The Histologic Spectrum of Rituximab-Associated Common Variable Immunodeficiency-Like Enteropathy

Rituximab (RTX) is a monoclonal anti-CD20 antibody widely used to treat B-cell neoplasms and autoimmune conditions. RTX has recently been linked to an enteropathy characterized by diarrhea, malabsorption, and hypogammaglobulinemia, closely resembling common variable immunodeficiency (CVID) enteropathy. We present the first dedicated histopathologic assessment of RTX-associated CVID-like enteropathy. Study inclusion criteria were the presence of diarrhea, weight loss, or other gastrointestinal symptoms in the setting of current/prior RTX use and associated hypogammaglobulinemia. Twenty-two patients (15 male:7 female; mean age at biopsy/resection, 63.4 years) across 9 tertiary medical centers met inclusion criteria and had small bowel (N = 20) and/or colon (N = 17) specimens (biopsies/resections) available for review; 71.4% of specimens dated from ≤5 years of last RTX dose. Cases were systematically evaluated by gastrointestinal pathologists at each institution. Key histologic features in the small bowel included sparse/absent lamina propria plasma cells (N = 10; 50%), intraepithelial lymphocytosis (N = 12; 60%), villous atrophy (N = 11; 55%), increased crypt apoptotic bodies (N = 6; 30%), and active inflammation (N = 5; 25%). Common features in the colon included sparse/absent plasma cells (N = 7; 41.2%), increased crypt apoptotic bodies (N = 7; 41.2%), active inflammation (N = 5; 29.4%), and intraepithelial lymphocytosis (N = 4; 23.5%). Goblet cell loss was appreciated in small bowel and/or colon specimens from 2 patients. Follow-up biopsies (interval, 2 months to 4 years) were available for 7 patients and largely recapitulated the histology of the index specimens, though 1 patient demonstrated improvement in villous blunting and intraepithelial lymphocytosis. In summary, the histologic spectrum of post-RTX CVID-like enteropathy encompasses lamina propria plasma cell depletion, increased crypt apoptotic bodies, small bowel villous atrophy, and goblet cell loss. While the underlying pathophysiology remains uncertain, the clinicopathologic picture may reflect post-RTX B-cell/plasma cell impairment. Although histologic findings may be subtle and variable, pathologists should be aware of this entity and should seek a history of RTX use in patients whose biopsies exhibit these CVID enteropathy-like features.