidelines differ as to whether or not biologic agents should be used first line.

To evaluate the effect of adding infliximab to a regimen of methotrexate, sulfasalazine, and hydroxychloroquine (plus low-dose corticosteroids), Rantalaiho and colleagues enrolled 99 patients who were randomized to 6 months of the TNF inhibitor or a placebo, treating them to a target of ACR remission for 5 years.

ACR remission was defined as no fatigue, joint pain, or tender joints, morning stiffness of less than 15 minutes, and erythrocyte sedimentation rate below 30 mm/hour for women and 20 mm/hour for men.

For the first 2 years, methotrexate was given in doses up to 25 mg/week, sulfasalazine in doses of up to 2 g/day, hydroxychloroquine at 35 mg/kg/week, and prednisone at 7.5 mg/day. Infliximab was given as infusions of 3 mg/kg at weeks four, six, 10, 18, and 26.

Intra-articular steroid injections were allowed for inflamed joints.

After 2 years, patients who were in remission could taper their medications, beginning with prednisone and then sulfasalazine and methotrexate, with treatment reinstatement if remission was lost.

At any point after 2 years if treatment response fell below the ACR 50% response criteria, treatment could be adjusted, including allowing TNF inhibitor therapy.

Patients' mean age was 46, symptom duration at baseline was 4 months, and two-thirds were women.

At 5 years, 84% of patients who had received infliximab and 89% of those given placebo were in remission according to the less stringent criteria of Disease Activity Score in 28 joints, and physical function scores on the Health Assessment Questionnaire were zero for both groups.

Progression rates in the two groups were 0.32 and 0.73 units per year in the infliximab and placebo groups, respectively, and no progression occurred in 64% of patients in the infliximab group and 43% in the placebo group.

Change in radiographic score of 0.73 units in the placebo group "is clearly below the limit for the minimal clinically important difference," the investigators pointed out.

"Adding initial infliximab decelerated the progression further, halting it during the first 2 years and lessening the progression of new erosive patients. However, the real life relevance of the difference between the groups remains ambiguous," they wrote.

Adverse events were similar in the groups.

"This study shows that excellent sustained clinical results can be achieved with early, remission-targeted treatment with a combination of traditional DMARDs and systemic (if needed, intra-articular) glucocorticoid therapy in patients with recent-onset RA," Rantalaiho and colleagues wrote.

"The main message here is that early aggressive therapy for RA is effective, and that using initial triple therapy is as effective as using initial added infliximab," commented Eric L. Matteson, MD, who chairs the department of rheumatology at the Mayo Clinic in Rochester, Minn.

"Initially those on the added infliximab tended to do a bit better, but in the long run there was really no difference in the disease activity or radiographic outcomes," he told MedPage Today.

Early studies that compared biologics plus methotrexate versus methotrexate alone showed superiority for the combination, but in "strategy trials" with goals of low disease activity or remission, conventional DMARDs have also done well, the study authors observed.

"It appears evident that regardless of the specific medications used, the stricter the treatment goal, the higher the proportion of patients reaching remission and a nonprogressive state of disease," the Finnish researchers noted.

But a downside of the triple therapy, according to Matteson, is "that the patients take a lot of pills, which can be a limiting factor for compliance because of the sheer number of pills and the tolerability of the regimen."

"Also, there is some doubt in the minds and experience of some U.S. rheumatologists about whether the triple therapy is better than, for example, early combination therapy with methotrexate and hydroxychloroquine (with or without prednisone), or even initial solo therapy with methotrexate (with or without prednisone), although the evidence for the effectiveness of triple therapy is compelling across a number of studies done in the past years," Matteson explained.

The 2012 ACR treatment recommendations for RA state, "In patients with early RA, the panel recommends the use of DMARD monotherapy both for low disease activity and for moderate or high disease activity with the absence of poor prognostic features."

But the Finnish researchers concluded that clinicians now have to decide which approach carries the most potential for harm: "Overtreating occasional patients with traditional, inexpensive, well known and relatively safe DMARDs in combination, or knowingly undertreating the majority of patients with methotrexate monotherapy, and then, after failing to reach the target, overtreating them with new, highly expensive biologics, which still have an unclear long-term safety profile," they stated.

A limitation of the study was its small sample size, according to Matteson. He added that "clearly, some patients will need more aggressive treatment than others in the course of their disease."