Lumpers vs. Spliters: Does it Make a Difference in Treating Rheumatoid Arthritis?
ABSTRACT & COMMENTARY
Synopsis: A group of patients with rheumatoid arthritis (RA), none of whom had any of the genes for peptide antigen presenting proteins (HLA-DR) which confer an increased risk of developing RA, were almost equally likely to achieve 50% or better improvement with methotrexate alone as with a three-drug combination of sulfasalazine, hydroxychloroquine, and methotrexate.
Source: O'Dell JR, et al. Ann Rheum Dis 1998;57:209-213.
Tailored therapy has a lot of appeal. in the management of patients with rheumatic diseases, for whom drug treatment is not predictably effective and may have serious adverse effects, it would be a major advance to be able to predict which of the many available drugs, or which drug combination, is most likely to be effective. O'Dell and colleagues presented the results of a subgroup analysis of the results of their earlier study of combination vs. monotherapy for rheumatoid arthritis (RA).1 That clinical trial compared the efficacy and safety of the three-drug combination of sulfasalazine (SSA), hydroxychloroquine (HCQ), and methotrexate (MTX) vs. a two-drug combination of SSA and HCQ vs. MTX alone. They performed genotyping to identify patients who carried HLA-DR genes for alleles that have been associated with an increased risk of development of RA and that also have a dosage effect on the severity of RA.2,3 They subgrouped their study cohort into patients with one or more of the "susceptible" alleles (epitope-positive) and those without (epitope-negative). The epitope-positive patients' responses to the three treatments were then compared with the responses of the epitope-negative patients to the same treatments. The main results of this subgroup analysis are shown in the Figure.
A "completer" was a patient who achieved and maintained a 50% improvement and completed the study. The Figure shows that for patients who were epitope negative, the mean percentage of completers was roughly the same for those treated with MTX alone vs. those treated with the three-drug combination (83% vs 88%; P = 0.69). For those who were epitope positive, however, there was a large and statistically significant difference between the response to the three-drug combination (94%) vs. MTX alone (32%; P < 0.001).
COMMENT BY JERRY M. GREENE, MD
The HLA-DR alleles that have been associated with an increased risk of RA share an identical motif in so-called third hypervariable region of the beta chain of the molecule. This area is in a groove in the floor of the portion of the molecule that binds the peptide antigens, which are then presented to T-cells by various antigen-presenting cells. Why these "susceptible" alleles are associated with an increased risk of RA is unknown, but they do, and homozygosity or carriage of two susceptible alleles is associated with an increase in severity of RA.
O'Dell et al's work suggests that, in the absence of susceptible alleles, patients respond equally well to MTX or a three-drug combination (SSA, HCQ, and MTX), while those with one or more of the susceptible alleles respond much better, on average, to the combination than to MTX alone. This study suggests that HLA-DR typing for RA-susceptible alleles may move from the research laboratory to the bedside. Though no guarantee of success, the prognostic information afforded by genotyping, and the promise of guiding drug selection, might offset the cost of testing. If outcomes are improved and disability decreased, the economic toll of RA could be reduced. Reserving combination therapy for those most likely to benefit from it could reduce the cost of care.
References
1. O'Dell JR, et al. N Engl J Med 1996;334:1287-1291.
2. Weyand CM, et al. Ann Intern Med 1992;117:801-806.
3. Nepom GT, Nepom BS. Rheum Dis Clin North Am 1992;18:785-792.
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