Rheumatoid arthritis in beta-thalassaemia trait

C. Montecucco, R. Caporali, S. Rossi and O. Epis

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 1Go). 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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TABLE 1.  Prevalence of beta-thalassaemic trait in RA from different Italian geographical areas as compared with patients with connective tissue disease (CTD) and seronegative spondyloarthritis (SSpA). The prevalence of beta-thalassaemic trait in the general population is ~1% in the north-west, 2–5% in the north-east, 5–8% in the south and 10% in the isles
 
As stated, a higher prevalence of RA in b-thal trait has already been reported [6], but we still do not know the reason for this. It could be due to a genetically determined susceptibility, even though we cannot exclude the contribution of environmental factors which may alter host susceptibility. Experimental and clinical evidence support the pathogenic role of iron overload in arthritis; although this possibility has not been fully evaluated in b-thal trait patients, data from the literature seem to exclude it [2]. Furthermore, none of our b-thal trait patients had serum ferritin values over the normal range nor had been previously transfused. As a matter of fact, the association of b-thal trait with RA we found in all the geographical areas of Italy seems to minimize the relevance of environmental agents.

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

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  2.  Dorwart BB, Schumacher HR. Arthritis in beta-thalassemia trait: clinical and pathological features. Ann Rheum Dis 1981;40:185–9.[Abstract]
  3.  Gorriz L, De Leon C, Herrero-Beaumont G. Arthritis in beta-thalassemia minor. Arthritis Rheum 1983;26:1292–3.
  4.  Arman MI, Butun B, Deseyen A, Bircan I, Guven A. Frequency and features of rheumatic findings in thalassemia minor: a blind controlled study. Br J Rheumatol 1992;31:197–9.[Medline]
  5.  Drosos AA, Lanchbury JS, Panayi GS, Moutsopoulos HM. Rheumatoid arthritis in Greek and British patients. Arthritis Rheum 1992;35:745–8.[ISI][Medline]
  6.  Marcolongo R, Trotta F, Scaramelli M. Beta-thalassemic trait and rheumatoid arthritis. Lancet 1975;i:1141.
  7.  Wordsworth BP, Lanchbury JSS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci USA 1989;86:10049–53.[Abstract]
  8.  Piazza A, Belvedere MC, Bernoco D et al. HLA variation in four Sardinian villages under differential selective pressure by malaria. In: Histocompatibility testing 1972. Copenhagen: Mungsgaard, 1972:73–84.
  9.  Contu L, Arras M, Mulargia M et al. Study of HLA segregation in 479 thalassemic families. Tissue Antigens 1992;39:58–67.[ISI][Medline]
  10.  Cucca F, Frau F, Lampis R et al. HLADQB1*0305 and DQB1*0304 alleles among Sardinians. Evolutionary and practical implications for oligotyping. Hum Immunol 1994;40:143–9.[ISI][Medline]
Accepted 19 April 1999





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