Takayasu and Giant Cell Arteritis Unmasked by Vedolizumab as Paradoxical Reactions: Two Case Reports

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by relapsing and remitting mucosal inflammation of the colon.1 The advent of biologics has significantly improved the management of UC, with vedolizumab (VDZ) as a key therapeutic option.2 VDZ is a humanized monoclonal antibody that targets the α4β7 integrin on the surface of circulating T lymphocytes.3 By blocking the interaction between α4β7 integrin and mucosal vascular addressing cell adhesion molecule–1 (MAdCAM-1), which is expressed explicitly on the vascular endothelium of the gastrointestinal tract, VDZ selectively inhibits lymphocyte trafficking to the gut.3 Due to its gut-selective mechanism, VDZ is generally associated with a low risk of systemic adverse events compared to other biologics like tumor necrosis factor (TNF) inhibitors.4 However, paradoxical inflammatory reactions, such as IgA and cutaneous vasculitis, following VDZ administration have been sporadically reported in patients with IBD.5-10 Among these, the development of systemic large-vessel vasculitis (LVV) is an exceptionally rare occurrence, with its underlying pathophysiology remaining largely unknown. In this report, we present two distinct cases of LVV: Takayasu arteritis (TAK) and giant cell arteritis (GCA) in one young male patient and one elderly male patient, respectively, both of which developed shortly after VDZ initiation for UC. These cases highlight the potential of gut-selective integrin inhibition to influence systemic inflammatory pathways, possibly by redistributing lymphocyte migration to nonintestinal vascular tissues. Ethical review and approval were not required for this study involving human participants in accordance with the applicable local legislation and institutional requirements. The data supporting these study findings are available from the corresponding author upon reasonable request. The patient, a 17-year-old boy, with a family history of type 1 diabetes was diagnosed with UC two years ago. At the time of referral to our department, the patient was receiving prednisolone (PSL) 5 mg/day, azathioprine 50 mg/day, and mesalazine 400 mg/day and had received two infusions of VDZ. After initiating VDZ, the patient developed persistent fever, headache, and general malaise, whereas hematochezia did not improve. Laboratory investigations revealed a white blood cell count of 12,700/μL, hemoglobin of 9.8 g/dL, platelet count of 743,000/μL, and elevated C-reactive protein (CRP) level of 11.34 mg/dL. Both the myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and proteinase 3 (PR3)-ANCA levels were within normal limits. Positron emission tomography–computed tomography (PET/CT) imaging showed intense fluorodeoxyglucose (FDG) accumulation in both the pulmonary artery and the aortic wall (Figure 1A). Malignant tumors, infectious diseases, and other vasculitides were excluded as differential diagnoses, and TAK was established. Treatment was initiated with PSL at 60 mg/day (approximately 0.8 mg/kg), which resolved the fever and normalized the CRP levels. The patient was subsequently discharged in stable condition. The patient, a 72-year-old man, with a history of prostate cancer and diabetes was diagnosed with UC 13 years before admission. After a long period of remission without medication, the patient had relapse characterized by diarrhea and hematochezia in the previous year. He was treated with high-dose PSL (40 mg/day); however, the response was inadequate and glycemic control deteriorated. Consequently, at the time of presentation to our department, PSL was discontinued, and the patient was receiving 6-mercaptopurine (6 mg/day) and three doses of VDZ but with no resolution of hematochezia. Two months after the third dose, the patient presented with fever, malaise, and weight loss of 3 kg within one month. Physical examination revealed pale palpebral conjunctiva, suggesting anemia, but no temporal artery tenderness nor carotid bruits. Laboratory findings showed an elevated white blood cell count of 7,200/μL, hemoglobin of 8.4 g/dL, high platelet count of 610,000/μL, and CRP level of 11.69 mg/dL. Immunologic testing was negative for MPO-ANCA, whereas PR3-ANCA was mildly elevated at 19.5 U/mL (normal range <3.4 U/mL); however, there were no organ manifestations suggestive of ANCA-associated vasculitis. A contrast-enhanced CT scan revealed wall thickening, with enhancement from the subclavian artery to the aorta. Subsequent PET/CT imaging demonstrated significant FDG accumulation in the aortic wall. Based on these findings, malignant tumors, infectious diseases, and other vasculitides were