Anaphylaxis to a Vedolizumab Infusion following Drug Holiday in a Patient with Ulcerative Colitis: A Case Report

Vedolizumab is a commonly prescribed biologic agent due to its safety profile and clinical efficacy in patients with inflammatory bowel disease. A humanised monoclonal IgG1 antibody, vedolizumab, reduces gastrointestinal inflammation by selectively targeting the α4β7 integrin found on T cells, thereby inhibiting lymphocytic translocation via the gut endothelium to the intestinal mucosa [1]. Safety assessments for vedolizumab have demonstrated infrequent rates of infusion-related reactions in ≤5% of patients, with the majority being of mild to moderate severity [1, 2]. Anaphylaxis to vedolizumab is an exceedingly rare complication, with very few reported cases in the literature [1, 3]. Here, we present the first documented case of anaphylaxis to a vedolizumab infusion following a drug holiday. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543387).

A 65-year-old male with ulcerative colitis (proctosigmoiditis) was admitted to our medical day unit for re-induction of vedolizumab after previously receiving two doses of vedolizumab 30 months prior. He had a past medical history of metastatic melanoma (TNM stage IV) with brain metastases for which he had undergone a right frontal craniotomy and stereotactic radiotherapy followed by three cycles of nivolumab and ipilimumab immunotherapy. His immunotherapy was complicated by frequent daily bowel motions up to 10 times per day with associated rectal bleeding, for which he was diagnosed with immune checkpoint-mediated colitis (Common Terminology Criteria for Adverse Events Grade 4).

Following diagnosis of checkpoint-mediated colitis, the patient was initially managed with intravenous methylprednisolone pulse therapy followed by two salvage doses of infliximab at 10 mg/kg. Given the refractory nature of the patient’s symptoms to infliximab, he received a dose of vedolizumab induction therapy (300 mg) and then again at 2 weeks. There were no infusion-related reactions with either vedolizumab infusion. Despite the additional introduction of oral tacrolimus and budesonide enemas, the colitis remained refractory and the patient underwent a total laparoscopic colectomy and end-ileostomy. Histopathology of resected bowel demonstrated extensive chronic colitis from caecum to sigmoid colon, most severe within the distal ascending and transverse colon with patchy mucosal ulceration and crypt abscesses.

In the months following colectomy, the patient had progressive symptoms of proctitis for which he was commenced on mesalazine and budesonide foam enemas. Despite topical therapy, there was biochemical and sonographic evidence of active inflammatory disease with a faecal calprotectin of >8,000 μg/g, and mild proctitis seen on intestinal ultrasound. A flexible sigmoidoscopy showed mild-moderate proctosigmoiditis, with histology demonstrating acute inflammation on a background of chronic inflammatory changes. Given these histological findings and the timeframe of 27 months since last cycle of ipilimumab and nivolumab, vedolizumab was reintroduced for a diagnosis of ulcerative colitis. The drug holiday interval from the last vedolizumab infusion was 30 months.

On presentation to the medical day unit for reintroduction of vedolizumab, the patient reported feeling well and was haemodynamically stable. No prophylactic antihistamine, antipyretic nor corticosteroid was administered prior to commencement of the infusion. Vedolizumab 300 mg was commenced at a rate of 8.33 mL/min as per protocol. Halfway through the infusion, the patient experienced nausea and abdominal cramping. The infusion was ceased, and oral ondansetron 4 mg, oral cetirizine 10 mg, and intravenous hydrocortisone 100 mg were administered. He then became flushed with associated oropharyngeal angioedema, at which point a medical emergency response was activated. A total of 0.3 mg of intramuscular adrenaline, intravenous fluid resuscitation, and a further dose of hydrocortisone 100 mg IV were given. Due to concerns for airway comprise, the patient was urgently transferred to the intensive care unit where he was commenced on nebulised adrenaline 5 mL (1:1,000) and an adrenaline infusion at 3 μg/min. He remained stable in the intensive care unit with resolution of his angioedema, and the adrenaline infusion was ceased after 8 h. Tryptase levels were 45.6 μg/L (normal range 0.0–11.4 μg/L) at time of initial reaction, 36.6 μg/L at 4 h, and 22.2 μg/L at 24 h. The patient was discharged to the ward the following day.

