[The role of rituximab in the treatment of ANCA-associated systemic vasculitis]. / Rituximab: quale ruolo nel trattamento delle vasculiti sistemiche ANCA-associate?

A considerable minority of patients with ANCA-associated small-vessel vasculitis are refractory to conventional therapy or experience dose-limiting side effects. Novel therapeutic approaches include rituximab, a genetically engineered chimeric murine-human monoclonal antibody that binds to CD20, which is expressed on human B cells. It was approved in 1997 for the treatment of CD20-positive B-cell non-Hodgkin lymphoma and in 2006 for the treatment of rheumatoid arthritis. The multiple mechanisms proposed for rituximab-mediated B-cell depletion are discussed in this paper. Cumulative data from several open studies on the treatment of microscopic ANCA-associated polyangiitis suggest that in the vast majority of cases rituximab has a beneficial effect. Two randomized controlled trials confirmed these promising results, suggesting that rituximab might be considered as an option for first-line therapy of induction of remission of ANCA-associated vasculitis, and providing an additional tool for treating patients with disease relapse after previous therapy. While rituximab is very effective in the depletion of B cells, current research suggests it could also influence other immune system cells and reestablish immune homeostasis and tolerance. The safety profile of rituximab reveals that most reactions are infusion-related and that the incidence of serious side effects is low. Systemic infection remains a major concern and may result in death. A small number of cases of progressive multifocal leukoencephalopathy reported in patients receiving rituximab in off-label use (albeit none with ANCA-associated vasculitis) highlights the importance of pharmacovigilance.

Thin basement membrane disease in patients with familial IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) can exist as a primary glomerulonephritis (GN) or in association with various clinical conditions, suggesting that it could include several heterogeneous disorders. The familial form of IgAN has been increasingly recognized, supporting the suggestion that genetic factors could be involved in the disease pathogenesis, although it remains unclear whether the familial form is itself heterogeneous. METHODS: This study included 24 patients with a biopsy-proven IgAN from 11 unrelated families coming from five geographically distinct regions of Italy, and 90 of their relatives investigated for the presence of nephritis. Families were included in a genome-wide linkage analysis to identify loci responsible for the disease. RESULTS: Liver or systemic disease was not found in any case, and no hearing loss or ocular alterations were detected. Renal biopsy showed mesangial expansion at light microscopy, with glomerular sclerosis involving from 11 to 35% of glomeruli in eight patients. Ultrastructural examination revealed mesangial electron dense deposits along with a diffuse glomerular basement membrane (GBM) thinning typical of thin basement membrane disease (TBMD) in eight patients belonging to six families. Of the 90 relatives, 12 had "suspected IgAN", 73 were defined as "unaffected" and five as "probably unaffected". Families with co-existent TBMD failed to link to the IGAN1 locus. After a follow-up of 3-19 yrs, nine patients (37%) showed a progressive reduction in renal function and five of them reached end-stage renal disease (ESRD). CONCLUSION: These data demonstrate that familial IgAN is present outside geographically confined regions of Italy. Co-aggregation of IgAN with TBMD suggests that familial IgAN itself is a heterogeneous disorder and that inherited GBM abnormalities could be the first alteration, in some cases.

Plasma exchange treatment improves prognosis of antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis: a case-control study in 26 patients from a single center.

Twenty-six patients with Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (GN) were divided into two groups according to the acute phase treatment: drug therapy consisting of steroids and oral cyclophosphamide plus a plasma exchange (PE) course (group A, 13 patients) or drug therapy alone (group B, 13 patients). Group A patients had a more severe clinical picture and higher serum creatinine than group B (12.7 +/- 6.9 vs. 8.5 +/- 5.3 mg%); nine patients from group A (69%) and five from group B (38%) required dialysis. At follow up (mean 35 months) all patients treated with PE were alive: four of them were in end-stage renal disease. Among group B patients, three (23%) died in the acute phase; 6 (46%) needed renal replacement therapy at follow up. Of the dialysis-dependent patients, five out of nine from group A were free of dialysis, while in group B two out of five patients had died, two had entered a regular dialysis treatment and one had received a cadaver graft. These data suggest that PE may significantly improve the prognosis of patients with ANCA-associated crescentic GN even if they are not dialysis-dependent at the time of diagnosis.