SANTA MONICA, CALIF. — Progression of early rheumatoid arthritis is likely in any woman who smokes, has active disease at the time of presentation, and is positive for both rheumatoid factor and anti–cyclic citrullinated peptide antibodies.
Sex and clinical disease activity are the most frequent risk factors for progression of rheumatoid arthritis (RA), and rheumatoid factor and anti–cyclic citrullinated peptide (anti-CCP) antibodies are the most frequent tests that physicians use to assess the likelihood of such progression. Other genetic tests that offer information about progression risk, such as that for HLA-DRB1, are not widely used. And yet other tests for genetic determinants of treatment response and the likelihood of developing adverse events in response to treatment are encouraging, but remain largely in the realm of research, according to Dr. Daniel E. Furst, who is the Carl M. Pearson Professor of Rheumatology at the University of California, Los Angeles.
No single marker can absolutely predict disease progression, at least in part because RA is probably more than one disease, dependent on the presence or absence of anti-CCP antibodies. Anti-CCP antibodies are the result of a genetic predisposition and a systemic stress, such as smoking. However, Dr. Furst pointed out that even among all anti-CCP antibody–positive people, the course of RA may vary because of the effects of environmental stimuli, immune events, and interventions (Annu. Rev. Immunol. 2008;26:651-75).
Citrullination is present in a wide range of inflammatory tissues, suggesting that this process is a nonspecific response to inflammation, rather than a disease-specific response, Dr. Furst noted at a meeting sponsored by Rheumatology News and Skin Disease Education Foundation. Anti-CCP antibodies are more likely to be elevated in patients who both have the susceptibility epitope and smoke.
Subset analyses of data from the PROMPT (Probable Rheumatoid Arthritis: Methotrexate vs. Placebo Treatment) study, presented by Dr. Henrike Van Dongen of Leiden (the Netherlands) University Medical Center at the 2006 congress of the European League Against Rheumatism (EULAR), demonstrated that the presence of anti-CCP determined response to methotrexate. Responses at 15 months after diagnosis in a group of 27 anti-CCP antibody–positive patients were below 10% in those on placebo, but were close to 50% in those on methotrexate. There was no treatment effect in a group of 83 anti-CCP–negative patients (Arthritis Rheum. 2007; 56:1424).
The HLA-DRB1 gene is associated with extra-articular manifestations of RA and the development of Felty's syndrome. That syndrome occurs in fewer than 1% of RA patients and is considered to be a complication of long-standing disease. It involves a triad of conditions: RA, splenomegaly, and an abnormally low white blood count. Findings from an unpublished study show that Felty's syndrome was associated with HLA-DRB1.0401.
Other extra-articular manifestations of RA (such as pericarditis, vasculitis, interstitial lung disease, and neurologic involvement) were seen not with individual alleles, but with DRB1.04SE double-dose genotypes.
Findings from numerous other studies show that multiple single nucleotide polymorphisms (SNPs) of the PTPN22 gene have a significant association with RA, as does TRAF1-C5 (on chromosome 9).
Smoking and anti-CCP antibody status seem to be associated in RA, but PTPN22 is an independent risk factor for developing RA, according to Dr. Furst. Although not yet directly applicable to clinical care, attempts are being made to predict response to RA medications using genetic signatures or gene SNPs.
For now, other factors are more practical predictors of good response.
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For a video interview with Dr. Furst, go to www.youtube.com/rheumatologynews.
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