Reduced incidence and prevalence of atopy in rheumatoid arthritis. Results of a case–control study

P. Hilliquin, Y. Allanore, J. Coste1, M. Renoux, A. Kahan and C. J. Menkès

Service de Rhumatologie A and
1 Département d’Informatique Médicale, Hôpital Cochin, Paris, France


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To determine the cumulative incidence and the point prevalence of atopy in patients with rheumatoid arthritis (RA).

Patients and methods. A standardized questionnaire was sent to 300 RA patients. Questions concerned previous or present characteristics of atopy (hay fever, asthma and constitutive eczema) and RA. RA patients were matched with genetically unrelated controls (sister- or brother-in-law, neighbour or friend). The same questionnaire (except for questions about RA) was sent to the control subjects. In cases of atopy, patients, controls and the treating physicians were contacted by a physician to check the validity of the responses.

Results. Paired responses were obtained in 173 cases. Information about atopy was obtained for 69 other RA patients. The characteristics of RA were similar for patients who responded and those who did not respond. The frequency of atopy was significantly lower in RA patients than in controls, both for cumulative incidence (RA 7.5%, controls 18.8%; P < 0.01) and point prevalence (RA 3.5%, controls 16.2%; P < 0.0001). The clinical manifestations of atopy stopped before the onset of RA in eight of the 17 RA patients with an allergic condition, and there was no subsequent relapse. No effect of RA treatment could account for the remission of atopy.

Conclusion. These data support the concept that atopy protects against the future development of RA and that the two diseases could counterbalance one another.

KEY WORDS: Atopy, Hay fever, Asthma, Rheumatoid arthritis.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a chronic immune disorder of unknown cause. The inflamed synovium is infiltrated with CD4+ T cells, most of them expressing several activation markers [1]. At least two functional subsets of T cells can be distinguished according to their cytokine secretion profiles [2, 3]. Th1 cells produce interleukin 2 (IL-2) and interferon {gamma} (IFN-{gamma}) and are involved in delayed-type hypersensitivity and macrophage activation. Th2 cells produce IL-4, IL-5, IL-10 and IL-13 and are involved in allergy and the response to parasites. Th2 cells down-regulate IL-1 and tumour necrosis factor {alpha} in a variety of experimental conditions [46]. Each subset, Th1 and Th2, regulates the other in a dynamic process. Different disease manifestations are associated with prominence of one or the other of the Th1 and Th2 phenotypes [7].

RA is generally thought to be a Th1 disease, T-cell clones from synovium or peripheral blood usually having a Th1-like phenotype [811]. T-cell clones from joints affected by RA produce large amounts of IFN-{gamma} but very small amounts of IL-4, and synovitis is associated with lack of the IL-4 gene [8, 9, 12, 13]. Studies in animal models have suggested that Th2 cytokines attenuate Th1-dependent autoimmune disorders [1416].

Atopy is a genetically determined disorder in which the IgE antibody is formed in response to specific allergens. IgE production is initiated by interaction between antigen-presenting B cells and antigen-specific Th2 cells. Atopy is clearly a Th2 disease, T cells producing the IgE-switching cytokines IL-4 and IL-13 [1719].

We conducted a case–control study to test whether two diseases with opposite immunological cytokine profiles were mutually exclusive. The preliminary results of this study have been published recently [20]. Our results clearly demonstrate, for the first time, that a Th2 condition protects against the future development of RA.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients and controls
This case–control study initially included 300 consecutive RA patients admitted to our department between 1 July 1995 and 31 December 1996. RA was defined according to the revised American Rheumatism Association criteria [21]. There were 245 women and 55 men, with a mean disease duration of 12.9 ± 9.7 yr (mean ± S.D.).

A standardized questionnaire about atopic symptoms and RA characteristics was sent to all patients (see below). Each mailing explained the design of the study and provided a clear definition of atopy, but patients and controls were blind with respect to the aim of the study. Atopy was defined as the previous or present occurrence of at least one of the following symptoms: asthma, hay fever and atopic eczema. At least two flare-ups were required for each clinical manifestation. Each RA patient was asked to give the name of someone who could act as their own control, e.g. a sister-in-law or brother-in-law, or, if these were unavailable, a neighbour or friend. Each RA patient was therefore individually matched according to age, sex, social and geographical environment to a genetically unrelated control. This method was chosen to prevent the potential confounding effects of these factors on the prevalence of atopy.

