Dual-Targeted Therapy Brings Remission to Half of Patients with Hardest-to-Treat Inflammatory Bowel Disease

For patients with inflammatory bowel disease whose condition has resisted every advanced therapy thrown at it, the therapeutic options have long been grim: surgery, another round of a drug that already failed, or an uncertain gamble on combining two powerful immunosuppressive agents. A new real-world study from a tertiary centre in Abu Dhabi now offers some of the clearest evidence yet on that last option, reporting that advanced combination treatment achieved clinical and biochemical remission together in just over half of treatment courses in a cohort of profoundly multi-refractory patients. The findings, published in Advances in Therapy, come from one of the first centres in the Middle East to systematically document this increasingly used but poorly characterised strategy.

The study, led by Enas Fouad Ahmed and Mohammed Nabil Quraishi at Sheikh Shakhbout Medical City, identified 16 patients who received 21 courses of advanced combination treatment between June 2021 and May 2026. Eleven patients had Crohn’s disease and five had ulcerative colitis, and the cohort was predominantly Emirati, with 13 of the 16 patients holding Emirati nationality. These were not treatment-naive individuals testing a new option early: they had failed a median of four prior lines of advanced therapy before their clinicians turned to combination treatment. The median age at the first combination was just under 30 years, and three patients were under 18. Half had undergone previous IBD-related surgery or carried extraintestinal manifestations of their disease, underscoring how severe and complicated this population was.

Advanced combination treatment, or ACT, is defined as the concurrent use of two advanced therapies with distinct mechanisms of action, either two biologic agents or a biologic paired with a small molecule. The rationale rests on a biological observation that has become increasingly hard to ignore: blocking a single inflammatory pathway is often insufficient to control disease sustained by redundant immune circuits. Approximately one-quarter of patients receiving advanced therapy now meet consensus criteria for difficult-to-treat IBD, and for them the immune system’s parallel signalling networks appear to require parallel inhibition. The proof-of-concept came from the VEGA trial in ulcerative colitis, which tested guselkumab plus golimumab, and the observational evidence base has since grown to encompass nearly 2,100 patients across 63 studies.

What the Abu Dhabi team found was that the most popular pairing in their cohort combined a selective anti-interleukin-23 antibody with a Janus kinase inhibitor, accounting for 10 of the 21 courses. The most frequent specific pairing was guselkumab with upadacitinib, used in eight courses. The mechanistic logic is coherent: the antibody neutralises a single upstream cytokine, interleukin-23, while the small molecule interrupts signalling downstream of several other cytokine pathways simultaneously. A further five courses paired an anti-interleukin-23 agent with an anti-tumour necrosis factor antibody. In total, 12 distinct regimens were deployed, reflecting the fundamentally individualised nature of the strategy, in which the choice of pairing is dictated largely by what has already failed.

The primary outcome was deliberately strict: composite remission, requiring clinical and biochemical remission simultaneously. Clinical remission was measured with the Harvey–Bradshaw Index for Crohn’s disease or the Simple Clinical Colitis Activity Index for ulcerative colitis, while biochemical remission demanded both a C-reactive protein below 10 mg/L and a faecal calprotectin below 250 µg/g. Across the 21 courses, composite remission was achieved in 11 courses, or 52 percent, with a wide 95 percent confidence interval of 30 to 74 percent reflecting the small sample. Clinical remission alone was reached in 71 percent of courses, and two-thirds of courses were corticosteroid-free at the latest assessment. At the patient level, 11 of the 16 patients achieved composite remission during at least one combination course, and 14 achieved clinical remission.

One of the study’s most instructive findings lies in the gap between those two numbers. Symptoms outpaced the resolution of objective inflammation in roughly one course in five, precisely the courses that a clinical endpoint alone would have counted as successes. The authors point to individual cases where clinical and laboratory measures pointed in opposite directions at baseline, with one patient entering treatment with severe symptoms but near-normal inflammatory markers and another with minimal symptoms but a calprotectin of 1,500 µg/g and extensive endoscopic damage. Either marker alone would have misclassified one of these patients, which is why the composite outcome mattered. Endoscopic reassessment, performed when clinically indicated in 14 courses, confirmed endoscopic remission in five.

