Editorial: Dual Advanced Therapy in Refractory Ulcerative Colitis—Hope Beyond Monotherapy

Managing refractory ulcerative colitis (UC) remains a difficult clinical challenge. In recent years, the therapeutic arsenal expanded to different drug classes such as integrin inhibitors (vedolizumab), anti-IL-12/23 inhibitors (ustekinumab), anti-IL-23 inhibitors (risankizumab, guselkumab and mirikizumab), sphingosine-1-phosphate inhibitors (ozanimod and etrasimod) and Janus kinase inhibitors (tofacitinib, filgotinib and upadacitinib). However, some patients fail multiple therapies, often leading to colectomy. In this context, dual advanced therapy (DAT) with different drug classes may offer a potential treatment strategy for this difficult-to-treat population. Historically, the strategy of combining two immunosuppressive drugs in UC came from pairing thiopurines with anti-TNF inhibitors (Table 1). This approach, validated by trials such as SONIC in Crohn's disease 1 and UC SUCCESS in UC 2, showed superior clinical remission and mucosal healing rates compared to monotherapy. The synergy appeared to stem not only from enhanced immunomodulation but also from reduced immunogenicity against TNF-alpha antibodies and improved serum concentrations. Yet, long-term safety concerns—particularly infections and malignancy risk—have prompted clinicians to be cautious in prescribing prolonged dual immunosuppression 9. We applaud the well-designed study by Neelam et al. 7 who performed a randomised trial on the DAT of vedolizumab and tofacitinib (VETO) in 24 patients with anti-TNF-inhibitor refractory moderate-to-severe UC who also failed to achieve adequate disease control with either vedolizumab or tofacitinib monotherapy. Clinical response was achieved in 71% of patients at 24 weeks of follow-up, and clinical remission increased from 21% at week 8 to 58% at week 24 in patients receiving VETO. No patients experienced any treatment-related adverse events leading to discontinuation of VETO. The sample size is admittedly limited, and the absence of a concurrent control group receiving continued monotherapy or placebo limits the ability to attribute all improvements directly to the combination. Still, this was a highly refractory cohort, and observing improved clinical remission in 58% of patients at week 24 is hopeful. As mentioned by the authors, the affordability and availability of DAT are a challenge in low- and middle-income countries (LMICs), but may also be a problem for financially underprivileged patients in high-income countries. It is important that advanced therapies are also available and accessible for patients in these countries 10. This trial 7 was performed in India, which highlights the potential of DAT in contexts other than North America, Europe, and East Asia where most evidence on combining immunosuppressive medicines (including DAT) is derived from (see Table 1). In conclusion, this study offers a compelling case for considering VETO therapy in selected patients with refractory UC. As the field continues to evolve, DAT regimens may become increasingly relevant, bridging the gap between innovation and the unmet needs of those most in need of effective treatment. Financial barriers for access to DAT in LMICs need to be further addressed to ensure global treatment equality and quality of care. Ahmed B. Bayoumy: conceptualization, writing – original draft, writing – review and editing, visualization, project administration. Nanne K. de Boer: conceptualization, writing – original draft, writing – review and editing, supervision. Ahmed B. Bayoumy has received (unrestricted) research funding from HLW Pharma BV. Nanne K. de Boer has served as a speaker for AbbVie and MSD and has served as a consultant and/or principal investigator for TEVA Pharma BV and Takeda. He has received a research grant (unrestricted) from Dr. Falk, TEVA Pharma BV, Dutch Digestive Foundation (MLDS) and Takeda. All outside the submitted work. This article is linked to Neelam et al papers. To view these articles, visit https://doi.org/10.1111/apt.70309 and https://doi.org/10.1111/apt.70339. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.