The Use of Biologics in the Early Treatment of RA

Doctors are starting to treat patients with rheumatoid arthritis or RA from the first onset of symptoms, with powerful medications. For example, as soon as you are diagnosed with RA you are treated with disease-modifying antirheumatic drugs or DMARDs for short, probably something like leflunomide or Arava or maybe even methotrexate. There was a Dutch study that took that trend on step further and suggested that even more powerful drugs like tumor necrosis factor or TNF inhibitors may beneficial from the start.

Research, reported in November 2008, piggybacked on data collected in an earlier study (the BeSt study), this earlier controlled trial tested four regular patterns of medication used by people recently diagnosed with RA. This new study compared the group who was given the anti-TNF drug infliximab or Remicade, plus methotrexate from the start of BeSt study with people who only got this treatment after the traditional DMARDs didn’t help them.

Researchers wrote that in many countries the normal RA treatment is to start with traditional DMARDs and that 1/3 of the patients diagnosed with RA responded adequately to methotrexate or MTX alone, thus saving money and reducing the risk of side-effects from the more powerful drugs.

The piggyback study was made up of 117 people who began therapy with infliximab plus the methotrexate and the comparison group was made up of 67 people who had no success with three or more traditional DMARDs. These 67 people got infliximab and methotrexate within 2 years of enrollment in the BeSt study, but there was a delay of 13 months before this group received infliximab.

All people with RA symptoms were checked every three months, using the standard disease activity scores (DAS) during the BeSt study and the doctors took x-rays of their hands and feet when they had begun the BeSt study three years earlier. Their success was measured by the DAS, the rate at which joint space had narrowed on the x-rays, and whether the participants achieved remissions that were long enough (six months) and strong enough (on the DAS a score of 2.4 or less) to all them to taper off of the infliximab.

Those who had the delayed access to infliximab had more severe RA that had not responded to other medications. Adjustments for the differences in making the two groups comparable so the BeSt data made sense in connection with the piggyback study, researchers had to go back to the original baseline characteristics of all the people who participated and incorporate 30 of those characteristics, such as, age, gender, symptom duration, weight, rheumatoid factor, DAS, pain, joint erosion, overall health, and etc., into a learning model. With a learning model they were able to sort people according to shared characteristics and in this study researchers were also able to sort the two study groups into five sets. Each of these five sets had characteristics that matched enough that the likelihood of the people who participated developing severe RA was equal to each other. This made it possible to compare the immediate infliximab and the delayed infliximab groups inside of the five sets.

The people who got the infliximab and the methotrexate from the very beginning showed a greater improvement in functioning between baseline and the end of the BeSt study compared to the people getting the delayed infliximab. The x-rays showed that over the last 3 years of the study, joint damage had progressed less in the initial infliximab group and when the learning scores had been taken into consideration, there was a significant progression of joint damage that was twice as likely in people whose infliximab was delayed. Also, those with the initial infliximab were significantly more likely to taper off the drug because they had achieved sustained remission. The people who received the delayed doses of infliximab were more likely to need increased doses of the infliximab before achieving remission. About the same number of the people who received the initial doses and the people who received the delayed doses, stopped taking the infliximab treatments because of the toxicity or ineffectiveness of the drug. There was one person in each group who contracted tuberculosis, a serious potential complication of the infliximab therapy.

The drawbacks to the piggyback study come from its being after-the-fact, rather than designed to specifically to address the insight of the delayed anti-TNF treatment. The timing and limited number of x-rays ruled out relating radiological changes directly to treatment changes. And the use of a learning model helped to make the treatment groups more comparable, based on their traits when they began the BeSt study, but it couldn’t eliminate the effects that the failed treatments during the BeSt study, may have had on those who participated. After the learning adjustments were made, the piggyback study was not designed to compare toxicity between the people who took the delayed doses and the people who took the initial doses of infliximab.

Researchers say the evidence supports a “window of opportunity” hypothesis that the earliest possible treatment of RA with the combination of infliximab and methotrexate, may stop the disease activity in the critical period before joint damage gets started. They also recommend more studies to be done to confirm their findings of improved functioning, delayed joint damage, and less total use of infliximab when people start RA treatment with anti-TNF treatments rather than waiting to see if the other medications fail.