Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, inflammatory disorder characterized by joint inflammation and joint destruction.
If left untreated or poorly treated, RA is associated with progressive functional disability, significant morbidity, and even increased mortality. What this means is that RA is not just a disease associated with painful stiff joints but a disease which can lead to inability to perform even the simplest daily taks… as well as significantly shortening lifespan. This reduction in years lived can range anywehre from 3-7 years in mild disease and 10-15 years with more serious disease.
In recent years, the addition of biologic therapies to standard disease-modifying anti-rheumatic drug (DMARD) treatment has improved the prognosis of RA, with better symptom improvement as well as slowing of x-ray progression.
The idea that early RA may be better controlled if treated earlier in the disease course has been supported by by animal models as well as human studies.
Early RA is now defined as RA of as little as 3 months to as long as 1 year’s duration.
Patients with early RA exhibit a typical picture in their joints when the inflamed tissue is examined in the laboratory indicating that there is a narrow “therapeutic window of opportunity” in which to put the disease into remission.
Studies have indicated that early treatment with combinations of DMARDs has been shown to be superior to single DMARDS.
More recent trials have shown the addition of biologics to DMARD therapy also exhibits positive outcomes.
Clinical trials of the 3 currently FDA-approved tumor necrosis factor (TNF) inhibitors – etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) — have been conducted in patients with early RA. In these studies, the comparison drug has between methotrexate, the typical standard of care.
One example is the the Etanercept in Early Rheumatoid Arthritis (ERA) trial which compared Enbrel at 2 different doses with methotrexate, all as single drugs. Although the clinical responses to all three drugs were good, patients receiving Enbrel alone also had a more rapid clinical response. In addition, x-rays demonstrated the superiority of Enbrel in slowing x-ray progression compared with methotrexate alone.
The Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial compared the efficacy of Remicade at 2 different doses, given in combination with methotrexate vs methotrexate alone in patients with early RA who had never received methotrexate. Patients treated with the combination had faster and greater clinical improvement and better x-ray outcomes.
The PREMIER study evaluated the effectiveness of combination therapy with adalimumab (Humira) plus methotrexate in comparison with each treatment alone. In this trial, clinical responses with methotrexate or with Humira were similar, but the best responses were aobtained with combination therapy. In regards to joint damage, Humira alone did better than methotrexate alone, but the best x-ray results were seen with the combination.
Results from all of these studies clearly showed the benefit of TNF blockers in early RA. Also, it was clear that the combination of TNF blockers with methotrexate was extremely effective in regard to signs and symptoms of disease, improvements in function, and slowing of x-ray damage.
Another study evaluating the best approach to early RA was the BeSt trial. BeSt was a randomized clinical trial of 508 patients with early RA, defined as patients with less than 2 years of disease conducted in Europe.
Patients were randomized to receive 1 of 4 different treatment strategies including methotrexate alone, methotrexate with another DMARD, methotrexate with sulfasalazine, and methotrexate with Remicade.
After more than 4 years of follow-up, nearly 50% of patients in each of the 4 groups of the BeSt study went into remission. Regardless of the type of initial treatment, a strategy of frequent evaluation of disease activity and change of therapy to achieve low disease activity,
Both practitioners and patients have expressed concerns about the long-term safety of using biologic medicines which alter immune function. Although much is known about the safety issues with biologic agents in general, there is little information in regard to the safety of biologics in early RA. What happens when a young person receives biologic therapy and is kep on it for 20-30 years? We really don’t know yet. The risk-benefit ratio will depend on continued close monitoring and analysis of safety information as it becomes available.
What we do know is the dramatic improvement in quality of life and slowing of progression of disease that is experienced by patients treated with these agents.