Annals of the Rheumatic Diseases

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Ann Rheum Dis 1998;57:265–267 265 Ann Rheum Dis: first published as 10.1136/ard.57.5.265 on 1 May 1998. Downloaded from Annals of the Rheumatic Diseases

Leaders See article on page 275

Will the increasing prevalence of atopy have a favourable impact on rheumatoid arthritis?

Changes in the prevalence or incidence of certain diseases cytes to produce TNFá and IL1, which are known to be over time are likely to provide clues to pathogenesis. While important in synovitis, and Th1 cells can themselves make we rheumatologists worry from time to time about the TNFâ. It has also become clear that these kinds of immune possible disappearance of rheumatoid arthritis (RA), one response are mutually antagonistic, as interferon ã down of our major reasons for getting up in the morning,12our regulates IL4 production, while IL4 down regulates inter- colleagues in the chest and allergy clinics have no such feron ã production, as does IL10, which is a Th2 cytokine anxieties, presiding as they do over a substantial increase in in the mouse. Analysis of rheumatic diseases by applying the prevalence of asthma and other atopic disorders.3 Par- the Th1/Th2 paradigm is not always straightforward, but ticularly striking have been the changes, over comparatively with respect to synovitis, particularly in RA but also in short periods of time, in the prevalence of atopic disorders reactive arthritis and Lyme disease, there is general agree- in countries of the former Eastern bloc, particularly East ment that T cells in the joint have a predominantly Th1 Germany, where relative genetic homogeneity of the popu- phenotype.10–16 Thus, the idea has emerged that in some lations in the former East Germany and West Germany sense atopy and RA might be at opposite ends of an immu- makes comparisons particularly telling. Thus despite heavy nological spectrum as far as T cell responses are http://ard.bmj.com/ levels of atmospheric pollution in the east, which would concerned. Following on from this, it might be predicted have been thought likely to exacerbate respiratory diseases, that atopy could protect against the development of RA, or the prevalence of asthma was found to be considerably conversely, that RA would decrease atopic diseases. higher in the less polluted west.4 A more recent study shows These predictions have now been tested. In a paper in that only four years after the fall of communism, the preva- this issue, Verhoef and colleagues demonstrated that the lence of hay fever and atopy were measurably increased in prevalence of hay fever in RA patients was around half of 5

