Upadacitinib in Crohn’s disease: needs more insight

It has been very informative to go through the review article of upadacitinib in Crohn’s disease by Dignass et al. The review has been comprehensive ranging right from the pharmacology to relevant pathophysiology and various clinical trials of Upadacitinib [1]. The effectiveness and safety of upadacitinib for treating moderate to severe active Crohn’s disease in adult patients were proved in the phase 3 randomized control trial (RCT), which included the pivotal placebo-controlled induction studies U-EXCEED and U-EXCEL, as well as the maintenance study U-ENDURE. The main objectives of the study were to assess clinical remission and endoscopic response either at week 12 (U-EXCEED, U-EXCEL) or week 52 (U-ENDURE). Patients aged 18 to 75 years with moderate to severe active Crohn’s disease, characterized by a stool frequency of at least 4 and/or a daily abdominal pain score of at least 2, and a simplified endoscopic score for Crohn’s disease (SES-CD) score of at least 6 (or at least 4 if only the ileum is affected), who did not respond well or could not tolerate immunosuppressants, steroids, and/or biologics, were enrolled in the multinational, multicenter, randomized, double-blind, placebo-controlled phase 3 studies [2]. Biroulet et al. have recently published a post hoc analysis of these trials showing the achievement of upadacitinib for clinical, biochemical and endoscopic improvements in Crohn’s disease regardless of prior biological exposure [3]. Though the review has been exhaustive and elucidative however there are few concerns that need to be addressed.

Upadacitinib is a small molecule, a hydrocarbon, and around half of it gets bound to proteins in the blood. Patient with moderate to severe Crohn’s disease has higher chances of protein losing enteropathy. The phase 3 study has used sustained release (SR) preparation of upadacitinib once a day basis. Interestingly in the CELEST phase 2 study had used immediate release preparation on multiple frequency basis. Though CELEST study improvement was lower than phase 3 study with SR preparations of upadacitinib, it points out the role of drug preparations. Mesalamine preparations are good example with granules in sachet form with time controlled release, PH-dependent release, extended release, enema, and suppositories [4]. Can upadacitinib with different preparation used as per location of crohn’s to minimize the adverse effect. Recently, a real-world study has shown better result from immediate release preparation for patient with diversion stomas in whom sustained release preparation came out from the stomas [5]. Though patient with stoma were excluded from the analyzed study but these patients can’t be overlooked.

Inflammatory bowel disease (IBD), true to its name causes inflammation in the bowel. IBD is phenotypically and histologically divided into ulcerative colitis, Crohn’s disease, and the indeterminant type, which shares the features of both. Out of the three types, Crohn’s disease has been most difficult to treat. The exact etiology still remain elusive and only various inflammatory cascades involved in inflammation are targeted to treat it. NSAIDs worsen IBD and are detrimental, whereas steroids have beneficial role as inducer. However, steroids could not be used as maintenance due to it adverse effects on prolonged use. Various biologics has been used targeting tumor necrosis factor (TNF), interleukin 12/23, α4β7 Integrin, lymphocyte egress inhibitor, and other pathways [6]. Inflammatory cascade is very versatile, it gets rerouted to another pathway when one pathway is blocked. Patient treated with TNF blockers the expression of Janus Kinase (JAK) 1 signaling pathway increases [7]. Tofacitinib, a 1^st generation tyrosine kinase-inhibitor (TKI) with pan JAK inhibitor fails in Crohn’s but upadacitinib a 2^nd generation TKI with reversible highly selective JAK- 1 inhibitor has shown statistically significant improvement in moderate and severe previously treated crohn’s disease. Crohn’s disease has relapse and remitting course and therefore patient get benefited from placebo even in moderate and severe disease. Overall, less than 50% has clinical and endoscopic remission despite increasing the induction period up to 24 weeks from the standard 12 weeks and a maintenance phase of 52 weeks. Though there has been statistically significant improvement as compared to placebo but overall majority (>50%) fails the treatment highlighting the need of addon to increase the success rate. There is also an urgent need to relook into factors leading to failure of therapy including the inflammatory pathways. Patient has been primary and secondary non-responders from upadacitinib which need to be work out.

It will be essential to have a comprehensive knowledge of the effectiveness of upadacitinib throughout the whole range of diseases associated with Crohn’s disease. Perianal fistulas are a troublesome, often severe consequence of Crohn’s disease and very difficult to treatment despite the best multidisciplinary management. Polymorphisms in JAK1 have been linked to perianal fistulizing illness [8]. Data are sparse on the use of upadacitinib in individuals who have perianal illness, as well as Crohn’s disease in people of Indian subcontinent, African and Hispanic descent, who were underrepresented in this and earlier trials. Crohn’s disease is treated with top down, whereas ulcerative colitis is treated with step up approach. The STRIDE consensus for treat-to-target (T2T) parameters of clinical, endoscopic, biochemical and even histological remission hold more significance for Crohn’s than ulcerative colitis [9]. As in the phase 3 RCT and various post hoc analysis, upadacitinib has shown good result in terms of clinical, endoscopic and biochemical parameter in moderate and severe crohn’s disease regardless of prior biologics exposure [10]. The author suggestion that upadacitinib has the potential to significantly impact our existing treatment protocols for Crohn’s disease is commendable. However, additional head-to-head trial, add-on trials, and real-world studies including with newer drugs preparations are required to determine the appropriate placement of upadacitinib in our existing treatment protocols for Crohn’s disease.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This letter has not been funded.