ALPHA(1)-ANTITRYPSIN (AAT) DEFICIENCY AND ANCA-POSITIVE SYSTEMIC VASCULITIS - GENETIC AND CLINICAL IMPLICATIONS

A high incidence of alpha(1)-antitrypsin (AAT) deficiency has been rep orted in patients with C-ANCA systemic vasculitis in association with antibodies against proteinase-3 (PR3). To clarify the role of AAT defi ciency in the acute vasculitic process as well as in progression of th e disease, we studied 84 patients with either C-ANCA or P-ANCA vasculi tis with special reference to: (a) the AAT gene, (b) the phenotypic (P i) variants and (c) the serum levels during both acute illness and rem ission. The PiZ gene was found in six patients (8% vs. 1.5% controls) irrespective of the type of autoantibodies (C-ANCA vs. P-ANCA). All Pi Z patients displayed the ability to raise their AAT serum levels up to the normal range during acute illness. In contrast, 24 patients with the PiM phenotype presented low AAT serum levels during acute illness. In all these patients, the AAT levels returned to normal values durin g the remission. Low AAT levels were associated with low levels of C-r eactive protein (PCR) (P<0.001), with a less severe renal involvement or a minor risk of death, and, in one tested patient, with a novel poi nt mutation (TCGA--> TCAA) at the enhancer-promoter region of the AAT gene. Low AAT serum levels did not correlate with either type/titre of autoantibody or distribution/severity of the vasculitis process. In t he case-control study, high AAT levels emerged as a major determinant of progression towards end-stage renal failure [odds ratio 3 (95% CI 1 .1-8.4)]. These results indicate: (a) a high incidence of the PiZ gene of AAT in systemic vasculitis irrespective of the type of autoantibod ies; (b) a novel form of AAT deficiency associated with the normal PiM phenotype becoming manifest only during acute illness; (c) dysregulat ion of the acute-phase response affecting selectively AAT or both AAT and PCR; (d) correlation between low plasma levels of AAT and less sev ere renal involvement or risk of death.