The RA Revolution is Incomplete, Cure Remains Elusive

Progress in RA research has stalled. "It is clear that the revolution is incomplete,” Lasker Award winners say.

There have been tremendous advancements in the treatment of rheumatoid arthritis. From basic science discoveries to the introduction of anti-tumor necrosis factors (anti-TNFs) and other biologic drugs, RA patients now have more options that can reverse the course of the disease. Despite developments in rheumatoid arthritis (RA) research, progress has stalled in the last 10 years, write professors Sir Marc Feldmann and Sir Ravinder Maini in a new series in the journal of Arthritis & Rheumatology called “Perspectives From Masters in Rheumatology and Autoimmunity.”

Feldmann and Maini are winners of the Lasker Award and many other awards for groundbreaking research on the role of tumor necrosis factor in the pathogenesis of rheumatoid arthritis and in the development of tumor necrosis factor antagonists. Their discoveries have transformed the lives of people who live with rheumatoid arthritis. The following content is based on excerpts from their “Perspectives” article in Arthritis & Rheumatology. “When we were medical students, autoimmunity was a vague concept, inflammatory mediators were a few small chemicals, cellular signaling was a mystery, and therapeutics was dominated by the organic medicinal chemists,” Feldmann and Maini wrote. “Rheumatoid arthritis was an incurable, painful, life-damaging, and life-shortening disease for which prior attempts at a cure, as with the lauded discovery of corticosteroids, ended lamentably.”

"It is clear that the revolution is incomplete. It has not resulted in 'cures.' As a medical community, we need to pick up the challenge again and get the job completed. We have new powerful tools and much more knowledge. Do we have the ambition and the will?"

Discoveries in basic science played a crucial role in the design of treatments that are used for RA today. Breakthroughs in cellular immunology, autoimmunity, molecular biology and the discovery of therapeutic monoclonal antibodies were pivotal, they wrote. The 1990s brought the introduction of a slew of new drugs for RA used today: biologics, antibodies or “antibody-like Ig-receptor fusion proteins.” For patients with a severe form of rheumatoid arthritis, disease-modifying antirheumatic drugs (DMARDs), anti-TNF and other biologic drugs, translates into a much better quality of life, even though few achieve remission. “Despite all the available chemical and biologic DMARDs, the expectation is that approximately 60% will meet the American College of Rheumatology criteria for 20% improvement (ACR20), 40% will meet the ACR criteria for 50% improvement, and 20% will meet the ACR criteria for 70% improvement - or, if expressed according to the useful Disease Activity Score, there will be a reduction of disease activity from high to a sustained level of low or, less commonly, remission, in approximately 50% of treated patients,” the authors wrote. There are many factors that affect disease outcomes. For rheumatoid arthritis patients with long disease duration, these include impaired physical function, structural damage or high disease activity, but also for older adults, smokers and the obese, significant improvements in their condition is unlikely. Biologics are quite possibly poised to halt the progression of rheumatoid arthritis, however, access to biologics remains an issue despite $25 billion in sales for all biologics sold in the United States in 2013. (50% percent of the $25 billion was for RA with the rest for psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and ulcerative colitis). The accessibility of these medications, plus insurers willingness to pay, is impeding research. Biologics are expected to be far more affordable than most current options, but are still very expensive and unaffordable for some patients, the authors wrote. “The notable commercial success of anti-TNF has put a stop to efforts to seek new indications for this class of drugs because of concerns regarding safety or lack of efficacy, e.g., in heart failure and obstructive airways disease, which might adversely impact existing markets,” they wrote.

Combination therapy in RA could offer a promising way forward in research.

Combination therapy worked for the treatment of the human immunodeficiency virus (which is no longer a death sentence, they note) and for the treatment of some leukemias and lymphomas, so the authors suggest the need for further exploration of combination therapy for rheumatoid arthritis, but the scientific, commercial and legal hurdles are considerable despite evidence showing that combination treatment can be effective and safe.

“The combination of low-dose MTX and anti-TNF, which we pioneered, is more effective than monotherapy with MTX or TNF inhibitors in controlling symptoms, signs, physical function, and joint integrity and, with adequate risk management, has an acceptable level of safety in routine use. Each of the five approved anti-TNFs are mostly used together with MTX,” they wrote. There are still no cures and there are few sustained remissions. It’s time for a new approach, Feldmann and Maini wrote. "It is clear that the revolution is incomplete. It has not resulted in 'cures.' As a medical community, we need to pick up the challenge again and get the job completed. We have new powerful tools and much more knowledge. Do we have the ambition and the will?"

References:

Marc Feldmann and Ravinder N. Main. Can We Get Closer to a Cure for Rheumatoid Arthritis? Perspectives from Masters in Rheumatology and Autoimmunity. Arthritis & Rheumatology. September 2015. DOI 10.1002/art.39269