Safety data were broadly reassuring for a strategy that doubles immunosuppression. Only one serious adverse event occurred during combination therapy, a urinary tract infection requiring hospital admission during a course of risankizumab with adalimumab; it resolved and the combination was continued. No thromboembolic or major cardiovascular events occurred, and all 16 patients remained alive and under active care at the census date. However, the study also documents a sobering case: a patient previously treated with infliximab, ustekinumab and the thiopurine azathioprine developed an Epstein–Barr virus-positive mucocutaneous ulcer with a clonal B-cell lymphoproliferative disorder fourteen months after that combination ended, while on upadacitinib monotherapy. The lesion resolved completely after withdrawal of immunosuppression and rituximab therapy, and the authors note that the preceding cumulative immunosuppression may have contributed. Notably, a large nationwide study found that anti-TNF therapy combined with a thiopurine more than tripled the odds of lymphoma, whereas vedolizumab, ustekinumab and JAK inhibitors carried no excess risk, leading the authors to argue that thiopurines should be withdrawn when a second advanced therapy is introduced.

Therapeutic drug monitoring emerged as a critical practical tool. Immunogenicity to adalimumab, with antibody titres exceeding 200 and negligible drug concentrations, terminated the anti-TNF component of two courses. Both affected patients had previously developed antibodies to infliximab during earlier treatment, consistent with evidence that immunogenicity to one anti-TNF agent predicts de novo antibodies to the next. In contrast, serial trough monitoring in three other patients detected no anti-drug antibodies across eight measurements, and drug concentrations rose appropriately after dose intensification. The authors argue that serial monitoring of the anti-TNF component during combination therapy, with dose escalation when trough levels fall, is currently the most practical response to this risk.

The study also highlights how much remains unknown. How long a combination should continue once remission is achieved has no evidence base; one patient in the cohort who was stepped down from vedolizumab and ustekinumab to ustekinumab alone relapsed 13 months later. When disease flares on a combination, whether to stop one agent or both is similarly unresolved, and an adverse event on two drugs cannot be confidently attributed to either. Convenience carries a real cost too, with patients juggling two injection schedules or two separate intravenous inductions. Yet patients appear willing to bear this burden: in a discrete-choice experiment, respondents accepted a 17.5 percent risk of serious infection for an improvement in remission probability from 50 to 70 percent.

Perhaps the study’s most important contribution is methodological. The authors report every course at the level of the individual drug pairing, with exposure, baseline activity, outcome and reason for discontinuation, so that their data can be pooled with other small series. This matters because the randomised trial programme, including the DUET trials of a guselkumab-golimumab co-antibody and the ongoing VICTRIVA study of vedolizumab with upadacitinib, tests fixed pairs in populations far less refractory than the patients who actually receive combination treatment in practice. In this cohort were a renal transplant candidate, three patients with primary sclerosing cholangitis and a patient with a stoma, none of whom would fit typical trial eligibility criteria. Until trials designed for multi-refractory disease report, carefully documented real-world series of this kind will remain the principal evidence guiding which combination to use, in whom, and for how long.

Subject of Research: Real-world effectiveness and safety of advanced combination immunotherapy in refractory inflammatory bowel disease

Article Title: Real-World Effectiveness and Safety of Advanced Combination Treatment in Patients with Refractory Inflammatory Bowel Disease

Article References: Ahmed, E. F., Oribiana, C. C., Alahmad, M. A., Omar, N. M., Chitra Kumar, K. K., & Quraishi, M. N. (2026). Real-World Effectiveness and Safety of Advanced Combination Treatment in Patients with Refractory Inflammatory Bowel Disease. Advances in Therapy. https://doi.org/10.1007/s12325-026-03828-5

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03828-5

Keywords: inflammatory bowel disease, Crohn's disease, ulcerative colitis, advanced combination treatment, dual-targeted therapy, guselkumab, upadacitinib, Janus kinase inhibitors, anti-interleukin-23, therapeutic drug monitoring, real-world evidence, refractory IBD