Risk Factors

The incidence of idiopathic lupus is approximately 10-fold higher in females than in males. Although the incidence of drug-induced lupus is often said to be the same in males and females, as with many idiosyncratic drug reactions, it seems that the incidence is somewhat higher in females than in males. However, the issue is complicated by the fact that many categories of drugs are used more frequently by one sex than the other. For example, in Table 9.1,41% of patients with procainamide-induced and 64% of patients with hydralazine-induced lupus were females, but many more males than females are treated with these drugs. In one study, the incidence in males treated with hydralazine was 2.8% and that in females was 11.6% (Cameron and Ramsay 1984). Unlike idiopathic lupus, drug-induced lupus usually occurs in an older age group, and it has been reported to be more common in caucasians, whereas idio-pathic lupus is more common in blacks (Dubois and Wallace 1987). Specific HLA types have been associated with an increased risk of drug-induced lupus. For example, 73% of patients with hydralazine-induced lupus were HLA-DR4, which is significantly higher than the incidence of this HLA type in patients with idiopathic lupus (Batchelor et al. 1980). However, others have failed to find this association (Brand et al. 1984). HLA-DR4 was also found in 9 of 13 patients with minocycline-induced lupus, and the other 4 patients were HLA-DR2, whereas all of the patients had an HLA-DQB1 allele encoding for tyrosine at position 30 (Dunphy et al. 2000). In contrast, penicillamine-induced lupus is associated with HLA-DR6 (Chin et al. 1991), and chlorpromazine-induced lupus is associated with HLA-Bw44 (Canoso et al. 1982). These findings are in contrast to the HLA associations found in patients with idio-pathic lupus.

Although all adverse drug reactions are dose dependent, idiosyncratic drug reactions are often referred to as independent of dose because they do not occur in most patients at any dose and the usual dose range is sufficiently narrow that the dependence on dose is not apparent. In the case of drug-induced lupus, the dose dependency is more obvious. The best-documented example is hydralazine-induced lupus, which is much less common if the dose is kept below 200mg/d (Cameron and Ramsay 1984). Being of the slow acetylator phenotype is a risk factor for drug-induced lupus when the drug involved is an aromatic amine or hydrazine (Uetrecht and Woosley 1981). This is quite apparent in the case of hydralazine, where acetylation is the major metabolic pathway and rapid acetylators are at significantly decreased risk of hydralazine-induced lupus. It is also apparent for sulfasalazine-induced lupus (Gunnarsson et al. 1997). In contrast, the major mode of elimination of procainamide is renal excretion of unchanged drug; therefore, acetylation makes a much smaller contribution to the elimination of procainamide. Thus, although the time to onset of procainamide-induced lupus seems to be shorter in slow acetylators, the overall incidence is not significantly higher (Woosley et al. 1978). The formation of the reactive metabolite of procainamide in the liver is mediated by CYP 2D6 (Lessard et al. 1997); therefore, patients with the impaired metabolism phenotype may be protected from pro-cainamide-induced lupus. However, if oxidation by leukocytes mediated by myelo-peroxidase is the more important mode of activation, the CYP 2D6 phenotype should not be a factor (Uetrecht 1988).

Although drugs associated with the induction of lupus do not seem to exacerbate idiopathic lupus, the incidence of drug-induced lupus may be higher in patients with certain diseases. However, the use of specific drugs in specific diseases makes it very difficult to sort out this possible risk factor.

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