excluded, and the patient was diagnosed with a large-vessel GCA. Interestingly, upon admission and cessation of VDZ, the patient's markers of inflammation and liver enzymes improved with rest, and radiologic wall thickening also resolved without specific immunosuppressive therapy for GCA after six months (Figure 1B and C). His UC maintained in remission with 6-mercaptopurine. The association between UC and TAK has been increasingly recognized, despite the rarity of both conditions in Japan.11 Epidemiologic and genetic studies have demonstrated shared epidemiologic and genetic susceptibility, particularly with the HLA-B*52:01 allele, which is a shared risk factor for both diseases.12 In addition, an association between GCA and IBD has been reported.13 Long-term safety data have indicated that VDZ is generally well tolerated, with no new safety signals identified during extended follow-up.14 Musculoskeletal symptoms have been reported during VDZ therapy; however, these have been considered potentially related to prior TNF inhibitor withdrawal.15, 16 Several cases of TAK developing during infliximab therapy for UC have been reported, suggesting that TAK may represent either an extraintestinal manifestation of UC or a paradoxical immune-mediated reaction to TNF inhibitors.17, 18 One proposed mechanism involves immune complex deposition within the vasa vasorum, which may trigger vascular inflammation.19 In the present report, we describe two cases of LVV, such as TAK and GCA, occurring after the initiation of VDZ, a gut-selective α4β7 integrin antagonist. The development of vasculitis as a paradoxical reaction to VDZ is rare but has been documented in cutaneous cases.5, 6 These cases reported cutaneous or nodular vasculitis that developed after VDZ induction and showed a favorable response to glucocorticoids, consistent with our first case. In addition, several case reports have described IgA vasculitis following VDZ treatment.7-10 IgA vasculitis is a small-vessel vasculitis, and has been reported in patients with UC during treatment with TNF inhibitors, suggesting that biologic therapies targeting intestinal inflammation may, in certain contexts, promote paradoxical vasculitic reactions.20 IgA plays a central role in mucosal immunity, particularly within the gastrointestinal tract. VDZ selectively inhibits lymphocyte trafficking to the gut by blocking α4β7–MAdCAM-1 pathway, altering the distribution and functional balance of mucosal immune cells. One hypothesis is that the suppression of lymphocyte homing to the intestinal mucosa paradoxically promotes immune cell “redistribution” to extraintestinal sites, such as the skin or vascular tissues, thereby facilitating vasculitic manifestations. Although the precise mechanisms remain unclear, the dysregulation of IgA-mediated immune responses induced by gut-selective immune modulation may contribute to the development of vasculitis in genetically predisposed individuals. When the gut-specific trafficking pathway is blocked, α4β7-positive lymphocytes might be redirected to other vascular beds where alternative adhesion molecules, such as vascular cell adhesion molecule–1or intercellular adhesion molecule–1, are expressed. This “trafficking shift” hypothesis has not been proposed in other cases of vasculitis following VDZ treatment. In terms of GCA in case 2, markers of inflammation and vascular wall thickening improved spontaneously upon discontinuation of VDZ, further supporting a drug-induced paradoxical reaction. Although UC predisposes patients to TAK, selective blockade of gut-homing lymphocytes may exacerbate or unmask latent systemic vascular inflammation. Furthermore, in both cases, the gastrointestinal symptoms of UC did not improve clinically despite VDZ administration. This lack of response in the target organ suggests that although VDZ successfully blocked the α4β7-MAdCAM-1 pathway in the gut, the inflammatory lymphocytes that were excluded from the intestinal mucosa may have been redirected to the systemic circulation and subsequently infiltrated the large-vessel walls. The refractory nature of intestinal inflammation at the time of LVV onset may serve as a clinical clue, indicating a massive redirection of the systemic inflammatory burden toward nonintestinal vascular tissues. Clinicians should remain vigilant for signs of systemic vasculitis such as unexplained fever, general malaise, and inflammatory response in patients receiving VDZ for IBD, especially given the potential for paradoxical inflammatory events. 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 Sakai 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. Disclosure form. 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