Dear Editor:
We read with great interest the contribution by Heras, et al.1. They reported a significant case that seemed not to respond to intravenous (IV) cyclophosphamide (CPM) induction treatment at 1 g but to respond to increased CPM dose to 1.5 g. Reading the case report, we wondered whether CPM certainly induced the lupus flare or other mechanisms were involved in the pathogenesis. They speculated that the lupus flare might have been due to the initial underdosing of cyclophosphamide. This explanation is plausible, but we would like to say that lupus flares can occur during or after stopping CPM treatment, suggesting the possible pathomechanisms of lupus flare.
In the immunological test after the first treatment of IV CPM, the patient had increased C3 level, but C4 was decreased. According to a previous study by Ho, et al.2, a decrease in C4 was associated with a concurrent increase in renal disease activity (p = 0.02). A decrease in C4 was especially associated with concurrent decreases in the hematocrit levels (p = 0.009), and previous increases in C3 were also associated with a higher frequency of decrease in platelet counts (p = 0.02). These data show that the renal and hematologic systemic lupus erythematosus (SLE) activity and flares are strongly associated with decreased C4.
Recently, Finke, et al.3 demonstrated that complement C4-deficient mice result in elevated intravascular levels of apoptotic DNA, targeted to the splenic marginal zone where it accumulates and induces type I interferon-gamma (IFN-γ). Type I IFN-γ is important for the initiation and potentiation of SLE activity and correlated with the renal disease and the presence of cutaneous manifestations4.
Therefore, we suggest that CPM is not an inducer but an inhibitor of lupus flare, and decreases in C4 and increased type I IFN-γ might play the central role in the development of lupus activity and flares. However, further studies are necessary to elucidate the exact molecular roles of complement deficiency and elevated levels of IFN-γ. The potential therapeutic antibodies directed to either type I IFN-γ or IFN α chain of the receptor 1 (IFNAR1)/IFNAR2 should also be further evaluated in the future.
