Results

Of the 215 patients with SLE, 202 were women (94%) and 13 men (6%). The mean age at original diagnosis was 30.5 years (range 12 to 78). The mean age at follow up was 42.2 years (range 16 to 87) with a range of follow up from 2 to 18 years. One hundred and forty six were white (68%).

Discussion

This study confirms previous reports1-6 that clustering of both systemic and organ specific AID occurs in patients with SLE with almost a third of patients in this study having at least one other AID (30%).

The majority of patients with an additional AID (62%) developed the latter after SLE had been diagnosed, which may merely reflect the relatively early age of onset of SLE. However, it may also suggest that SLE itself predisposes to the development of further AID. In a 10 year follow up of RA patients in multicase RA families, a similar prevalence of patients were observed to have an additional AID (37.5%).11 The only AID in the latter population that was increased compared with population controls however, was AITD and no patient developed SLE.12 Furthermore, the RA patients tended to be older at follow up than the SLE patients in this study (RA mean age 57.1 years, range 33 to 77 years).11 Therefore, SLE may be particularly prone to developing additional AID during the course of the disease. Well matched case-control studies are required to determine whether this observation is merely an effect of age or related to the disease itself.

The finding that in 18% of patients, the development of SLE was preceded by another AID suggests that it is not simply SLE itself that predisposes to the development of additional AID. Greenet al reported a high incidence of AITD in MLR-lpr/lpr mice that in turn develop a lupus-like disease and have a defect in the fas gene that regulates apoptosis12—that is, different manifestations of autoimmunity but the same immunological defect. Such diversity may be explained by other immunogenetic, environmental and hormonal factors.

The majority of patients had SLE without evidence of any additional AID despite follow up ranging up to 18 years. Such disease stability would be consistent with a primary genetic aetiology but the significant minority (30%) who changed their autoimmune profile over time supports a role for environmental or random factors, or both, in the pathogenesis of SLE. Certain chemicals have been reported to induce autoantibodies and lupus-like disease in strains of mice not considered genetically susceptible to autoimmune disease.13

SLE does not seem to influence the age at which a second AID develops as there was no difference in the age of onset of RA, Sjögren's syndrome or hypothyroidism in those patients in whom SLE developed first compared with those in whom it followed another AID. AITP however was an exception to this rule (see below).

The finding of hyperthyroidism, AITP and myasthenia gravis antedating SLE was in agreement with previous reports.4 ,6 ,14

In this study, all six patients with myositis developed the latter after a median interval of 2.5 years (range 1 to 10) following diagnosis of SLE. This is in agreement with previous reports15 but in contrast with other reports.16

Neither of the two patients who had myasthenia gravis that had occurred before onset of SLE, had had a thymoma. Interestingly, Aarliet al 17 reported an increased incidence of non-muscle AID among myasthenia gravis patients with follicular hyperplasia of the thymus but not among myasthenia gravis patients with thymoma.

Vaiopoulos et al reviewed the literature and reported that of 26 reported cases of myasthenia gravis associated with SLE, half had preceded and half had followed the development of SLE.6 Interestingly, one patient in this study was noted to have developed SLE after a thymectomy in the absence of myasthenia gravis. In a review of the literature, Ciaccio et al reported 13 cases of SLE that followed thymectomy.18 The role of thymectomy and the theoretical subsequent effects on suppressor cell function in the development of SLE has been debated19 but controversy remains.

There are various significant methodological issues that should be highlighted. The study population had a mean age of 49 years and was representative of a demographic population also at risk of other diseases, for example, autoimmune thyroid disease. The apparent increase in AITD in SLE patients may therefore simply be on the basis of chance alone. Furthermore, those patients with additional AID tended to be older and were younger at time of onset of SLE and therefore may merely have had a longer potential period of “immune disregulation” to develop an AID.

Does the association of SLE with some AID represents an autoimmune overlap or manifestations of the same disease? For example, it may be argued that the patients defined in this study as primary Sjögren's syndrome were simply SLE patients with secondary Sjögren's syndrome. However, all patients with primary Sjögren's syndrome satisfied the European consensus criteria for Sjögren's syndrome8including a positive labial biopsy. Such patients can therefore be classified as having an “overlap syndrome”—that is, the coexistence of two separate diseases.

The association of additional AID in SLE patients is likely to be multifactorial with an interplay of ubiquitous environmental and hormonal (or sex related) factors in genetically predisposed people. Physicians caring for SLE patients should remain alert to the possible development of a second AID during follow up and regular serological testing may be advantageous.