Ulcerative colitis induced by ixekizumab: a case report

Abstract

A possible case of ulcerative colitis (UC) developed during treatment with ixekizumab is reported. Ixekizumab is a human monoclonal antibody approved for chronic plaque psoriasis that works by blocking interleukin-17 (IL-17). Cytoquines, such as IL-17, may be involved in the pathophysiology of psoriasis and inflammatory bowel diseases. We describe the case of a 76-year-old woman who presented with an episode of acute self-limited colitis after receiving ten doses of ixekizumab. It was resolved after treatment withdrawal. A re-challenge was done after 3 months and symptoms returned. Colonoscopy results confirmed the diagnosis of UC. Symptoms remitted after drug discontinuation and treatment with corticosteroids. Four months after stopping ixekizumab, she remains asymptomatic and she is being treated with guselkumab with adequate response. The Naranjo algorithm revealed a probable causal relationship.

This adverse event should be taken into account by physicians and pharmacists before prescribing or reviewing therapies in order to improve patients’ safety.

BACKGROUND

Plaque psoriasis is an immune-mediated inflammatory skin disease with increased risks for other inflammatory conditions such as inflammatory bowel disease (IBD).¹ However, the mechanism underlying is still unclear. Several studies have demonstrated an increase in IBD prevalence among patients with psoriasis.²

Ixekizumab is a subcutaneously administered, humanised anti-interleukin (IL)−17A monoclonal antibody indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy.³ IL-17A is involved in immune system effects, including inflammation caused by psoriasis. Elevated concentrations of IL-17A have been implicated in the pathogenesis of psoriasis by promoting keratinocyte proliferation and activation, as well as in the pathogenesis of psoriatic arthritis.⁴ Neutralisation of IL-17A by ixekizumab inhibits these actions.

The safety profile from ixekizumab studies in patients with dermatological pathology has shown a low incidence of adverse events in the digestive tract.⁵ According to available data from seven ixekizumab trials, 19 patients were considered to have definite or probable IBD out of 4209 treated. In addition, only 12 patients were reported to have ulcerative colitis (UC). As a result, the authors concluded that cases of Crohn's disease (CD) and UC were uncommon (<1%).²

Although cases of new or exacerbations of CD and UC have been reported in the ixekizumab product information,³ in the EudraVigilance database of the European Medicines Agency, only 26 cases of UC associated with ixekizumab have been reported.⁶

Herein, we present the case of a woman with chronic plaque psoriasis treated with ixekizumab, who developed two episodes of bloody diarrhoea and abdominal pain. The biopsy confirmed the diagnosis of UC. The episodes were resolved after ixekizumab withdrawal and treatment with corticosteroids.

Consequently, we consider it relevant to describe this case to highlight that UC might be a severe adverse event potentially related to ixekizumab use, and that this should be studied.

Case presentation

A 76-year-old Spanish woman with a 21-year history of chronic plaque psoriasis in treatment with ixekizumab was admitted due to developing an episode of bloody diarrhoea of 2 weeks’ duration and intermittent abdominal pain accompanied by weight loss and fever.

She had a history of asthma and osteoporosis. Her usual treatment included montelukast 10 mg/day, pantoprazole 40 mg/day, calcium 500 mg/day, denosumab 60 mg/6 months and as topic treatment, methylprednisolone, calcipotriol/betamethasone and pimecrolimus.

Previous treatments included methotrexate 20 mg, acitretin 25 mg (both of them stopped due to intolerance) and adalimumab 40 mg for 2 years. Then, because of a flare-up after adalimumab treatment, ustekinumab 45 mg every 12 weeks was prescribed. However, after five ustekinumab doses, she developed a possible case of bullous pemphigoid potentially caused by this treatment.⁷ This adverse event was resolved after ustekinumab withdrawal and treatment with dapsone 50 mg/day, prednisone 40 mg/day and zinc sulfate 1/1000 mg (topical). Three months after stopping ustekinumab treatment she remained asymptomatic and she was prescribed ixekizumab 80 mg every 4 weeks (with a previous induction regimen) for psoriasis control. After ten months from the beginning of this treatment, the patient developed the aforementioned episodes. She had no family history of IBD.

Investigations

On admission, doctors’ suspicion was a possible case of UC. The clinical pharmacist was asked by the clinicians to review the patient's medication list to determine whether UC could be secondary to some of the drugs she was receiving. On suspicion that the causative drug of UC was ixekizumab, this drug was discontinued.

An endoscopic study was performed which was macroscopically compatible with an inflammatory colitis of the left colon. Microbiological examination of blood culture, stool culture and Clostridium difficile toxin determination were negative.

The results of the biopsy revealed inflammatory alterations compatible with acute self-limited colitis of unknown aetiology instead of the initial suspicion of UC. As a consequence, clinicians tried a re-challenge with the biological treatment. However, the patient developed a second episode and biopsy confirmed the diagnosis of UC potentially caused by ixekizumab.

