Behçet’s disease (BD), a chronic multisystemic inflammatory disorder characterized by recurrent mucocutaneous ulcers, ocular inflammation, and vascular involvement, exhibits a strong genetic predisposition, particularly among populations along the historic Silk Road (1). While its pathogenesis remains incompletely elucidated, dysregulated immune responses involving Th1/Th17 polarization and cytokine-driven inflammation are central to disease progression (1). Emerging evidence highlights a distinct clinical subset of BD complicated by myelodysplastic syndrome (MDS), a hematologic malignancy marked by cytopenias and clonal chromosomal abnormalities (2). Notably, trisomy 8—a karyotypic aberration observed in 7–9% of primary MDS cases—is present in over 80% of BD-MDS patients, suggesting a unique pathophysiologic interplay (3–5). These patients often present with severe gastrointestinal (GI) involvement, including deep ileocecal ulcers requiring surgical intervention, alongside hematologic abnormalities such as macrocytic anemia and thrombocytopenia (6–8). Despite aggressive management, BD-MDS patients exhibit poor responses to conventional therapies, including corticosteroids and tumor necrosis factor-alpha (TNF-α) inhibitors, with mortality rates exceeding 25% (6, 9). This underscores the urgent need for novel therapeutic strategies targeting the underlying molecular drivers of refractory disease.

The JAK-STAT signaling pathway, a critical mediator of cytokine signaling, has emerged as a key contributor to BD pathogenesis. Upregulated JAK1 and STAT3 activation in monocytes and T cells drives the production of pro-inflammatory cytokines (e.g., IL-6, IL-17, IFN-γ), perpetuating systemic inflammation and mucosal damage (10). Preclinical and clinical studies suggest that selective JAK inhibitors, such as upadacitinib, may attenuate Th1/Th17 responses and induce remission in refractory BD (10). However, evidence supporting their efficacy in genetically complex BD-MDS cases, particularly those with dual trisomy 8/9, remains scarce.

Here, we present a case of refractory intestinal BD complicated by MDS and dual trisomy 8/9, a rare karyotypic profile associated with heightened treatment resistance. Through immunohistochemical analysis of intestinal specimens, we further elucidate the role of JAK-STAT hyperactivation in BD-associated vascular pathology. Our findings highlight the therapeutic potential of upadacitinib in this challenging patient population and provide mechanistic rationale for JAK inhibition as a targeted strategy in TNF-α inhibitor-resistant BD.

A 29-year-old female patient presented with a two-year history of recurrent oral ulcers and a one-year history of genital ulcers and thrombocytopenia. In August 2019, she was admitted due to acute small bowel perforation. Emergency laparotomy revealed a perforation 30 cm proximal to the ileocecal valve, accompanied by a deep ulcer in the terminal ileum ( Figures 1A, B ). Segmental resection of the ileum, ileocecal region, and ascending colon was performed, followed by end-to-end anastomosis. Histopathological examination of the resected specimen revealed submucosal vascular dilation, intimal hyperplasia of small arteries, and thrombi within the arterial and venous lumina. Postoperative diagnosis confirmed BD. A bone marrow biopsy performed due to persistent thrombocytopenia. Bone marrow biopsy was performed due to persistent thrombocytopenia. The biopsy revealed increased myeloblasts (1.6%), active erythroid hyperplasia (mainly intermediate/late-stage erythroblasts), and significant nuclear/cytoplasmic abnormalities in erythrocytes, with pathological cells comprising 38% of the erythroid lineage. Flow cytometry showed 1.1% CD34-positive immature myeloid cells. Karyotype analysis indicated trisomy 8 and trisomy 9 ( Figure 1C ). Although next-generation sequencing was recommended, the patient declined due to cost. The diagnosis of MDS was confirmed based on these findings. The patient was classified as International Prognostic Scoring System (IPSS) intermediate-2 (11) and revised IPSS (IPSS-R) high-risk (12). However, the patient refused allogeneic hematopoietic stem cell transplantation due to associated risks and costs. Initial treatment with thalidomide (50 mg/day) was discontinued after six months due to peripheral neuropathy. In July 2020, a recurrent oral ulcer prompted the initiation of prednisolone (40 mg/day), which was gradually tapered. However, disease relapse occurred in March 2021 (prednisone 10 mg/day), characterized by new oral ulcers and right mid-abdominal pain. Colonoscopy revealed an anastomotic ulcer, prompting infliximab induction (5 mg/kg) at weeks 0, 2, 6, and 8, followed by maintenance therapy every 8 weeks. A follow-up colonoscopy at three months confirmed ulcer healing, and maintenance infliximab therapy (every 8 weeks) was initiated.