The standardized questionnaire requested the following information: (i) demographic characteristics [date of birth, sex, and place of residence (1 = Paris; 2 = Ile de France but outside Paris; 3 = another city with >100 000 inhabitants; 4 = a city with <100 000 inhabitants; categories 2 and 3 were pooled for statistical analysis)]; (ii) working status, recorded in three categories: not employed; blue collar; white collar and others; (iii) manifestations of atopy in cases and controls (clinical expression, age at onset, frequency, local and systemic treatments and the name of the referring physician); and (iv) characteristics of RA [date of onset, number of previous disease-modifying anti-rheumatic drugs (DMARDs) used, number of hospital stays, number of surgical procedures, current treatment with dose and duration (non-steroidal anti-inflammatory drugs, oral corticosteroids, DMARDs)].

Procedure
The questionnaire was mailed first to all RA patients, and then to controls after answers had been received from the RA patients. The answers were checked systematically by the same physician (Y.A.), who telephoned all RA patients, and if the patient had atopic symptoms these were reported to the patient's physician. The procedure is shown in Fig. 1Go.

Cumulative incidence was defined as the occurrence of atopic manifestations throughout the patient's life. Point prevalence concerned only those subjects with clinical symptoms at the time of the study.



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FIG. 1. The recruitment procedure for questionnaires. A standardized questionnaire was sent to 300 RA patients admitted to our department between 1 July 1995 and 31 December 1996. The same physician (Y.A.) telephoned all RA patients and their physicians to check their responses. He also telephoned patients who did not give the name of a control or did not respond to the questionnaire up to three times. The same questionnaire (except for questions about RA) was sent to matched controls. Those who did not answer were also contacted by telephone.

 
Statistics
The {chi}2 test was used to compare the prevalence and cumulative incidence of atopy between RA patients and controls. Conditional multiple logistic regression was used to determine the relationship between RA and atopy and to adjust for the confounding effects of age, occupation and place of residence. Odds ratios (OR) were estimated by the maximum likelihood method and 95% confidence intervals (CI) were calculated.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Answers to the questionnaire
Answers to the questionnaire were of three types. (Group 1) 173 RA patients returned the completed questionnaire and gave the name of a control. The age- and sex-matched control was a sister-in-law or a brother-in-law in 98 cases and a neighbour or friend in 75 cases. (Group 2) Sixty-nine patients responded to the questionnaire but did not give the name of a control. They were contacted by telephone, but could not or would not give the name of a control. (Group 3) Fifty-eight patients did not respond (change of address, lost to follow-up, or refusal); however, RA characteristics were obtained from their medical records.

There were no significant differences between these three groups in age, sex, duration of RA, dose of oral corticosteroids, number of previous DMARD treatments, number of hospital stays, number of surgical procedures, place of residence and working status ({chi}2 test) (Table 1Go).


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TABLE 1. Demographic characteristics and treatment of RA patients

 
We therefore concluded that the statistical study could be conducted considering only group 1 patients (n = 173) and their controls. There were no significant differences between patients and controls in age, sex, working status and place of residence (Table 2Go).


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TABLE 2. Characteristics of RA patients and controls

 

Cumulative incidence and prevalence of atopy
The cumulative incidence of atopy was defined as the proportion of patients with current or previous clinical manifestations of atopy. The cumulative incidence of atopy was significantly lower in RA patients than in matched control subjects (n = 173; RA 7.5%, controls 18.8%; P < 0.01, {chi}2 test; adjusted OR 0.39, 95% CI 0.19–0.81). When considering RA patients who responded (groups 1 and 2, n = 242), the cumulative incidence of atopy was 7% and did not differ from that observed in group 1 RA patients.

The point prevalence of atopy was defined as the proportion of subjects with atopic clinical manifestations at the time of the study. The point prevalence was also significantly lower in RA patients than in controls (n = 173; RA 3.5%, controls 16.2%; P < 0.0001, {chi}2 test; adjusted OR 0.19, 95% CI 0.08–0.47).