To our knowledge, this case represents the first documented case of anaphylaxis to vedolizumab following a drug holiday. Current literature describes serious infusion reactions to vedolizumab as exceedingly rare, occurring in less than 1% of patients [1]. The incidence of anaphylaxis is even more uncommon, with integrated safety data from phase II and phase III clinical studies reporting only 3 out of 2,830 patients (0.11%) who received at least one dose of vedolizumab experiencing an anaphylactic-like reaction [1]. Notably, however, none of these incidences required administration of adrenaline. In other studies, no events of anaphylactoid reactions nor anaphylaxis were recorded [2]. We identified only one previous case report of anaphylaxis secondary to vedolizumab infusion in the literature; this case was managed with immunological desensitisation [3].

Cessation of biologic therapies leading to drug holidays may be recommended electively after periods of prolonged remission or surgery, as a response to adverse events, or for practical reasons such as travel. Recommencement of biologic therapies after drug holidays, effectively representing episodic therapy, can be associated with increased risks of both immediate and delayed immunogenically mediated infusion reactions [4, 5]. These reactions have most commonly been seen with anti-tumour necrosis factor (TNF) agents and infliximab in particular [4, 5].

Re-treatment with vedolizumab is associated with a low incidence of serious adverse events when compared with anti-TNF agents, presumably related to its lower immunogenicity [6, 7]. While the prevalence of antidrug antibodies was found to be higher in patients retreated with vedolizumab compared to continuous treatment, there is no observed correlation between immunogenicity and infusion-related reactions [7, 8]. This contrasts with other biologics such as infliximab, where episodic therapy is associated with much higher levels of antidrug antibodies and a corresponding increased risk of infusion reactions [4, 5].

Further, when compared with vedolizumab, the frequency of any infusion reactions in patients receiving episodic infliximab therapy is more common at rates varying from 14 to 17% of patients [5, 9, 10]. Despite a reported hypersensitivity reaction frequency of 18.1%, major adalimumab studies have thus far shown no cases of anaphylaxis, though it has been documented seldomly during post-marketing surveillance [8, 11]. No anaphylactic reactions or serum sickness-like reactions to golimumab were reported in a pooled safety analysis of rheumatological phase III studies [12]. Ustekinumab is also associated with low rates of treatment-related hypersensitivity reactions, though one case of successful drug desensitisation in Crohn’s disease following an anaphylactic reaction has been reported [8, 13].

There are currently no studies that describe the effects of premedication on the incidence or severity of vedolizumab infusion reactions. This is in contrast to infliximab, for which it is common clinical practice for an antipyretic, antihistamine, and corticosteroid to be administered prior to infusions during initial induction therapy or after a drug holiday [14]. Interestingly, the efficacy of premedication remains unproven with data from a systematic review and meta-analysis finding that premedications may not reduce the incidence of adverse events in infliximab infusions for inflammatory bowel disease [15].

Our case highlights that despite its known safety profile and the paucity of reported instances of anaphylaxis, anaphylaxis to vedolizumab, particularly after prior sensitisation, can occur. We recommend administration of an antipyretic, antihistamine, and corticosteroid prior to vedolizumab re-induction infusions when it is given after a drug holiday.

Written informed consent was obtained from the patient for publication of this case report. Ethics approval was not required for this case in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

J.K. initiated case report and drafted manuscript. H.S., T.G., and M.P.S. reviewed and revised the manuscript. All authors approved the final version of the manuscript.

All data generated or analysed during this study are included in this article and its online supplementary material files. Further enquiries can be directed to the corresponding author.