Is it time to move away from legacy inflammatory bowel disease drugs?

INTRODUCTION

The conventional treatment algorithm for inflammatory bowel disease (IBD) usually adopts a step-up approach, particularly in Asia where resources are limited. With the availability of multiple new and highly effective advanced therapies, including biologics and small molecules, the role of conventional treatments such as 5-aminosalicylic acid (5-ASA) and immunomodulators in managing patients with IBD has become less clearly defined. In many Western countries, a top-down approach has been increasingly adopted, and conventional treatment may not be used at all. Long-term follow-up of the PROFILE trial from the United Kingdom showed that treating very early Crohn’s disease (CD) with infliximab reduced disease progression, hospitalisation and the need for abdominal surgery for up to 4 years.[1] These findings suggest that a gradual step-up approach may miss a golden opportunity to initiate a more aggressive treatment strategy and prevent future complications.

Before we drastically shift from a step-up to a top-down approach for all patients, it may be time to reconsider the roles of existing conventional therapies for IBD. Herein, the role of conventional IBD treatment options in three special clinical scenarios is discussed, with the aim of stimulating further research and real-world data on their cost-effectiveness.

CONVENTIONAL TREATMENTS

Is 5-aminosalicylic acid still needed?

In most guidelines and recommendations,[2,3,4] 5-ASA remains the recommended first-line therapy for patients with mild-to-moderate ulcerative colitis (UC). In particular, 5-ASA can be administered topically for proctitis or distal colitis. Various forms of oral preparations are also available, ranging from delayed-release to pH-dependent formulations, designed to deliver the drug to different sites of the intestinal tract. However, the role of 5-ASA in CD is limited, as most current guidelines recommend against its use in CD.[5,6] In the most recent Asia-Pacific consensus published in 2016, sulfasalazine, and not 5-ASA, was proposed as an option for mild CD confined to the colon.[7] Although some data have suggested a role for 5-ASA in maintaining surgically induced clinical remission in CD,[8] it has largely been replaced by more effective biologics for this indication.

At present, 5-ASA remains widely used in clinical practice across Asia for CD. In a recent survey of 384 doctors from 24 Asian countries and regions, 5-ASA was used in 61.2% of small bowel CD and 70.8% of colonic CD.[9] In another survey of Korean physicians, approximately one-third reported continuing 5-ASA even after initiating biologics or small molecules.[10] With the availability of more effective therapies capable of achieving mucosal and even transmural healing in CD, the role of 5-ASA in CD will likely diminish over time. Given that branded 5-ASA can be costly, more high-quality data are needed to substantiate or refute the use of 5-ASA in Asian patients with CD.

Is immunomodulator still needed?

Immunomodulators, particularly thiopurines, are frequently used in patients with steroid dependence or refractory disease. In a previous Asian survey, more than 50% of patients with CD and 60% of steroid-dependent patients with UC were receiving thiopurines.[9] Although the effect of thiopurines in induction therapy is minimal due to the delayed onset of action, their efficiency in maintenance therapy has been well established in both CD and UC.[11] They are, therefore, particularly relevant in regions where biologics or small molecules are less affordable.

Studies have also suggested that combining thiopurines with infliximab may prevent immunogenicity and improve pharmacokinetics, although the benefit of combining thiopurines with other advanced therapies remains unclear. The availability of a subcutaneous formulation of infliximab may also render combination therapy unnecessary.[12] Given their frequent side-effects—such as neutropenia in Asian patients related to NUDT15 polymorphisms—and the rare association with fatal lymphoid malignancies, the role of thiopurines may decline over time, particularly with the availability of multiple non-tumor necrosis factor-based advanced therapies. Similarly, given the potential long-term risks, the role of other immunomodulators such as methotrexate is even more limited.

Is cyclosporin still needed in acute severe UC?

Acute severe ulcerative colitis (ASUC) is a medical emergency that requires prompt escalation of therapy when steroids fail, in order to prevent colectomy and even mortality. Randomised controlled trials support the use of infliximab or cyclosporin for ASUC that fails to respond to intravenous steroids.[4] However, infliximab is generally preferred at present due to its simpler dosing regimen and favourable safety profile. In contrast, cyclosporin requires drug titration and close monitoring of renal function and cholesterol levels. In addition, cyclosporin usually requires transition to other advanced therapies after the initial response, which can further complicate treatment pathways.

Apart from infliximab, the recent availability of oral Janus kinase (JAK) inhibitors (tofacitinib and upadacitinib) has further reshaped the treatment landscape, as they have been shown to produce a rapid response in patients with ASUC.[13] With such emerging data, even the positioning of infliximab in the management algorithm of ASUC is being challenged. Apart from their rapid onset of action, the oral route of administration may potentially spare corticosteroid use and reduce medical costs by decreasing or shortening hospitalisation. Proper head-to-head comparisons between oral JAK inhibitors and the current step-up approach—from intravenous steroids to infliximab or cyclosporin—in patients with ASUC are eagerly awaited. However, even in the absence of robust trial data, the role of cyclosporin remains limited.

CONCLUSION

While many conventional therapies have been widely used in IBD treatment, most achieve only clinical remission rather than mucosal or deep healing, which may still result in long-term complications. Apart from the use of 5-ASA in mild-to-moderate UC, the role of many agents, such as immunomodulators, may gradually phase out of the treatment algorithm of IBD, particularly with the availability of small molecules that can be taken orally. The availability of biosimilars and generics could further reduce medication costs, making these treatments more affordable across many Asian countries. The future of IBD management is becoming increasingly promising, with emerging therapies that have the potential to change the natural course of the disease.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.