RA patients with atopy
Seventeen of the 242 RA patients were atopic. The clinical signs of atopy disappeared before the onset of RA in eight of these patients, with no further atopic manifestations noted. For two patients, the remission of atopy and the onset of RA occurred within 1 yr of each other. However, no overlap was observed between the two diseases in any patient, with an interval ranging from 6 months to 23 yr between them. Therefore, RA treatments, especially corticosteroids and methotrexate, were not responsible for the remission of atopy. The treatments and disease characteristics of these eight patients are given in Table 3Go.


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TABLE 3. Characteristics of the eight RA patients with previous symptoms of atopy

 
Remission of atopy occurred in only two atopic controls, after 15 and 45 yr.

Nine RA patients were still suffering from atopy at the time of the study. There was no difference in RA clinical status, response to treatment, extra-articular manifestations or disease progression between these nine patients and those of the other RA groups. Only one RA patient developed atopy after the onset of RA (patient 7) (Table 4Go).


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TABLE 4. Characteristics of the nine RA patients with symptoms of atopy at the time of the study

 


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The balance between Th1 and Th2 cells is critical in inflammatory and immune disorders. This study is the first to show that the occurrence of a Th2 disease is much lower in RA patients than in healthy subjects [20]. Our results suggest that atopy protects against the future development of RA. Both cumulative incidence and the point prevalence of atopy were low in RA patients, suggesting that atopy and RA counterbalance one another over long periods of time.

The controls were selected by a matching procedure designed to prevent factors such as age and environment from affecting the expression of atopy. The control subjects were not genetically related and most lived in the same social and geographical environment as their matched RA patient.

The frequency of atopy in the control group was similar to that reported for the general population. Atopy is generally defined as being a combination of some or all of allergic asthma, hay fever and atopic eczema. Atopy is common and affects at least 20%, and up to 40% of individuals in Western societies [2225]. Many reports have suggested that there has been an increase in atopy in recent decades [2628]. The most frequent condition is hay fever, with a prevalence of about 11–12%, followed by atopic asthma.

The reported prevalence of atopic diseases depends on the definitions and investigative methods used. Skin prick tests and serological tests for the presence of specific serum IgE against common inhaled allergens provide the most objective means of diagnosing atopic diseases. However, hay fever, which was the most frequent atopic condition in our patients, is easily diagnosed by means of a questionnaire because it has very typical symptoms and occurs during typical seasons. If a positive response was given in the questionnaire, the diagnosis of atopy was checked by contacting the referring physician. The use of a questionnaire is also indispensable for the evaluation of the lifetime prevalence of atopic diseases.

Environmental factors play a key role in the development of atopy, but a strong genetic predisposition is also required. Atopy involves the activation of Th2 cells, due to interaction with antigen-presenting B cells. Th2 cytokines, especially IL-4 and IL-13, induce IgE production by isotype switching, from mu to epsilon [19, 29]. Umbilical cord blood lymphocytes from newborn infants with atopic parents produce larger amounts of the Th2 cytokines IL-4 and IL-5 than do T-cell clones from newborn infants with non-atopic parents [30]. A mutation of the IL-4 receptor has been shown to be strongly associated with atopy, and this mutation may predispose the individual carrying it to allergic diseases [31].

Several immune disorders involve a predominance of Th1 or Th2 cells in their chronic phase. RA is classified as a Th1 immune disease, with less IL-4 than IFN-{gamma} in the inflamed joints [11, 32]. There is evidence to suggest that a Th2 response protects against or limits the development of Th1 autoimmune conditions [3334].

Atopy occurs long before RA during life, and a shift of T cells towards a Th2 pattern in atopy could limit the further occurrence of RA. Atopy disappeared before the onset of RA in eight of our 17 atopic RA patients, suggesting that T-cell cytokine production is involved in both diseases. Two reports have been published in which no difference was found in the prevalence of atopy between RA patients and controls [3536]. However, Verhoef et al. [37] showed that the prevalence of hay fever in RA patients is about half that in controls. Furthermore, RA was less severe in RA patients suffering from hay fever than in RA patients without hay fever, suggesting that atopy affects both the incidence and the severity of RA.

If preliminary reports suggesting a decrease in the incidence of RA in industrialized countries were to be confirmed [3839], it might be suggested that this finding and the increase in the incidence of atopic diseases are not independent. Moreover, it might be hypothesized that the same environmental or individual factors which induce the increase in the frequency of atopic diseases are also responsible for the reduced incidence of RA by means of a shift of the Th1/Th2 balance. These factors, as yet not clearly identified, may include a decrease in the incidence of infectious diseases in infants and children, changes in habitation and way of life, and increasing levels of pollutants.

