Gastrointestinal Tuberculosis after Vedolizumab Treatment in Inflammatory Bowel Disease: Brief Report

Abstract

Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody used to treat patients with moderate to severe inflammatory bowel disease who are refractory or intolerant to conventional therapy. It has an excellent safety profile in terms of the risk of serious or opportunistic infections primarily due to its gut-selective action. The reported risk of tuberculosis after vedolizumab treatment is considered very low. We report two cases of gastrointestinal tuberculosis in patients on vedolizumab who were tested negative for latent tuberculosis infection screening.

Keywords

microbiology - pathology - endoscopy - tuberculosis - vedolizumab

Introduction

Vedolizumab is a gut-specific antagonist of α4β7 integrin used in patients with inflammatory bowel disease (IBD) and is known for its excellent safety profile. The reported risk of tuberculosis (TB) on vedolizumab treatment is very low. This is in contrast to patients who are being treated with antitumor necrosis factor (anti-TNF) drugs where the reported incidence of TB is high. We report two cases of gastrointestinal TB (GITB) in patients treated with vedolizumab despite screening negative for latent TB infection (LTBI).

Case 1

A 43-year-old man was diagnosed with ulcerative colitis (E3; moderate severity at diagnosis) 3 years ago. He was induced with oral prednisolone and maintained with azathioprine. He was in clinical and biochemical remission for almost 2.5 years with regular follow-up. He had flare of ulcerative colitis on azathioprine with moderate to severe disease activity. After a detailed discussion with the patient, therapy with vedolizumab was planned and azathioprine was stopped. A checklist prior to biologic initiation was done and he was negative for latent TB (tuberculin skin test: negative; interferon gamma release assay: negative; and high-resolution computed tomography [HRCT] of the thorax: normal). He had significant improvement in his symptoms 6 weeks after starting vedolizumab. At around 4 months after starting vedolizumab, he presented with increased frequency of stools (7–8 bowel movements/d) with no blood or mucous and significant rectal pain. Investigations revealed mild leukocytosis, elevated C-reactive protein, and normal albumin levels. Stool routine had numerous pus and red blood cells. Stool cultures had no growth, and the stool test for Clostridioides difficile infection was negative. Unprepared sigmoidoscopy revealed patchy loss of vascular pattern, granularity, and mild friability along with two deep oval-shaped ulcers in the lower rectum (8–10 mm; [Fig. 1A]). Biopsies revealed chronic active colitis with caseating granulomas measuring 10 mm and Langhans cells suggesting GITB ([Fig. 1B]). No inclusion bodies were seen on histopathology and immunohistochemistry on the tissue was negative for Cytomegalovirus infection. Acid–fast bacilli smear with Ziehl–Neelsen stain was negative. Fungal stain was negative. Contrast-enhanced computed tomography (CECT) of the abdomen and thorax was done. Wall thickening was observed in the rectum and terminal ileum. No pulmonary involvement was seen. Vedolizumab was withheld and he was started on antitubercular therapy (ATT). Clinical improvement in symptoms was seen from 3 to 4 weeks and healing of the discrete rectal ulcers was seen at 12 weeks. Vedolizumab was restarted 6 weeks later and ATT was given for 6 months. Currently, the patient is on follow-up on vedolizumab for more than a year and is in clinical, biochemical, and endoscopic remission.

Fig. 1 (A) Unprepared sigmoidoscopy: features of ulcerative colitis with deep, oval-shaped ulcers (new onset). (B) HPE from the ulcers: epithelioid granuloma (borders marked with arrows) with Langhans giant cells (asterisk).

Case 2

A 19-year-old woman, was diagnosed with ulcerative colitis (left-sided colitis with moderate severity). She had steroid-dependent and thiopurine refractory disease. She was started on vedolizumab after a negative latent TB screen (chest X-ray, tuberculin skin test, and interferon gamma release assay). Clinical and endoscopic remission was documented 6 months later. She reported an increased stool frequency without any bleeding at 16 months after initiation of vedolizumab. Colonoscopy done revealed multiple round to ovoid ulcers of variable size (largest 1.5 cm) in the terminal ileum ([Fig. 2A]) and ileocecal valve ([Fig. 2B]) with normal colonic mucosa. The biopsies from the ileal ulcers revealed multiple granulomas and acid–fast bacilli smear with Ziehl–Neelsen stain was positive ([Fig. 2C] and [D]). The patient was initiated on standard four-drug ATT and showed resolution of symptoms. Repeat colonoscopy at 12 weeks showed a normal terminal ileum, and vedolizumab was restarted and ATT continued for another 12 weeks.

Fig. 2 (A) Ileal ulcer. (B) Ileocecal valve ulcer. (C) Hematoxylin and eosin stain images from the ileal ulcers showing granuloma. (D) Acid–fast bacilli positivity with Ziehl–Neelsen stain (encircled in red).

Discussion

Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody used to treat patients with moderate to severe IBD who are refractory or intolerant to conventional therapy. Various guidelines currently recommend use of vedolizumab as a first-line drug in patients with moderate to severe disease.[1] [2] It has an excellent safety profile in terms of the risk of serious or opportunistic infections primarily due to its gut-selective action. There were initial concerns regarding increased risk of gastrointestinal infections with vedolizumab due to its effect on lymphocyte trafficking of the gastrointestinal tract. However, long-term data in phase 3 and 4 studies have demonstrated a favorable safety profile of vedolizumab.[3] [4] [5] The reported risk of TB after vedolizumab treatment is considered very low (0.6%)[3] [6] [7] in the west as well as some counties in the east (South Korea with intermediate risk of TB[8]). The risk of TB in patients on anti-TNF drugs is much higher at 8 to 10%.[9] [10] Postmarketing global data of over 208,050 patients on vedolizumab showed 9 cases of TB (5 in Crohn's disease and 4 in ulcerative colitis): 1 cutaneous, 1 gastrointestinal, 3 latent, and 4 in unspecified locations.[5]

We report two cases of GITB in patients on vedolizumab. Both the patients were negative for LTBI screening, and azathioprine was stopped prior to starting vedolizumab. The first patient developed GITB 4 months after starting vedolizumab and the second patient 16 months later. No lymphadenopathy or pulmonary involvement was seen in both the patients. These findings are slightly different in comparison to patients with anti-TNF-related TB where pulmonary or lymph node involvement is more frequent.[9] The possibility of gut-selective action of vedolizumab predisposing to isolated gastrointestinal involvement in these two cases needs to be speculated.

These two case reports bring old and new issues for consideration. First, it reiterates the need for stringent screening for TB in patients being started on non-anti-TNF biologics as well, particularly in TB endemic regions. The ideal LTBI screening test is, however, elusive at this point as the discussed patients were negative for LTBI with the available tests. Second, the specific effects of gut immunity while using adhesion molecules pertaining to granulomatous disease like TB need further scientific evaluation. Finally, this study emphasizes the requirement of a national biologic registry and outlines the guidelines for TB screening, considering the rising incidence of IBD in India.

Conflict of Interest

None declared.

Acknowledgments

None.

Conference Presentation

This work has not been presented at any conference or meeting.

Ethical Statement

Informed consent was taken from both the patients.

Authors' Contributions

All the authors made substantial contributions to the design of the work. K.V.N. and V.S. drafted the work and N.B. revised it critically for important intellectual content. P.P., R.A., and N.P. contributed in compiling the endoscopy images, and K.V. contributed to the pathology images.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Publication History

Received: 07 October 2024

Accepted: 09 January 2025

Article published online:
06 March 2025