Drug Management of Rheumatoid Arthritis

In my last post, I discussed the aetiology and clinical presentation of rheumatoid arthritis, without delving into too many details with regards to treatment. Well, now's the time!

Pathogenesis

The inflammatory process kicks off when a self-reactive T-cell meets its antigen on an antigen-presenting cell, thus activating the T-cell. Activated T-cells can then activate B-cells to produce antibody, and/or activate macrophages to produce prostaglandins and cytokines such as TNFα. Prostaglandins are mainly responsible for pain and swelling, whereas TNFα is responsible for joint tissue damage. Various drugs can target different stages of the inflammatory process.

Methotrexate

Methotrexate (which got a cameo appearance here) is a disease-modifying anti-rheumatoid drug (DMARD) that targets T-cell proliferation. It does this by blocking dihydrofolate reductase (DHFR), which catalyses the conversion of folate into dihydrofolate, and dihydrofolate into tetrahydrofolate. As folate is important in nucleic acid synthesis (as described here), blocking folate regeneration can block T-cell proliferation.

TNFα antagonists

The two main types of TNFα antagonists are anti-TNFα antibodies and soluble TNFα receptors. Both types of antagonists bind to TNFα, preventing it from binding to its receptor.

Since humans can't produce antibodies against their own TNFα, antibodies are produced in other animals, such as mice. The problem is, mice antibodies are viewed as foreign by humans (which is why serum sickness is a thing). Hence, genetic engineering techniques have been made in order to make them more human. Infliximab is an anti-TNFα antibody that has a mixture of human and mouse sequences, whereas adalimumab has a completely humanised sequence. The "lim" in "adalimumab" indicates that the antibody targets a part of the immune system (in this case TNFα).

Glucocorticoids

See previous post: Drugs for asthma. Prednisolone is the most common glucocorticoid used in RA treatment. Since systemic glucocorticoids can have adverse metabolic and CVS effects, inflammatory arthritis is generally treated with local intra-articular injections.

NSAIDs and coxibs

See previous post: Analgesics

Treatment

Usually the first drug of choice is either methotrexate or leflunomide. Low-dose systemic glucocorticoids may also be used. The next drug to be added is usually hydroxychloroquine or sulfasalazine (they haven't been discussed in this blog post since it's still not 100% clear how they work). Next up is a biological agent such as TNFα. Throughout the course of the disease, NSAIDs might be used for analgesia and some anti-inflammatory action, though they do not slow the progression of the disease.

There are also several non-drug treatments for RA. These include joint protection with splints, management of cardiovascular risk and other kinds of support (e.g. assistance with tasks and psychological support).