Treating Rheumatoid Arthritis

Our understanding of antibodies has come a long way since the early days of immunology. As early as the 10th century, Chinese doctors experimented with smallpox vaccines by exposing patients to dried, powdered smallpox pustules. These treatments are some of the earliest recorded instances of doctors influencing the immune system to treat disease. It wasn’t until Linus Pauling confirmed Paul Ehrlich’s theory of the antibody in 1940, however, that the idea of directly engineering immune molecules seemed like a possibility. It took another decade for scientists to understand antibodies as the primary mediators of immune resistance. Finally, in 1976, Susumu Tonegawa identified the genetic mechanism by which the vast diversity of antibody sequences is created. Armed with this groundbreaking understanding, researchers were able to develop the world’s first antibody drug, Muromonab-CD3. This drug, marketed as Orthoclone OKT3, was given to organ transplant recipients to reduce transplant rejection. Today, more than 30 years later, new approaches have triggered a medical revolution. Diseases that once would have led to long-term pain and suffering, or even death, are controlled by treatments developed through methods inconceivable in decades past. Rheumatoid Arthritis is one such disease.

Ulnar drift (ulnar deviation) is a long term symptom of RA

What is Rheumatoid Arthritis?

Rheumatoid Arthritis (RA) is an autoimmune disease caused by a hyperactive immune response to native connective tissues in the joints, heart, and lungs. RA is known to be a genetic disease, but the specific markers and trigger are unknown. The disease does not typically present until individuals are between the ages of thirty and sixty. When it does present, the development is slow and the symptoms are mild. Patients first notice stiffness in their joints, followed by tenderness when moving, inflammation and pain. Alternatively, patients may experience an onset of pain in a few joints lasting several days or weeks before disappearing entirely. The pain later returns to these or other joints for another span. Joints continue to slowly grow stiffer, often resulting in permanent stiffness and, eventually, joint instability. RA can also cause ulnar drift — a deformity in which swelling of the knuckle joints at the base of the fingers causes them to become gnarled and displaced. Long-term stress on the heart, lungs, and joints from RA inflammation also leave sufferers at at higher risk of other diseases, including vasculitis, heart attack, stroke, endocarditis, valvulitis, fibrosis, left ventricle failure, among several others. These symptoms are part of why it is so important to begin treatment for RA quickly after its onset. At one time, treatment largely consisted of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids which both addressed inflammation. Disease-modifying anti-rheumatic drugs (DMARDs) were used to suppress the immune response component of RA which have the unfortunate side effect of suppressing the entire immune system. Advances in immunotherapies have led to the emergence of a new approach.

Medicinal Development

Crystal structure of TNFɑ

Adalimumab is a designer antibody which was engineered to target specific parts of the immune system that trigger inflammation. Tumor Necrosis Factor (TNF or TNFɑ) is a cell signaling protein responsible for inflammatory responses and regulating immune cells. A few of its main duties include inducing fever and preventing infection. TNF Inhibitors are a type of drug designed to prevent TNF from binding to its receptors and initiating the inflammatory response that affects people suffering from RA. Adalimumab — the first fully human mAb to be approved by the FDA — functions as such an inhibitor.

Conclusion

Prior to the development of Adalimumab, the treatment of RA was limited to non-specific drugs which failed to address the root cause of the disease. Use of NSAIDs and corticosteroids can diminish inflammation and pain temporarily, but symptoms inevitably return. These drugs are not sufficient to preserve the condition of sufferer’s joints. DMARDs were a more effective solution, however suppressing the immune system altogether substantially increases the risk of serious infections. Today, Adalimumab has dramatically improved the quality of life for those living with RA.

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