We found that atopic diseases were three times more common in control subjects than in RA patients, suggesting that atopy in childhood or early adulthood protects against the future development of RA. Atopy involves a genetically driven tendency towards the predominance of Th2 cytokines. Th1 and Th2 cytokines have antagonistic effects, so this Th2 condition may limit the incidence and perhaps the severity of Th1 autoimmune diseases. Further studies are required to identify the factors, especially the genetic background, affecting the expression of RA and atopy.


    Notes
 
Correspondence to: C. J. Menkès, Service de Rhumatologie A, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum1992;35:729–35.[ISI][Medline]
  2. Mossmann TR, Coffman RL. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol1989;46:11–47.
  3. Romagnani S. Human Th1 and Th2 subsets: doubt no more. Immunol Today 1991;12:256–7.[ISI][Medline]
  4. Briolay J, Dechanet J, Blanchard D, Banchereau J, Miossec P. IL-4 inhibits polyclonal immunoglobulin secretion and cytokine production by peripheral blood mononuclear cells from rheumatoid arthritis patients. J Clin Immunol1992;12:36–44.[ISI][Medline]
  5. Essner R, Rhoades K, McBride WH, Morton DL, Economou JS. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol1992;142:3857–61.
  6. Del Prete G, de Carli M, Almerigogna F, Grazia Giudizi M, Biagiotti R, Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 (Th2) T-cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993;150:353–60.[Abstract/Free Full Text]
  7. Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol1994;12:256–7.
  8. Miltenburg AMM, van Laar JM, de Kuiper R, Daha MR, Breedveld FC. T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand J Immunol1992;35:603–10.[ISI][Medline]
  9. Quayle AJ, Chomarat P, Miossec P, Kjeldsen-Kragh J, Forre O, Natvig JB. Rheumatoid inflammatory T-cell clones express mostly Th1 but also Th2 and mixed (Th0-like) cytokine patterns. Scand J Immunol1993; 38:75–82.[ISI][Medline]
  10. Schulze-Koops H, Lipsky PE, Kavanaugh AF, Davis LS. Elevated Th1- or Th0-like cytokine mRNA in peripheral circulation of patients with rheumatoid arthritis: modulation by treatment with anti-ICAM-1 correlates with clinical benefit. J Immunol1995;155:5029–37.[Abstract]
  11. Dolhain RJEM, van der Heiden AN, ter Haar NT, Breedveld FC, Miltenburg AMM. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum1996;39:1961–9.[ISI][Medline]
  12. Simon AK, Seipelt E, Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA1994;91:8562–6.[Abstract]
  13. Cohen SBA, Katsikis PD, Chu CQ, Thomssen H, Webb LMC, Maini RN et al. High level of interleukin-10 production by the activated population within the rheumatoid synovial membrane. Arthritis Rheum1995;38:946–52.[ISI][Medline]
  14. Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today1995;34:34–8.
  15. Saoudi A, Kuhn J, Huygen K, de Kozak Y, Velu T, Goldman M et al. Activated TH2 cells prevent experimental autoimmune uveoretinitis, a TH1 dependent autoimmune disease. Eur J Immunol1993;23:3096–103.[ISI][Medline]
  16. Bessis N, Boissier MC, Ferrera P, Blankenstein T, Fradelizi D, Fournier C. Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13. Eur J Immunol1996;26:2399–403.[ISI][Medline]
  17. Pene J. Regulatory role of cytokines and CD23 in the human IgE antibody synthesis. Int Arch Allergy Appl Immunol1989;90(Suppl. 1):32–40.[ISI][Medline]
  18. Vercelli D, Jabara HH, Arai K, Geha RS. Induction of human IgE synthesis requires interleukin 4 and T/B cell interactions involving the T cell receptor/CD3 complex and MHC class II antigens. J Exp Med 1989;169:1295–307.[Abstract]
