For decades, rheumatoid arthritis (RA) was blamed solely on an overactive immune system that damaged the joints. Based on recent research, specialists in the Center for Arthritis and Joint Diseases – part of the Orthopedic and Arthritis Center at Brigham and Women’s Hospital – have identified a 1-2-3 framework comprised of three large mechanistic issues in the development of RA:

• Inflammation and autoimmunity;

• Synovial tissue response to inflammation;

• Resulting bone and cartilage damage.

The framework not only helps in the organization of the extremely broad array of past discoveries about the complex RA pathogenesis, it also suggests new avenues to understand the underlying biology of the disease and pursue future therapeutics. In addition, the three categories within the framework can be targeted independently and may help physicians identify the disease and provide intervention in earlier stages.

Inflammation and Autoimmunity

Research into inflammation and autoimmunity, historically the most actively studied areas of RA, continues to generate fresh insights and new biological response modifying drugs.

The new generation of biologics works primarily by neutralizing the inflammatory chemicals generated by inflammatory cells, as well as T-cell activating messages. While the potential side effects of these drugs (cancer and greater infection rates) seem to be far less than originally predicted, these new therapies significantly benefit only about half of the patients who are treated with them.

As such, researchers at the Center continue to probe deeper into the disease process. Laurie H. Glimcher, MD, senior rheumatologist at Brigham and Women’s Hospital, has conducted studies from her immunology lab that suggest a new drug target – blocking the activity of an immune system regulatory protein, T-bet, to interrupt the ability of RA to cause joint inflammation. In addition, recent gene association studies have revealed new candidates in the autoimmune arena, which may lead to other novel drug targets.

Joint Tissue and RA

While research into the synovial tissue lining the joint is at an earlier stage, scientists are optimistic about insights gleaned from recent studies. An inflamed synoviumis central to the path physiology of RA, but researchers now see this encounter as two interacting mechanisms.

Associate Physician David Lee, MD, PhD, and colleagues in the lab of Michael B. Brenner, MD, Chief of the Division of Rheumatology, Immunology, and Allergy, discovered a molecule, cadherin-11, in the synovium that responds to the immune attack and sets in motion another set of contributing factors in the development of RA.

In adults with RA, cadherin-11 appears to deform the parchment-thin tissue to its painfully bloated pannus that attacks and erodes cartilage. Studies in Dr. Brenner’s lab also show that cadherin-11 seems to direct invasion of synovial tissue and serve as the dominant mode of cartilage damage in RA.

Bone Erosion

Studies of RA mechanisms that regulate the destruction of the bone in RA have shown that blocking the osteoclast activity can interrupt the ability of full-blown RA to disrupt the bone. Dr. Glimcher and her colleagues have also discovered a protein, Schnurri-3, that may help gain bone during aging and may be a potential target for maintaining or building bones eroded by RA and osteoporosis, as well as other contributors in the osteoclast bone-remodeling pathway in RA.

Pioneering Medical Therapies for RA

Led by Michael E. Weinblatt, MD, the Therapeutics Unit for Rheumatoid Arthritis within the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital includes an active clinical development program with ongoing clinical trials. Specialists in the Unit have developed groundbreaking treatments and are providing profound insight into the most effective delivery of these therapies.

A key contributor to the development of the RA gold standard medication Methotrexate, Brigham and Women’s Hospital was also one of the lead sites in the development and study of two new medications recently approved by the FDA for patients with RA:

• Rituximab (a B-cell directed therapy);

• Abatacept (a T-cell blocking agent).

Ongoing studies of rituximab at Brigham and Women’s Hospital are evaluating specific methods of redosing to determine whether redosing on regularly timed intervals at a lower dose produces better outcomes for patients and more effectively prevents flare ups.

A separate, recently concluded study at Brigham andWomen’s Hospital showed that combining abatacept with a TNF-blocking agent (etanercept, infliximab oradalimumab) posed four times the risk of infection forpatients. Consequently, a warning label has been placed on abatacept to notify physicians and patients of the risks.

The Brigham and Women’s Rheumatoid Arthritis Sequential Study (BRASS), which includes more than1,000 enrolled patients, is one of the largest registries for rheumatoid arthritis in the world. A landmark longitudinal study co-directed by Dr. Weinblattand Nancy A. Shadick, MD, MPH, and sponsored by Millennium Pharmaceuticals and Biogen/Idec, BRASS has made significant contributions to understanding the genetic basis of rheumatoid arthritis, to identifying potential targets for new drug development, and to defining the most effective clinical management strategies for each patient.

Indications for Referral

Patients presenting with the following may be referred for evaluation and treatment:

• Confirmed rheumatoid arthritis diagnosis;

• Symptoms of rheumatoid arthritis.

Information and Referrals