Secukinumab as a Potential Trigger of Inflammatory Bowel Disease in Ankylosing Spondylitis or Psoriatic Arthritis Patients

Ioana A. Onac; Benjamin D. Clarke; Cristina Tacu; Mark Lloyd; Vijay Hajela; Thomas Batty; Jamie Thoroughgood; Sandra Smith; Hannah Irvine; Diane Hill; Grace Baxter; Natalie Horwood; Suma Mahendrakar; Rizwan Rajak; Sian Griffith; Patrick D. W. Kiely; James Galloway

Disclosures

Rheumatology. 2021;60(11):5233-5238. 

In This Article

Abstract and Introduction

Abstract

Objective: Real-world secukinumab gastrointestinal-related adverse events (GIRAE) data during treatment for AS and PsA are lacking. We aimed to obtain this through baseline evaluation of pre-existing IBD rates and predictors of GIRAE.

Methods: Patient electronic and paper records commencing secukinumab from 10 UK hospitals between 2016 and 2019 were reviewed. GIRAE after initiation were defined as: definite [objective evidence of IBD (biopsy proven), clear temporal association, resolution of symptoms on drug withdrawal, no alternative explanation felt more likely], probable (as per definite, but without biopsy confirmation) or possible (gastrointestinal symptoms not fulfilling definite or probable criteria).

Results: Data for all 306 patients started on secukinumab were analysed: 124 (40.5%) AS and 182 (59.5%) PsA. Twenty-four of 306 (7.8%) experienced GIRAE after starting secukinumab. Amongst patients who developed GIRAE, four (1.3%) had definite, seven (2.3%) probable and 13 (4.2%) possible IBD. All definite cases were patients with AS and stopped secukinumab; two had pre-existing IBD and two (0.7%) were de novo cases of which one required surgical intervention. Seven patients (2.3%) had pre-existing diagnoses of IBD prior to initiation, of which five patients experienced GIRAE.

Conclusion: Absolute rates of new IBD in patients starting secukinumab are low. The majority of patients developing new GIRAE did not develop objective evidence of IBD or stop therapy. For patients with pre-existing IBD and AS the risk of GIRAE is much higher, and prescribing alternatives should be considered.

Introduction

The seronegative spondyloarthritides are immune-mediated diseases that share common clinical phenotypes. A distinct mixture of clinical, laboratory and imaging features help distinguish them from other types of inflammatory arthritis. Clinically, seronegative spondyloarthritis is typified by asymmetrical peripheral joint disease, often with axial involvement, overlap with inflammatory bowel or skin disease. Targeted immune therapies exist, but activation of IL-17 has emerged as a common causal pathway, and consequently drugs that block IL-17 are now widely in use. Concern has been raised about the potential for triggering bowel inflammation in patients treated with IL-17 inhibition.[1]

IL-17A is one of the six IL-17 cytokines.[2] Studies in mice suggest that IL-17A seems to have a central role in driving autoimmunity, stemming from the potent strength of signalling.[3] The IL-17 cytokines are produced by lymphocytes, primarily T cells and NK cells.[3,4] Production of IL-17 cytokines varies by tissue, with intestinal production characterized by IL-17A and F from Th17 cells.[2] Animal models of colitis suggest IL-17A has a protective role in the intestine, contributing to homeostasis and tissue repair.[2,5–7] In T-cell-deficient mice lacking IL-17A and IL-17 receptor activity, and IL-17 knock-out mice, more aggressive colitis has been observed.[6,7] Pre-treatment of mice with a monoclonal antibody against IL-17A has resulted in similar exacerbations of colitis.[5] Studies suggest that IL-17A has a protective effect mediated by improving barrier functions in the gut through the tight junction between proteins occludin and claudin, by stimulating mucin production.[8]

Secukinumab is a selective IL-17A inhibitor, and an effective treatment for PsA and AS.[9,10] These diseases are polygenic and demonstrate overlapping features with IBD, although the immune-related mechanisms are not yet understood. Of patients with PsA or AS, 50% have microscopic intestinal inflammation evident on colonoscopic biopsy[11,12] and 7% will develop Crohn's disease (CD) or ulcerative colitis (UC).[12,13] Patients with PsA and AS have a threefold increased risk of developing IBD relative to the general population.[12]

After secukinumab was licenced, inflammatory bowel changes were reported ranging from severe new cases of IBD to inflammatory bowel lesions, not fulfilling the diagnostic criteria for CD or UC.[14,15] The possible risk of worsening IBD symptoms was highlighted in a phase 2 secukinumab trial in CD, which reported exacerbation of gastrointestinal symptoms.[16]

Real-world data for secukinumab gastrointestinal safety remain limited. We set out to describe the post-licencing experience of secukinumab in routine care, assessing baseline evaluation of pre-existing IBD, rates of gastrointestinal adverse events and predictors of adverse gastrointestinal outcomes.

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