Explain the pathophysiology of Rheumatoid Arthritis (RA), including systemic and

Question

Explain the pathophysiology of Rheumatoid Arthritis (RA), including systemic and local symptoms associated with the disease, long-term complications, and current treatments.

Explanation / Answer

The recognition of antibodies directed against citrullinated peptides in RA has been a major development to improve disease identification and provide prognostic information. Citrulline is a post-translational modification that occurs on arginine residues contained within proteins and peptides. There are a number of enzymes that can cause citrullination to occur, present in various cell types and tissues known as peptidylarginine deiminases (PADs). Citrullination is a normal process, required for normal skin formation and other physiologic functions. However, in rheumatoid arthritis an autoimmune response develops against citrullinated peptides detected as anti-citrullinated peptide antibodies (ACPA). One of tests to detect these antibodies detects anti-cyclic citrullinated peptides (anti-CCP), currently the most commonly used diagnostic test for them. The presence of anti-CCP are >98% specific for the diagnosis of rheumatoid arthritis; however, not all patients with RA will develop anti-CCP antibodies. Of significant importance is the recognition that these anti-CCP antibodies may be detected up to 15 years before the onset of clinical symptoms of RA indicating a preclinical phase of disease in which immunologic activation is already ongoing. Moreover, it has recently been demonstrated that specific citrullinated peptide sequences bind to shared epitope alleles with high affinity and can lead to T cell activation. The mechanisms to citrullination that lead to RA remain unclear. A polymorphism in the PAD4 gene which may lead to increased citrullination has been described populations. In RA patients, autoantibody responses also develop against the PAD4 protein, associated with a more aggressive disease course. One species of oral bacteria Porphyromonas gingivalis has a PAD enzyme. Given the relationships described with periodontal disease and RA, it has been hypothesized that this bacteria may also serve to initiate citrullination in the preclinical phases of RA.

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