Pharmacogenetics of Rheumatoid Arthritis and Spondyloarthropathies

Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic and systemic diseases with an important inflammatory component and differing manifestations, all causing a significant decline in the quality of life of patients. RA produces bone and cartilage destruction, as well as a wide variety of extra-articular manifestations; AS mainly affects joints in the spine and sacroilium in the pelvis, and can cause eventual fusion of the spine; and PsA is an inflammatory arthritis associated with psoriasis.

These diseases are characterized by an unknown aetiology as well as a strong genetic contribution, supported by evidence from family and twin studies, linkage studies and population-based association studies. Proinflammatory cytokines, such as tumour necrosis factor-α (TNF-α) and several interleukins (IL-1, IL-6, IL-12) mediate the pathogeneses of these diseases. The human leukocyte antigen (HLA) region has been consistently associated with autoimmune pathologies, with HLA-DR mainly associated with RA and HLA-B27 with both AS and PsA.

These chronic inflammatory diseases are highly heterogeneous in all their aspects, including drug efficacy and toxicity in individual patients. A substantial proportion of patients do not respond efficiently to classical therapies and/or experience toxicity limiting further treatment, both of which lead to progression of inflammation. This high inter-individual variability in drug response and toxicity gives rise to the need to individualize and optimize therapy with anti-rheumatic agents, such as DMARDs [i.e., Methotrexate (MTX) and biological agents (i.e., anti-TNF agents)]. Studies in the field of pharmacogenetics are necessary to identify potential markers associated with clinical response. To date, many polymorphisms in genes associated not only with the diseases, but also with drug-metabolizing enzymes, drug targets and transporters, have been analysed, showing in some cases conflicting results. The aim of this review is to describe the state of the art of pharmacogenetics in three important chronic inflammatory diseases, RA, AS and PsA.

Keywords: Genetics, pharmacogenetics, inflammatory disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis.