Servizio di Reumatologia, IRCCS Policlinico S. Matteo, Pavia, Italy
Correspondence to:
C. Montecucco, Servizio di Reumatologia, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
SIR, The arthritis occurring in patients with beta-thalassaemia trait (b-thal trait) is still a controversial issue. A mild, seronegative, HLA-B27-negative arthritis, mainly affecting the wrists, has been reported in several patients with b-thal trait [1, 2]. On the other hand, Gorriz et al. [3] did not find any significant difference between b-thal trait patients and controls with regard to the clinical features of musculoskeletal complaints, and Arman et al. [4] did not find any exclusive form of chronic arthritis in b-thal trait patients in spite of an increased frequency of chronic arthralgia. So, the actual nature of the b-thal trait-associated arthritis is still unknown and there is no definite proof that it may be regarded as a distinct clinical entity. A possible explanation is that arthritis in b-thal trait may represent a mild form of seronegative rheumatoid arthritis (RA) since RA may have a milder clinical course in people from Mediterranean countries [5]. Furthermore, a higher prevalence of both rheumatoid factor-positive and rheumatoid factor-negative RA has been reported in b-thal trait subjects from the endemic area of Ferrara, Italy [6].
To ascertain whether patients with b-thal trait actually had an increased risk of developing RA, we first undertook a retrospective analysis of 3836 clinical records of in-patients consecutively admitted to the Department of Internal Medicine of the University Hospital of Pavia, Italy. Clinical records were evaluated for the presence of b-thal trait as documented by Hb electrophoresis and for a clinical diagnosis of RA. Among 3836 clinical records examined, we found b-thal trait in 91 (2.37%) patients. Among the 96 RA patients so recorded, we found seven with b-thal trait (7.3%), i.e. a percentage significantly higher than that found in non-RA patients (84/3740=2.25%) (P <0.01). A subsequent, prospective study was carried out on Italian patients consecutively admitted to a rheumatology out-patient clinic because of RA or other inflammatory rheumatic diseases. In this prospective study, we evaluated 374 RA patients fulfilling the 1987 criteria of the American College of Rheumatology. The data obtained in RA were compared with those found in 278 consecutive patients suffering from either connective tissue disease (CTD) and vasculitis (198 patients) or seronegative spondyloarthritis (SSpA) (80 patients). These patients were chosen as a control group because they were believed to have a geographical distribution similar to that of patients referring to our clinic for RA and to have at least a haemocytometric analysis performed at the time of clinical examination. Patients with a mean corpuscular volume of <76 fl were studied further for iron status and Hb electrophoresis. Oral iron supplementation was given before Hb electrophoretic analysis in cases with iron deficiency. Patients were considered to have b-thal trait if Hb A2 was >3.5% of total Hb.
The percentage of b-thal trait was significantly higher in RA patients (24/374=6.4%) compared to control patients (6/278=2.15%) (P=0.017). The figures obtained for CTD and SSpA patients were similar to those found by retrospective analysis of clinical records in the overall in-patient population suffering from diseases other than RA.
To exclude the possibility that differences between RA and other rheumatic diseases could be due to a different geographical distribution of patients, we analysed RA and non-RA patients according to the place of birth. Italy was divided into four areas with different b-thal trait prevalence, i.e. north-west, north-east, south and isles (Sicily and Sardinia). The geographical distribution was roughly similar for RA and other rheumatic diseases; furthermore, an increased frequency of b-thal trait in RA was apparent in all of the geographical areas, while the frequency of b-thal trait in non-RA patients was similar to that expected for the general population (Table 1). No differences were found between b-thal and non-b-thal RA patients for sex, age, disease duration and rheumatoid factor-positive cases (67% in b-thal and 68% in non-b-thal).
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The association between HLA antigens and RA is well established [7]. The relationship between HLA and b-thal trait has been investigated only rarely. Beta-thalassaemia occurs worldwide, but it is most frequent in populations of the malaria belt (Mediterranean, Middle East, Asia and Africa). HLA-BW35 is significantly increased in the malarial environment [8] and may offer an independent advantage in those populations in which malaria plays a pivotal selective role. A recent survey of HLA segregation in 479 thalassaemic Sardinian families failed to show any significant differences between the probands and the controls [9]. However, the study of more recently identified alleles might open new perspectives in this field [10].
In conclusion, our data suggest that the subjects with b-thal trait have a high prevalence of polyarthritis resembling RA. The percentage of rheumatoid factor-positive cases in b-thal patients was almost identical to that found in non-b-thal RA; this supports the view that b-thal may increase the risk of developing true RA. The existence of a peculiar form of arthropathy associated with b-thal trait cannot be excluded by the present study, even though it is possible that some of these cases might be regarded as a particularly mild, seronegative form of RA. A prospective, controlled study is in progress to better evaluate the clinical, serological and genetic characteristics of RA with b-thal trait as compared with RA without b-thal trait, and to obtain more information about whether some patients with b-thal trait develop an arthropathy different from RA.
References