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    • The pathogenesis of d penicillamine induced MG

    2023-09-25

    The pathogenesis of d-penicillamine-induced MG is not clear. The repertoire of anti-AChR Signaling Pathways in d-penicillamine-induced MG has been shown to be similar to that in idiopathic MG in terms of AChR antigenic regions, suggesting a common immune mechanism (Tzartos et al., 1988). About 20% of d-penicillamine-induced MG patients do not have detectable anti-AChR antibodies in their sera (Katz et al., 1989) and it is possible that, at least in some of these, MG is caused by anti-MuSK antibodies. However, d-penicillamine has not previously been reported to cause the production of anti-MuSK antibodies. We here report the case of a Greek Caucasian female, who developed d-penicillamine-induced MG with both anti-MuSK and anti-AChR antibodies, which disappeared some time after d-penicillamine discontinuation. Interestingly, the predominance of the unusual IgG4 subtype of the anti-MuSK antibodies is further support for the notion of a similar immune mechanism in idiopathic and d-penicillamine-induced AChR-MG and MuSK-MG.
    Methods
    Results
    Discussion d-penicillamine treatment is known to occasionally induce anti-AChR antibody production and MG symptoms (Vincent et al., 2001, Conti-Fine et al., 2003). After discontinuation of treatment, both the antibodies and symptoms disappear, usually over a period of a few months (Conti-Fine et al., 2003). However, to our knowledge, d-penicillamine-induced anti-MuSK MG has not been previously reported. In the present report we mainly present the case of a double seropositive (anti-AChR and anti-MuSK antibodies) MG patient identified after administration of d-penicillamine for treatment of scleroderma. The scleroderma and d-penicillamine-induced MG in this patient seemed to occur in the context of an underlying autoimmune diathesis. After two years of d-penicillamine treatment, the patient developed clear MG symptoms and positive antibody titers for both the AChR and MuSK. Both antibody species started decreasing from the first month after discontinuation of d-penicillamine therapy. By the fourth month, the anti-MuSK antibodies had disappeared completely and this result has been maintained for the past 3years. The anti-AChR antibody titer followed a slower and two-phase decrease, dropping to 18% of the initial value in seven months, then with a slower decrease to a zero titer after another 2.5years. Nevertheless, both anti-MuSK and anti-AChR antibodies showed a steady decrease without any increase at any time after discontinuation of d-penicillamine. Anti-MuSK antibodies are generally identified in MG patients without anti-AChR antibodies (McConville et al., 2004). In the present study, in addition to the d-penicillamine-induced double-positive patient, four more patients out of 1012 anti-AChR-positive and 115 anti-MuSK-positive patients were identified as potentially double-positive (three were positive for anti-MuSK and ambiguous for anti-AChR autoantibodies). Thus, these results support the notion that anti-AChR antibodies generally do not coincide with anti-MuSK antibodies, but the presence of very few exceptions was also established. The anti-MuSK antibodies in MG patients are mostly of the non-complement-binding IgG4 subclass (McConville et al., 2004, Tsiamalos et al., 2009). However, immunization of animals with purified MuSK induces anti-MuSK antibodies of the IgG1 subclass (Jha et al., 2006, Shigemoto et al., 2008). This suggests that the predominance of the IgG4 subclass in human MG is due to the immunization mechanism rather than to a peculiarity of the antigen, although the latter cannot be excluded due to differences between the human and animal immune systems. It was therefore of interest to determine whether the d-penicillamine-induced anti-MuSK antibodies and those of the idiopathic double-positive MG patients followed this general trend. Fig. 2 shows that the anti-MuSK autoantibodies in these patients were also mostly or exclusively IgG4. This similarity in antibody characteristics between idiopathic and d-penicillamine-induced anti-MuSK-MG is reminiscent of similarities found previously between idiopathic and d-penicillamine-induced anti-AChR-MG (Tzartos et al., 1988) and suggests that the immune response in d-penicillamine-induced anti-MuSK-MG is similar to that in idiopathic anti-MuSK MG. It further suggests that d-penicillamine-induced immunization is fundamentally different from the classical immunization of experimental animals. Finally, it also suggests that the anti-MuSK immune response in the idiopathic double-positive MG patients does not differ from that in the usual exclusive anti-MuSK MG and it is probably independent of the coexisting anti-AChR response.