In August 2021, the patient developed a perianal abscess with necrotizing fasciitis ( Figure 1D ). She recovered well after surgical drainage and continued regular infliximab therapy. Despite regular infliximab, disease activity recurred in December 2022, marked by oral ulcers, abdominal pain, and elevated CRP. Infliximab dosing was escalated to every 4 weeks, yet symptoms progressed. By February 2024, colonoscopy revealed recurrent anastomotic and descending colon ulcers ( Figures 1E, F ). Infliximab was discontinued, and upadacitinib (45 mg/day) was initiated.

Clinical improvement was noted within one week, with complete resolution of abdominal pain. A repeat colonoscopy performed three months after the initial procedure demonstrated mucosal healing ( Figures 1G, H ). The platelet count remained subnormal (95×10^9/L; reference range 150–450×10^9/L), but the CRP level normalized, and no active ulcers were observed. Dose reduction to 15 mg/day resulted in recurrent oral ulcers, necessitating maintenance therapy with 30 mg/day. At the last follow-up (March 2025), the patient remained asymptomatic on upadacitinib 30 mg/day. The patient’s clinical course is shown in Figure 2 .

Based on these clinical observations, we performed IHC staining on surgically resected intestinal specimens from the patient. The study was approved by the Ethics Committee of the Shengjing Hospital of China Medical University (approval number: 2024PS1286K). The expression of phosphorylated JAK-1, JAK-2, JAK-3, STAT1, and STAT3 was detected in the mucosal epithelium, mucosal stroma, intrinsic glands, small blood vessels, and peripherally infiltrating inflammatory cells within the submucosal layer ( Figures 3A-E ). Notably, phosphorylated JAK-1 and STAT3 exhibited strong expression in the lumen of occluded small vessels in the submucosal layer, smooth muscle cells, and peripherally infiltrating inflammatory cells ( Figures 3F, G ). These findings suggest that upadacitinib may represent a promising therapeutic option for patients with Behçet’s disease (BD) who are refractory to TNF-α inhibitors.

The present case illustrates the sustained efficacy of upadacitinib, a selective JAK1 inhibitor, in achieving remission for refractory intestinal BD complicated by MDS and dual trisomy 8/9—a rare and genetically complex phenotype. MDS is increasingly recognized for its association with autoimmune and autoinflammatory manifestations, which significantly influence clinical trajectories and outcomes. These manifestations, ranging from mucocutaneous involvement to systemic inflammatory syndromes, are mechanistically linked to somatic mutations (e.g., RUNX1, TP53, TET2, ASXL1) and epigenetic alterations that disrupt immune cell homeostasis and promote dysregulated cytokine signaling (13). Aberrant innate immune activation, mediated by NLRP3 inflammasome hyperactivity and oxidative stress, further amplifies inflammatory cascades (14, 15). Additionally, dysfunction within the bone marrow microenvironment, including stromal cell abnormalities, contributes to chronic inflammation and hematopoietic failure (16). Notably, somatic mutations such as RUNX1 have been implicated in atypical inflammatory presentations preceding MDS progression, underscoring the interplay between clonal hematopoiesis and immune dysregulation (17). While genetic profiling was unavailable in our case due to patient refusal, the observed dual trisomy 8/9—a karyotype associated with aggressive disease phenotypes—likely exacerbates treatment resistance through undefined molecular mechanisms. This highlights the critical need for comprehensive genomic analyses in similar cases to elucidate genotype-phenotype correlations and identify actionable therapeutic targets.

Emerging evidence supports JAK inhibition as a promising strategy for cytokine-driven inflammatory disorders, particularly in cases refractory to conventional biologics. By reviewing the published literature associated with JAK inhibitors in treatment of BD, we identified 13 studies or case reports on BD treated with JAK inhibitors, including 3 pilot studies, 2 case series, and 8 case reports, totaling 69 cases. Among these, 32 patients received tofacitinib (18–23), 30 received baricitinib (24–26), and 7 received upadacitinib (27–32) ( Table 1 ).

This case reinforces JAK inhibition as a promising strategy for TNF-α inhibitor-resistant BD, even in the context of dual trisomy 8/9 and MDS. The dose-dependent response and mechanistic correlates underscore the importance of individualized therapy. While preliminary, these findings warrant further investigation through randomized controlled trials to establish standardized protocols for JAK inhibitor use in complex BD phenotypes.