Susceptibility to rheumatoid arthritis (RA) is complex; although a number of genetic susceptibility loci have been identified that appear to confer increased risk. Among these, genes encoding sequence variants in the major histocompatibility complex (MHC) class II molecule, known as the “shared epitope” (SE), have been known for decades and have the strongest link to RA susceptibility.
Atacicept is a recombinant fusion protein that binds and neutralizes two molecules important for the maturation, proliferation, and survival of B cells: BLyS and APRIL. While B-cell depleting therapies have demonstrated efficacy in RA, atacicept differs from the anti-CD20 targeted monoclonal antibodies, such as rituximab, as its effects extend over the entire lineage of B lymphocytes, including plasma cells.
RA is associated with an increase in cardiovascular (CV) events, such as myocardial infarction (MI) and sudden cardiac death. Inflammatory cytokines, such as TNF-α, are implicated in atherothrombosis and the RA disease state, potentially explaining the increased risk of CV events in RA. The use of TNF inhibitors was associated with a reduced risk of cardiovascular events in RA patients in one study, although it is not clear whether these effects are due to unique features of TNF inhibitors or are a consequence of non-specific suppression of inflammation.
The potential for hepatotoxicity is a well-recognized feature of therapy with a number of DMARDs in rheumatoid arthritis (RA), with methotrexate (MTX) being the most common utilized. Concomitant use of other hepatotoxic agents has the potential to compound the risk of significant liver damage. Among these, isoniazid (INH) is increasingly used in RA patients receiving MTX with evidence of latent tuberculosis infection (LTBI) or prior active tuberculosis for whom TNF inhibitor therapy is planned.
Patients with early inflammatory arthritis not meeting classification criteria for rheumatoid arthritis (RA) may have treatment delayed until typical phenotypic features accumulate. Due to the concern for toxicities of DMARDs, patients are often treated with NSAIDs and simple analgesics during this period. However, delay in DMARD treatment in early RA has been shown to result in poorer outcomes, such as irreversible radiographic damage.