Service de Rhumatologie A and
1 Département dInformatique Médicale, Hôpital Cochin, Paris, France
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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- 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 casecontrol 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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. 1.
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.
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 (2 test) (Table 1
).
|
|
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, 2 test; adjusted OR 0.39, 95% CI 0.190.81). 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, 2 test; adjusted OR 0.19, 95% CI 0.080.47).
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 3.
|
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 4).
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 1112%, 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- 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 |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|