Leipzig schoolchildren. The slogan that has emerged from that in appropriate controls (8% v 15%), and the diagnosis on September 27, 2021 by guest. Protected copyright. such observations is that, with respect to atopic disorders, was confirmed in each case by skin prick testing with “civilisation is bad for you”, civilisation being a synonym inhaled allergens, or demonstration of allergen specific IgE. for western lifestyle.6 What are the likely reasons for this, Furthermore, there was evidence that in the small number and why would they be of interest to rheumatologists? of RA patients who did suVer from hay fever, the arthritis To explain the rheumatology interest requires a little was less severe than in the non-hay fever RA patients. As immunological background. One of the main advances in expected, in the light of what is known about Th1 and Th2 immunology in the past decade has been the realisation cells, these RA patients with hay fever had higher levels of that recognition of antigen by T lymphocyte can lead to serum IgE and peripheral blood eosinophils than other RA quite diVerent outcomes, depending on the set of cytokines patients, and T cells that produced lower levels of made by the responding T cell.7 Two such sets have been interferon ã after a maximal in vitro stimulus. The levels of defined, and the cells making them termed Th1 and Th2 IL4 produced were not significantly diVerent, but the ratio cells (Th referring to CD4+ T helper cells, although a of IL4 to interferon ã, which indicates the Th1:Th2 similar sub-division of CD8+ cytotoxic T cells has been balance, was significantly changed. During the hay fever demonstrated). The division is clearest for murine T cells, season, these changes were more marked, and although no but is also generally applicable to human T cells.8 While statistically significant alleviation of disease occurred at this postulating only two categories of T helper cell is rather time, there was a trend towards less active disease even in simplistic,9 the Th1/Th2 division has nevertheless been a this rather small group of patients. Similar observations useful concept. Th2 T cells are required for atopic have been reported in another study, where the lifetime responses, with an absolute requirement for IL4, the signa- prevalence of asthma, hay fever, and eczema (taken ture Th2 cytokine, in generating IgE responses. Th2 cells together) was 7.5% in RA and 18.8% in controls; the dif- also make IL5, which is important for eosinophil ference in point prevalence was even more striking (3.5% v activation. In contrast, Th1 T cells, via their production of 16.2%).17 This study relied on questionnaires without any interferon ã, are critical for protection against intracellular confirmation of diagnosis by challenge. Before these recent pathogens such as mycobacteria. They also activate mono- studies there was a report that the prevalence of RA in an 266 Leaders allergy clinic (two of 266) was the same as in the normal irrespective of whether the antigen is exogenous or an population, and that RA patients and controls had a simi- autoantigen. Although a Th2 pattern of cytokine produc- Ann Rheum Dis: first published as 10.1136/ard.57.5.265 on 1 May 1998. Downloaded from lar prevalence of positive skin prick tests (five of 40 v nine tion can be associated with autoimmune disease in experi- of 40) or atopic disease (14 in each group).18 However, mental models,27 it is more often the case that the Th2 these numbers are too small to resolve the issue, and the response is protective.28–30 In fact, even an ongoing Th2 diVerence in prevalence of positive skin prick tests is response to an irrelevant antigen can protect against the suggestive of a real diVerence that would emerge in a larger development of autoimmune disease after challenge with cohort of RA patients. There is another negative study in autoantigen.31 Secondly, RA might still be induced but be the literature when 100 RA patients showed no diVerence less severe—as suggested by the observations on the in the prevalence of positive skin prick tests compared with minority of RA patients with hay fever. Again, in patients with degenerative disease,19 so further confirma- experimental models, joint inflammation and cartilage tion of the findings of Verhoef et al may be required. destruction can be lessened by treatment with the Th2 What explanations can be oVered for these findings? It is cytokine IL4 or IL10,32 or with IL13,33 a close cousin of possible that having RA produces a cytokine milieu that is IL4. not conducive to developing atopic disease. The data In conclusion, the “Th2 immune deviation” that is typi- showing a reduced lifetime prevalence of atopy do not sup- cal of an increasingly westernised European population port this idea, as atopic disease will commonly present in may have very significant eVects on the incidence or sever- childhood, long before RA develops. Conversely, does the ity of RA. An important research priority is to ensure that atopic state make it less likely that RA will develop? If so, this possibility is thoroughly investigated, particularly in what are the factors that determine whether atopy places where lifestyle changes are occurring rapidly, so as to develops, and why is it getting more frequent? Both genetic gain as much insight as possible into the influence of and environmental factors control atopy; some of the cytokine balance in rheumatoid disease. If it is too late to genetic influences are now being recognised (such as a do a study in Leipzig because westernisation there is mutation in the IL4 receptor20), and others will no doubt already at an advanced stage, perhaps we should begin col- emerge from whole genome surveys.21 As the genome sur- laborations with our colleagues in the Baltic states. Time veys proceed in RA, it may turn out that quite diVerent for a “Norfolk”34 Arthritis Register in Vilnius, Riga, and genes are linked to susceptibility to the two diseases, and Tallinn? that the population at risk of developing RA is separate from the potentially atopic population. More interestingly, J S H GASTON University of Cambridge it might be that diVerent alleles of the same gene are associated with each disease, which would mean that the 1 Dugowson C, Koepsell T, Voigt L, Bley L, Nelson J, Daling J. Rheumatoid diseases had some degree of mutual exclusion at a genetic arthritis in women. Incidence rates in group health cooperative, Seattle, level. However, the rapid changes in the prevalence of Washington, 1987–1989. Arthritis Rheum 1991;34:1502–7. atopy observed at the same time as changes in 2 Spector T, Hart D, Powell R. Prevalence of rheumatoid arthritis and rheumatoid factor in women: evidence for a secular decline. Ann Rheum Dis environment/lifestyle strongly argue that genetic influences 1993;52:254–7. do not predominate in determining atopy, and that 3 Hopkin J. The rise of asthma and atopy. Q J Med 1998;91:169–70. 4 vonMutius E, Martinez F, Fritzch C, Nicolai T, Roll G, Thiemann H. environmental influences are critical; of these the most Prevalence of asthma and atopy in two areas of West and East Germany/. important identified thus far are infectious agents. Am J Respir Crit Care Med 1994;149:358–64. 5 vonMutius E, Weiland S, Fritzsch C, Duhme H, Keil U. Increasing http://ard.bmj.com/ Atopy is less common after measles or hepatitis A prevalence of hay fever and atopy among children in Leipzig, East infection3 and, in a recent study in Japan, was negatively Germany. Lancet 1998;351:862–6. 6 Holgate S. Asthma and allergy - disorders of civilization? Q J Med 1998;91: correlated with responsiveness to mycobacterial antigens 171–84. after immunisation or natural subclinical infection.22 The 7 Mosmann T, Cherwinski H, Bond M, Giedlin M, CoVman R. Two types of murine helper T cell clone. I. Definition according to profiles of activities diVerentiation of T cells into eVectors with a Th1 pattern and secreted proteins. J Immunol 1986;136:2348–57. of cytokine release depends principally on the cytokine 8 Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol 1994;12:227–57. IL12, which is secreted by dendritic cells and macro- 9 Mosmann T, Sad S. The expanding universe of T-cellsubsets: Th1, Th2 and phages, particularly when they are infected with intracellu- more. Immunol Today 1996;17:138–46. on September 27, 2021 by guest. Protected copyright. 23 24 10 Miossec P, vandenBerg W. Review: Th1/Th2 cytokine balance in arthritis. lar pathogens such as mycobacteria. 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