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 Pregnant with Controversy
Rheumatoid arthritis (RA) has a tendency to exhibit significant clinical improvement, and occasional remission, during pregnancy1. This observation has fired the imaginations of investigators since it was first reported by Hench over 60 years ago2. A focus on the hormonal change in pregnancy led to the use of steroids as a new therapy, but so far has failed to definitively explain the clinical phenomenon. With the rise of modern immunology, and the focus on immune mechanisms in RA, new ideas suggested themselves. Among the more creative of these ideas was that the specific immune relationship between mother and fetus might alter immune response patterns in the mother and modify disease activity. Support for this hypothesis came in the 1993 report by J. Lee Nelson, in which she observed a correlation between pregnancy induced remission of RA and MHC disparity between mother and fetus3. For researchers working on the immunopathogenesis of RA, this result had a particularly optimistic message: it suggested that a fairly subtle (and normal) modulation of the immune response could result in disease remission. Coming in the midst of exciting progress in the molecular definition of MHC restricted T cell recognition, this hypothesis found fertile ground. Perhaps we just need to tweak the immune system with the correct MHC peptide and cure will be at hand! At first consideration, the report by Brennan, et al4 in this issue of The Journal appears to let quite a bit of air out of this balloon; to fans of Winnie the Pooh, the results may conjure up Piglet's poignant birthday present to Eeyore. In a large study of over 100 pregnancies in women with polyarthritis, no evidence of an association between fetal-maternal HLA disparity and improvement or remission of disease was observed. Despite some methodological issues, it is very unlikely that maternal-fetal MHC relationships at standard class II loci are playing a major role in pregnancy induced remission of disease in this population of patients. Criticisms can be raised in an attempt to explain or reduce the impact of the negative result. For example, Brennan, et al performed only one clinical evaluation of subjects during pregnancy (in the third trimester) and relied largely on self-report to determine whether a change in disease activity had occurred. This appears to contrast with the somewhat more stringent efforts of Nelson, et al to define the level of disease activity before, as well as during early pregnancy3. Indeed, in order to be classified in the "remission" or "improved" groups, active RA was required by Nelson during the 6 months prior to pregnancy. Further, in the Nelson study, a subset of patients was followed prospectively through pregnancy. Despite these differences in study design, it is notable that the degree of fetal-maternal HLA disparity is virtually the same in the two studies for the "improved" or "remission" groups; about three-quarters of these patients had maternal-fetal HLA disparity at DQA. Even higher levels of disparity (> 90%) were observed at the more polymorphic DRB1 locus, again with no difference in the two studies. However, the real issue is the state of maternal-fetal HLA compatibility in the smaller subgroup of patients who exhibit no improvement of disease. Nelson reported data on 12 such pregnancies, only 3 (25%) of which had HLA disparity between mother and fetus at DQA. (Interestingly, two of these cases involved RA with onset during the pregnancy.) Data on a strictly comparable clinical group are difficult to extract from the Brennan study. Presumably all of the "deteriorated" group, and a substantial portion of the "unchanged" group, had active disease and are relevant for this analysis. It is therefore striking that not even a hint of an increase in HLA sharing at DQA is observed in these groups. How can we reconcile these contrasting results? A false positive result in the Nelson study is certainly a possibility. However, as should be evident from the above discussion, the sample sizes for the relevant clinical subgroup (namely, the patients with active and unimproved disease in the third trimester) are not very large in either study, particularly if one restricts the analysis to Brennan's "deteriorated" subgroup who meet American College of Rheumatology criteria5 for RA. Nevertheless, it seems unlikely that sharing at DQA has a major role to play in the clinical outcome of inflammatory arthritis during pregnancy. This does not necessarily mean that Eeyore's birthday balloon is irreparably deflated. With birthday presents, it's the thought that counts -- in this case, the hypothesis that immune responsiveness to MHC encoded products from the fetus can modulate the immune response of the mother. One possibility is that the effects of fetal-maternal HLA disparity are only relevant in certain subgroups of patients, or in the setting of particular combinations of MHC haplotypes. Perhaps these combinations are more likely to occur in certain populations. Since DQA may not be the functionally relevant locus, the Nelson result could be due to patterns of linkage disequilibrium in her local population that have revealed the involvement of other genes in the MHC in this clinical phenomenon. Now that the full MHC sequence of over 3 million base pairs has been completed, we have been presented with a rich genetic harvest -- over 200 loci and at least 128 functional genes, of which roughly 40% appear to be primarily involved in immune function6. Certainly, there are plenty of interesting phenomena linking the MHC, reproduction, and immunity. Not all readers of The Journal may be aware of the early (and continuing) Y maze studies of Boyse, in which it was clearly established that mice can distinguish MHC haplotypes by olfaction7,8. This suggested a possible role in mate selection, and a mechanism for maintaining MHC diversity in populations. Carol Ober and colleagues have identified polymorphisms in human MHC linked olfactory receptor genes9, and also have provided evidence that in some human populations, mating selection and/or fetal survival may be influenced by the MHC10,11. We have recently speculated that maternal-fetal relationships at the MHC may influence the survival of dizygotic twin pairs in utero12. These effects in humans are subtle, generally require the study of large numbers of subjects, and may only be observed in selected populations. Clearly, further investigation of why clinical improvement of RA often accompanies pregnancy could lead to very important insights into disease mechanism. The collection of large numbers of well defined RA patients who do, or do not, exhibit this phenomenon is an extremely difficult, time consuming, and expensive proposition. Large patient collections for the purpose of genetic study are now widely recognized as a prerequisite for scientific progress. Perhaps the time is right to pursue a similar multicenter collection strategy for RA in pregnancy.
PETER K. GREGERSEN, MD,
Supported by the National Institutes of Health (RO1-AR44222 and NO1-AR-7-2232) and by the National Arthritis Foundation. Address reprint requests to Dr. Gregersen. REFERENCES
1. Barrett JH, Brennan P, Fiddler M, Silman AJ. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum 1999; 2. Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis, and intermittent hydrarthritis. Mayo Clin Proc 1935;13:161-7.
3. Nelson JL, Hughes KA, Smith AG, Nisperos BB, Branchaud AM, Hansen JA. Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. 4. Brennan P, Barrett J, Fiddler M, Thomson W, Payton T, Silman A. Maternal-fetal HLA incompatibility and the course of inflammatory arthritis during pregnancy. J Rheumatol 2000;27:2843-8. 5. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24. 6. The MHC Sequencing Consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 1999;401:921-3.
7. Yamazaki K, Yamaguchi M, Baranoski L, Bard J, Boyse EA, Thomas L. Recognition among mice. Evidence from the use of a 8. Yamazaki K, Beauchamp GK, Singer A, Bard J, Boyse EA. Odortypes: their origin and composition. Proc Natl Acad Sci USA 1999;96:1522-5. 9. Eklund AC, Belchak MM, Lapidos K, Raha-Chowdhury R, Ober C. Polymorphisms in the HLA-linked olfactory receptor genes in the hutterites. Hum Immunol 2000;61:711-7. 10. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S. HLA and mate choice in humans. Am J Hum Genet 1997;61:497-504. 11. Ober C, Hyslop T, Elias S, Weitkamp LR, Hauck WW. Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study. Hum Reprod 1998;13:33-8. 12. Jawaheer D, MacGregor AJ, Gregersen PK, Silman AJ, Ollier WE. Unexpected HLA haplotype sharing in dizygotic twin pairs discordant for rheumatoid arthritis. J Med Genet 1996;33:1015-8. |