Oral iron chelator L1 and autoimmunity.

As Brittenham’ has reviewed in detail, the use of the oral iron chelator LI has been associated with significant clinical and animal toxicity. One of the more controversial issues surrounding the human use of LI has been the possible development of autoimmune phenomena as manifested by development of autoantibodies such as antinuclear antibodies (ANA). The Canadian group investigating LI did not describe any immunologic abnormalities in their initial report,’ but later reported positive ANA in 5 of 12 thalassemics with negative antibodies to double-stranded DNA (AdsDNA) and antibodies to histones (AHA) in all before starting LI ,3 after we reported possible drug-induced lupus in a patient taking L1.4 The phase I1 LI trial report on 52 thalassemics in India showed no “significant toxicity” on “extensive clinical and laboratory monitoring” of several organ systems and f ~ n c t i o n s . ~ An update of the Indian trial6 then reported ANA-positivity in I O of 52 (19.2%) thalassemics on LI and in 12 of 83 (14.5%) thalassemics on L I . It is surprising that neither AI-Refaie et ai’ nor Agarwal et aI6 mention AHA in their patients on LI who developed ANA because AHA are supposed to be specific for drug-induced lupus,* and the triad of positive ANA and AHA, and negative AdsDNA is typical of drug-induced lupus.* To address the question of autoimmunity in transfusion-dependent thalassemia, we investigated 90 patients with thalassemia major for the occurrence of autoantibodies?,” ANA were detected in 7 of 27 (25.9%) patients on LI , and in 2 of 63 (3.2%) patients not on L1 ( P < .01). AHA were seen in 4 of 7 patients on LI with positive ANA, and in neither of the 2 not receiving LI ( P < .03). AdsDNA were undetectable in all patients with positive ANA. Five months after discontinuation of LI, one of the patients with positive ANA and AHA became negative for both, and four months after discontinuation of LI , another patient with a positive ANA and a negative AHA became negative for ANA. Our investigations show that while there is a small amount of background ANA-positivity in patients with thalassemia major, AHA are always absent. The frequency of ANA-positivity is significantly higher in thalassemics receiving LI , some of whom also have positive AHA, consistent with drug-induced lupus.* The development of ANA may precede the development of AHA as shown by the AHA-negative patient whose ANA became negative after discontinuation of LI . While the exact mechanism and significance remain unknown, LI seems to cause significant autoimmune phenomena in humans that may be reversible if the drug is stopped early enough but may progress to symptomatic systemic lupus erythematosus (SLE). The human use of LI should be very cautious and only under careful monitoring.