Genetic studies, clinical heterogeneity, and disease outcome studies in rheumatoid arthritis☆
Section snippets
HUMAN LEUKOCYTE ANTIGEN-RELATED RISK FOR RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) has a substantial genetic component influenced by sex and, in most populations, by the human leukocyte antigen (HLA) region on human chromosome 6p. To understand how HLA influences clinical heterogeneity and disease outcome, one may start with how HLA is associated with RA susceptibility. RA risk was originally associated with the cellular HLA type Dw4 and thereafter with the serologic marker HLA-DR4 in white populations in the United States.89, 90 Later studies
HETEROGENEITY IN RHEUMATOID ARTHRITIS
Not all RA is the same. This observation underlies current efforts to discern genetic, random, and environmental contributions to cause and pathogenesis. Clinicians have long noted that individuals with clinical illnesses classified as RA may vary regarding clinical features. These measures of RA may include those related to joint deformity, inflammation (tender joint count), natural history (definitions of joint disease course and mortality), therapy (e.g., number of slowly acting
CASE-CONTROL STUDIES REGARDING CLINICAL HETEROGENEITY AND DISEASE OUTCOME
Table 1 outlines selected case-control investigations regarding clinical measures in RA generally grouped according to ethnic origin of the study population. By examining the retrospective correlations between disease outcome and genetic markers, case-control studies answer the question, “What has happened?” For some studies, the RA subjects are divided according to genetic marker, and the frequencies of specific events are examined; for others, the RA subjects are divided according to specific
COHORT STUDIES REGARDING CLINICAL HETEROGENEITY AND DISEASE OUTCOME
Cohort studies help to resolve the concern, “What will happen?” They involve selecting individuals with RA, determining what genetic markers are present, and following the cohort over a certain period of time to observe the consequences of the genetic markers on events of interest. Because such investigations are less subject to intervening biases than are case-control studies, they are particularly important. Table 4 reflects selected cohort studies about HLA influences in RA, which are
SUMMARY
HLA haplotypes influence various clinical RA features considered to reflect severity in case-control and cohort studies. Of particular note is the fact that HLA generally influences the development of erosive and sometimes seropositive and nodular disease; in prospective studies, it noticeably affects joint surgical intervention. These are valuable clues indicating that HLA influences RA severity and chronicity. Nevertheless, HLA influences are generally weak enough so as to require large study
ACKNOWLEDGMENTS
The authors are grateful for the technical assistance of Jean Mallory and Nellie Curry and for the help of members of the Rheumatology Section, McGuire VAMC, and the Division of Rheumatology, Allergy, and Immunology, Virginia Commonwealth University, in identifying study subjects. Drs. Duncan S. Owen, Jr, and the late W. Robert Irby, Jr, were particularly helpful. The authors also thank Linda Benson for diligently obtaining and managing the literature and data reviewed in Table 1, Table 4.
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This work was supported by NIAMS K24 AR 02131 and the Grace Branch Moore/Arthritis Foundation Professorship, Medical College of Virginia Foundation.