In addition, this adverse event was evaluated. According to the Naranjo et al⁸ (table 1) adverse drug reaction probability scale, the causal relationship between UC and ixekizumab was classified as ‘probable’.

Table 1.

Naranjo adverse drug reaction probability scale

QUESTION	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	1
Did the adverse event appear after the suspected drug was administered?	+2	-1	0	2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	1
Did the adverse event reappear when the drug was re-administered?	+2	-1	0	2
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	-1	+2	0	-1
Did the reaction reappear when a placebo was given?	-1	+1	0	0
Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	0
Total score				5

Scoring: Definite: >9; Probable: 5–8: Possible: 1–4; Doubtful: 0.

Treatment

Ixekizumab was the main suspicious drug for this adverse event, so the pharmacist proposed the drug’s discontinuation.

Intravenous methylprednisolone (1 mg/kg/day) was prescribed for 2 days. In order to prevent secondary bacterial infections, metronidazole 1500 mg/day, ciprofloxacin 400 mg twice daily and ceftriaxone 2 g/day were prescribed for 2 days.

Two days later, fever disappeared and a significant improvement of the diarrheic episodes was observed. She was discharged with a prescription of oral prednisone 30 mg/day (gradually tapering over a 30-day course).

The results of biopsy revealed inflammatory alterations compatible with acute self-limited colitis of unknown aetiology (microbiological stools were negative) instead of UC. Therefore, 3 months after this episode, clinicians tried a re-challenge with ixekizumab and symptoms reappeared. The patient was re-admitted because she reported abdominal pain in the hypogastrium, diarrhoea, rectal bleeding and fever 1 month after the re-challenge with ixekizumab. On admission, colonoscopy was performed confirming the diagnosis of UC with severe inflammatory activity. Ixekizumab was discontinued. After 6 days receiving systemic corticosteroids (methylprednisolone 1 mg/kg/day), she experienced a significant clinical improvement and symptoms remitted.

Outcome and follow-up

She was discharged with a prescription of oral prednisone 60 mg/day (gradually tapering over a 60-day course). Four months after stopping ixekizumab treatment she remained asymptomatic. Clinicians decided not to try another re-challenge on account of the previous adverse event potentially caused by ixekizumab. She was prescribed guselkumab 100 mg every 8 weeks (with a previous induced regimen) for psoriasis control, with adequate response.

This adverse event was reported to the regional pharmacovigilance centre. Following the information on this adverse event potentially caused by ixekizumab, clinical pharmacists carried out a review of all patients in treatment with this drug but we did not find other probable cases. We must remain vigilant in order to improve patients’ safety.

Discussion

It is known that psoriatic patients have an increased prevalence of IBD.¹ Psoriasis and IBD share several pathogenic immune-based mechanisms and some pharmacological treatments. Cytokines, such as IL-23 or IL-17, tumour necrosis factor and T-helper 17 cells may be involved in both conditions.²

Ixekizumab is a biologic drug licensed for the treatment of psoriasis and psoriatic arthritis. By attaching to IL-17A, ixekizumab blocks its action and reduces the activity of the immune system and thereby reduces the symptoms of psoriasis. However, the role of IL-17 in IBD has remained controversial because some studies showed no efficacy of IL- 17 antagonist against CD or others showed worsening of CD.⁹

Other IL-17A antibodies such as secukinumab have shown to worsen these pathologies.¹⁰ However, the long-term safety data of both drugs are limited. It would be necessary to address safety studies in the post-marketing period.

In our case, the patient had no previous symptoms or family history of UC, so we conclude that she developed de novo UC potentially caused by ixekizumab. According to the available evidence, these symptoms potentially caused by the use of this drug are characterised by late onset.² In our patient, the first episode happened after receiving 20 doses of ixekizumab 80 mg. This drug was discontinued and she showed an improvement with corticosteroid treatment. Currently, she remains asymptomatic.

In conclusion, based on available clinical data, the literature review and application of causality analysis, a causal relationship between the administration of ixekizumab and UC is probable. Knowledge of the possible appearance of UC associated with this treatment allows early recognition of the causality and subsequent management of patients. In this context, it is appropriate to advise dermatologists to monitor patients closely when using IL-17 inhibitors in patients with psoriasis because ixekizumab may induce or exacerbate IBD. Treatment decisions for patients with psoriasis should take into account this rare adverse event.

Cooperation between clinicians and pharmacists is useful in detecting and reporting adverse events in the clinical practice, and promotes the safe use of medicines.

Learning points.

• Patients with psoriasis have an increased risk of suffering inflammatory bowel diseases.

• Ixekizumab might induce or exacerbate inflammatory bowel diseases. So, in patients with psoriasis, the risk of developing new-onset or exacerbate inflammatory bowel diseases should be taken into account in treatment decisions.

• In this case, the association between ixekizumab and UC was classified as probable by the Naranjo adverse drug reaction probability scale.