Long-Term Remissions of Severe Pemphigus After Rituximab Therapy Are Associated with Prolonged Failure of Desmoglein B Cell Response

Abstract

Pemphigus is a severe blistering condition of the skin and mucosa caused by autoantibodies directed against desmogleins, which are a type of keratinocyte adhesion protein. B cell depletion by rituximab has short-term efficacy against pemphigus. We aimed to assess the long-term course of pemphigus patients after B cell depletion and to understand the immunological mechanisms that mediate long-lasting remissions. We evaluated the clinical course of 22 pemphigus patients treated with rituximab after a 79-month median follow-up and compared the anti-desmoglein B cell response and B and T lymphocyte subpopulations and repertoire between patients who achieved complete remission (CR) and those who had incomplete remission (IR). Thirteen patients (59%) experienced CR during the study, including 10 patients off treatment and 3 patients with prednisone doses <10 mg/day; 9 patients had IR. A marked increase was observed in the ratio of CD19(+)CD27(-) naïve B cells to CD19(+)CD27(+) memory B cells. Indeed, patients in CR had a fourfold higher number of transitional B cells and interleukin-10-secreting regulatory B cells than those in IR. Furthermore, CR was associated with modification of the initial B cell repertoire and the disappearance of desmoglein-specific circulating immunoglobulin G-positive (IgG(+)) B lymphocytes, whereas a skewed B cell repertoire was observed in patients in IR. Thus, a blockage of B cell maturation, a prolonged repopulation with naïve B cells, and a delayed reappearance of memory B cells, which resulted in the disappearance of circulating desmoglein-specific IgG(+) B lymphocytes, contribute to the long-lasting effectiveness of rituximab for treating pemphigus.

Pathogenic IgG Antibodies against Desmoglein 3 in Pemphigus Vulgaris Are Regulated by HLA-DRB1*04:02–Restricted T Cells

“…This finding is in line with previous studies in rheumatoid arthritis which showed that serum IgG titers against pathogens such as pneumococcal capsular polysaccharides or TT were not significantly affected by rituximab (43). The dramatic inhibitory effect of rituximab on anti-Dsg3 IgG serum levels strongly suggests that their secretion largely depends on short-lived autoreactive plasma cells (44). Moreover, Dsg3-specific IgG-producing B cells were detected in PV patients by ELISPOT assay upon ex vivo stimulation of their peripheral lymphocytes with Dsg3 (45).…”

Adjuvant rituximab treatment for pemphigus: A retrospective study of 45 patients at a single center with long‐term follow up

“…Recently, Colliou et al reported a 77% relapse rate, comparable to our study, after a median 79-month follow-up period. 17 Taken together, we can suggest that a single cycle of rituximab may not achieve a long-standing remission for pemphigus.…”

Human regulatory B cells in health and disease: therapeutic potential

“…hi B cells and IL-10 production compared with untreated patients or patients not responding to therapy (53). It is possible that Bregs may contribute to restoration of tolerance in rituximabresponsive pemphigus patients.…”