  19. Vercelli D, Jabara HH, Lauener RP, Geha RS. IL-4 inhibits the synthesis of IFN-gamma and induces the synthesis of IgE in human mixed lymphocyte cultures. J Immunol 1990;144:570–3.[Abstract/Free Full Text]
  20. Allanore Y, Hilliquin P, Coste J, Renoux M, Menkès CJ. Decreased prevalence of atopy in rheumatoid arthritis. Lancet1998;351:497–8.[ISI][Medline]
  21. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum1988;31:315–24.[ISI][Medline]
  22. Peat JK, Haby M, Spijker J, Berry G, Woolcock AJ. Prevalence of asthma in adults in Busselton, Western Australia. Br Med J1992;305:1326–9.[ISI][Medline]
  23. Wüthrich B, Schindler C, Leuenberger P, Ackermann-Liebrich U, SAPALDIA Team. Prevalence of atopy and pollinosis in the adult population of Switzerland (SAPALDIA Study). Int Arch Allergy Appl Immunol1995;106:149–56.
  24. Schäfer T, Ring J. Epidemiology of allergic diseases. Allergy1997;52(Suppl. 38):14–22.
  25. Nelkirch F, Pin I, Knani J, Henry C, Pison C, Liard R, Romazzini S, Bousquet J. Prevalence of asthma and asthma-like symptoms in three French cities. Respir Med 1995;89:685–92.[ISI][Medline]
  26. Wüthrich B. Epidemiology of the allergic diseases. Are they really on the increase? Int Arch Allergy Appl Immunol1989;90:3–10.[ISI][Medline]
  27. Burney PGJ. Evidence for an increase in atopic disease and possible causes. Clin Exp Allergy1993;23:484–92.[ISI][Medline]
  28. von Mutius E, Weiland S, Fritzch C, Duhme H, Keil U. Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. Lancet1998;351:862–6.[ISI][Medline]
  29. Del Prete G, Maggi E, Parronchi P. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol1988;140:4193–8.[Abstract/Free Full Text]
  30. Piccinni MP, Beloni L, Giannarini L, Livi C, Scarselli G, Romagnani S et al. Abnormal production of T helper 2 cytokines interleukin-4 and interleukin-5 by T cells from newborns with atopic parents. Eur J Immunol1996; 26:2293–8.[ISI][Medline]
  31. Khurana Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of-function mutation in the {alpha} subunit of the interleukin-4 receptor. N Engl J Med1997;337:1720–5.[Abstract/Free Full Text]
  32. Miossec P, Vandenberg W. Review: Th1/Th2 cytokine balance in arthritis. Arthritis Rheum1997;40:2105–15.[ISI][Medline]
  33. Cus DJ, Hinton DR, Stohlman SA. Self-antigen-induced Th2 responses in experimental allergic encephalomyelitis (EAE)-resistant mice—Th2-mediated suppression of autoimmune disease. J Immunol1995;155:4052–9.[Abstract]
  34. Falcone M, Bloom BR. A T helper cell 2 (Th2) immune response against non-self antigens modifies the cytokine profile of autoimmune T cells and protects against experimental allergic encephalomyelitis. J Exp Med1997;185:901–7.[Abstract/Free Full Text]
  35. O’Driscoll B, Milburn H, Kemeny D, Cochrane G, Panayi G. Atopy and rheumatoid arthritis. Clin Allergy1985;15:547–53.[ISI][Medline]
  36. Hassan W, Keaney N, Holland C, Kelly C. Bronchial reactivity and air flow obstruction in rheumatoid arthritis. Ann Rheum Dis1994;53:511–4.[Abstract]
  37. Verhoef CM, van Roon JAG, Vianen ME, Bruijnzeel-Koomen CAFM, Lafeber FPJG, Bijlsma JWJ. Mutual antagonism of rheumatoid arthritis and hay fever; a role for type 1/type 2 T cell. Ann Rheum Dis1998;57:275–80.[Abstract/Free Full Text]
  38. Dugowson CE, Koepsell TD, Voigt LF, Bley L, Nelson JL, Daling JR. Rheumatoid arthritis in women. Incidence rates in Group Health Cooperative, Seattle, Washington, 1987–1989. Arthritis Rheum1991;34:1502–7.[ISI][Medline]
  39. Spector T, Hart DJ, Powell RJ. Prevalence of rheumatoid arthritis and rheumatoid factor in women: evidence for a secular decline. Ann Rheum Dis1993;52:254–7.[Abstract]
Submitted 24 March 1999; revised version accepted 17 March 2000.