Development of Celiac Disease After Immunotherapy for Psoriasis, Breast Cancer, and Renal Cell Carcinoma: A Case Series

Introduction: Immune-checkpoint inhibitors are associated with colitis and occasionally with celiac disease. We now report 3 cases of celiac disease after non-immune checkpoint inhibitor biologic agents. Case Description/Methods: Case 1. A 21-year-old woman with psoriasis on ixekizumab (IL-17A antagonist) and recent dose of risankizumab (IL-23A antibody) presented with abdominal pain, diarrhea, and bloating. Her workup revealed selective IgA deficiency and elevated tTG IgG and gliadin IgG. Colonoscopy showed lymphocytic colitis, and she started budesonide and gluten free diet with some improvement. Ixekizumab was stopped due to association with inflammatory bowel disease and microscopic colitis, and symptoms resolved. She received risankizumab, and symptoms recurred. Repeat endoscopy and colonoscopy showed nodular mucosa of the colon and terminal ileum and increased intraepithelial lymphocytes in the duodenum. Case 2. A 49-year-old woman with invasive ductal carcinoma was treated with leuprolide, exemestane, trastuzumab and pertuzumab (anti-HER2 antibodies) and developed severe watery diarrhea requiring hospitalization for electrolyte abnormalities and total parenteral nutrition. Diagnosis of celiac disease was confirmed by serologies and biopsy. Discontinuation of pertuzumab (previously associated with colitis and celiac disease) and gluten free diet led to resolution of symptoms. Other medications were resumed without issue. Case 3. An 82-year-old man with metastatic renal cell carcinoma was treated with axitinib, complicated by diarrhea requiring dose reduction, and pembrolizumab, discontinued due to colitis requiring prednisone, then cabozantinib, complicated by diarrhea which persisted after dose reduction. Endoscopy showed celiac disease with collagenous sprue (Figure 1). He started a gluten free diet, but had persistent diarrhea and weight loss, which improved on budesonide. Symptoms were then controlled on gluten-free diet alone, and cabozantinib was continued. Discussion: The above immunotherapies may have disrupted signaling pathways involving CD8+ T cells and precipitated de novo celiac disease or unmasked latent previously undiagnosed celiac disease. To our knowledge, this is the first case report of celiac disease after ixekizumab and risankizumab therapy. It is important to consider celiac disease in the differential for diarrhea after immunotherapy as it heavily impacts management and may eliminate the need for dose reductions, steroid courses, or cessation of therapy (see Table 1).Figure 1.: Duodenal Biopsy of Case 3, celiac disease in an 82-year-old man with metastatic renal cell carcinoma treated with axitinib, pembrolizumab, and cabozantinib (A). Routine HandE staining of a duodenal biopsy showed subtotal to total villous atrophy, (B). Duodenal biopsy with thickened sub-epithelial collagen layer highlighted on trichrome stain, (C). Duodenal biopsy with intraepithelial lymphocytosis confirmed by CD3 immunohistochemistry. Table 1. - Immunotherapies and Presentations of Celiac Disease Immunotherapy Indication Presenting Symptoms Diagnoses Ixekizumab (anti IL-17), risankizumab (antil IL-23) Psoriasis Abdominal pain, watery diarrhea, bloating Celiac disease, lymphocytic colitis, IgA deficiency Trastuzumab, pertuzumab Breast cancer Watery diarrhea, weight loss Celiac disease Pembrolizumab, axitinib, cabozantinib Renal cell carcinoma Watery diarrhea, abdominal cramps, tenesmus, and bleeding Celiac disease, collagenous sprue