Most celiac patients failing a gluten-free diet are not refractory; they are eating hidden gluten or have a coexisting condition, so a structured non-responsive differential precedes any refractory workup. When refractory disease is genuine, the type one versus type two split on intraepithelial lymphocyte phenotype separates a steroid-responsive disease with good survival from a pre-lymphoma syndrome. The malignancy spectrum, enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and small-bowel adenocarcinoma, is the payoff of getting that distinction right. Topics covered Non-responsive celiac differential Refractory celiac type 1 vs type 2 Intraepithelial lymphocyte phenotyping Enteropathy-associated T-cell lymphoma Ulcerative jejunitis Small-bowel adenocarcinoma Small-bowel imaging and surveillance Key decisions Persistent symptoms on a gluten-free diet are most often ongoing gluten exposure; the first step is a dietitian reviewing the diet line by line, not a refractory workup or steroids. Work the non-responsive differential in order: incomplete gluten avoidance, incorrect original diagnosis, coexisting condition (microscopic colitis, pancreatic insufficiency, overgrowth, IBS), then drug-induced enteropathy (olmesartan, NSAIDs, mycophenolate) before invoking refractory disease. Send duodenal biopsies for flow cytometry in saline or tissue medium, not formalin, because formalin destroys the surface markers; take extra samples for histology and T-cell clonality. Type 1: polyclonal, surface CD3 and CD8 retained, abnormal fraction under 20 percent, treated with open-capsule budesonide, good prognosis; check TPMT before a thiopurine. Type 2: over 20 percent abnormal clonal lymphocytes with loss of surface CD3 and CD8 but retained cytoplasmic CD3, monoclonal clonality, a pre-lymphoma diagnosis treated with cladribine and autologous transplant at a tertiary center. Worsening of a stable celiac course on a verified diet, even with negative transglutaminase, mandates capsule endoscopy plus CT or MR enterography and device-assisted enteroscopy to find lymphoma, ulcerative jejunitis, or adenocarcinoma. For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com. Questions or feedback: [email protected]. (00:00) - The non-responsive celiac differential (00:51) - Working the differential in order (02:21) - When it is truly refractory: type 1 vs type 2 (03:04) - Phenotyping the lymphocytes on flow cytometry (05:26) - The malignancy spectrum (05:56) - T-cell lymphoma and ulcerative jejunitis (08:44) - Small-bowel adenocarcinoma (09:40) - Surveillance and pulling it together

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