Lymphoproliferation Under Tumor Necrosis Factor Blockade: Parotid Mucosa‐Associated Lymphoid Tissue Lymphoma in Crohn Disease With Sjögren Disease

Patients with primary Sjögren disease (pSjD) carry a substantially increased baseline risk of extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT).1 When pSjD coexists with Crohn disease (CD) within inflammatory bowel disease (IBD), biologic selection must balance intestinal control with oncologic safety.2 We report a woman with pSjD and newly diagnosed CD who developed parotid MALT lymphoma shortly after initiation of a tumor necrosis factor inhibitor (TNFi). This case emphasizes prioritizing oncologic safety in multisystem autoimmunity and prompt tissue diagnosis with pathway withdrawal once suspicious signals arise. The patient, a 48-year-old woman, had a 6-year history of SjD. In 2021, she tested positive for anti-SSA, with an antinuclear antibody (ANA) titer of 1:80, and a minor salivary gland biopsy demonstrated focal lymphocytic sialadenitis with a focus score ≥1 focus per 4 mm² of glandular tissue. On August 12, 2024, she was admitted for worsening rectal bleeding and anal prolapse sensation. Laboratory tests revealed elevated markers of inflammation with mild anemia; her fecal calprotectin level was 786.64 μg/g (Table S1). Abdominal computed tomography demonstrated segmental wall thickening of the terminal ileum and colon (Figure 1A). Ileocolonoscopy showed rectal mucosal edema with petechiae, herpetiform lesions with purulent exudate at the ileocecal valve and terminal ileum (Figure 1B), and a circumferential edematous anorectal ring causing luminal narrowing. Histopathology revealed transmural chronic inflammation with skip lesions, noncaseating granulomas, and fissuring ulcers, establishing a diagnosis of CD (Figure 1C). Adalimumab treatment began on August 14, 2024, with standard induction and maintenance. Two months later, she developed marked bilateral parotid enlargement and cervical lymphadenopathy with systemic inflammatory exacerbation: C-reactive protein level of 16.24 mg/L, rheumatoid factor level of 51 IU/mL, interleukin-6 (IL-6) level of 19.48 pg/mL, and interferon-γ level of 9.37 pg/mL. Autoantibody levels rose (ANA level of 426.30 arbitrary units [AU]/mL; anti-SSA IgG level of 84.2 AU/mL). Lymphocyte immunophenotyping showed a CD19+ B cell percentage of 17.9% and a CD4+:CD8+ ratio of 0.8. The EULAR Sjögren's Syndrome Disease Activity Index was 18, and the EULAR Sjögren's Syndrome Patient Reported Index was 8 (Table S2). Parotid ultrasonography findings met Fidelix grade 3 criteria (≥3 hypoechoic foci >5 mm per gland, irregular ductal dilatation >2 mm, heterogeneous echotexture with posterior attenuation). The largest nodules measured 15 × 8 mm (parotid), 13 × 9 mm (left submandibular), and 14 mm (right submandibular) (Table S3). Magnetic resonance imaging (MRI) findings favored a lymphoproliferative process (Figure S1). Ultrasound-guided core-needle biopsy (CNB) of the parotid gland showed diffuse lymphoid proliferation with lymphoepithelial lesions (Figure 1D); immunohistochemistry findings were consistent with MALT lymphoma (Figure 1E). Cervical lymph node ultrasound-guided CNB demonstrated reactive lymphoid hyperplasia (Figure S2). Given the evidence of pSjD with B cell activation and concordant imaging/pathology, TNFi was discontinued and a B cell–directed strategy was planned. Acute bacterial/viral parotitis, IgG4-related disease, sarcoidosis, and reactive hyperplasia were considered. Given the pSjD background, a Fidelix grade 3 ultrasound phenotype, MRI suggesting lymphoproliferation, and ultrasound-guided CNB with lymphoepithelial lesions and a MALT immunophenotype favored parotid MALT lymphoma. For IBD classification, terminal-ileal involvement with skip distribution and noncaseating granulomas supported CD rather than ulcerative colitis. Adalimumab was stopped and prednisone plus rituximab (RTX) 500 mg every four weeks was initiated. After three months, parotid/cervical nodes regressed (Figure 1F, Table S3), SjD improved, and the peripheral CD19+ B cell percentage fell to 0.2% to 0.3% (Table S2), indicating effective B cell depletion. With fluctuating bowel symptoms and persistently elevated inflammatory indices, ustekinumab (UST; IL-12/23 blockade) was selected for CD maintenance. During follow-up, CD activity improved and the parotid MALT remained in remission. In this patient with quiescent pSjD, TNFi for CD was temporally associated with reactivation of B cell disease and development of parotid MALT lymphoma. Although causality remains disputed, rapid salivary gland or cervical node enlargement soon after TNFi initiation should be treated as a safety signal warranting urgent tissue diagnosis.3 Mechanistically, sustained BAFF up-regulation and ectopic germinal centers in pSjD promote B cell survival and clonal selection,4 while chronic CD mucosal inflammation provides antigenic drive and may blunt immune surveillance,5 together predisposing to marginal-zone expansion. In this patient, RTX targeted both aberrant B cell activation and lymphoma control; UST then maintained CD control without TNF re-exposure, aligning therapy by organ and pathway to maximize safety. For patients with multiple autoimmune comorbidities, lymphoma risk should be embedded in baseline assessment and follow-up; early postbiologic asymmetric, progressive salivary gland/lymph node enlargement, especially with new solid nodules or low C4 levels, should prompt ultrasound-guided CNB, with timely transition to safer alternatives. In pSjD with newly diagnosed CD, rapid glandular or cervical node enlargement after TNFi initiation warrants urgent ultrasound-guided CNB; discontinuing TNFi with RTX-based B cell depletion can balance oncologic safety with inflammation control, with subsequent intestinal management via non-TNF pathways under close surveillance. This case supports pathway-segmented, multidisciplinary management in multisystem autoimmunity to mitigate lymphoma risk. All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Li confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements. Appendix S1: Supplementary Information Disclosure Form: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.