HIGH-DOSE INTRAVENOUS IMMUNOGLOBULIN EXERTS ITS BENEFICIAL EFFECT IN PATIENTS WITH DERMATOMYOSITIS BY BLOCKING ENDOMYSIAL DEPOSITION OF ACTIVATED COMPLEMENT FRAGMENTS

In patients with dermatomyositis (DM) the earliest lesion is microvasc ulopathy mediated by deposition of C5b-C9 membranolytic attack complex (MAC) on intramuscular capillaries. This leads sequentially to muscle ischemia, necrosis of muscle fibers, and muscle weakness. High-dose i ntravenous immunoglobulin (IVIG), which can modulate complement-depend ent tissue damage in animal models, has been shown to be effective in the treatment of patients with DM. We used an in vitro C3 uptake assay to examine 55 coded sera from 13 patients with DM and 5 patients with other non-complement-mediated neuromuscular diseases, before and afte r treatment with IVIG or placebo. Patients with active DM had a signif icantly higher baseline C3 uptake compared with the others (geometric mean 12,190 vs 3,090 cpm). Post-IVIG but not post-placebo sera inhibit ed the C3 uptake, without depleting the complement components, by 70.6 -93.4%. The maximum inhibition of C3 uptake occurred within hours afte r IVIG infusion, started to rebound 2 d later, and reached pretreatmen t levels after 30 d. The serum levels of SC5b-9 complex production wer e high at baseline but normalized after IVIG therapy. Repeat biopsies from muscles of improved patients showed disappearance of C3b NEO and MAC deposits from the endomysial capillaries and restoration of the ca pillary network. We conclude that IVIG exerts its beneficial clinical effect by intercepting the assembly and deposition of MAC on the endom ysial capillaries through the formation of complexes between the infus ed immunoglobulins and C3b, thereby preventing the incorporation of ac tivated C3 molecules into C5 convertase. These findings provide the fi rst serological and in situ evidence that IVIG modulates complement at tack in a human disease.