When One IBD Treatment Is Not Enough: A 2026 Review on Combining Biologics

For people living with Crohn's disease or ulcerative colitis whose condition has not responded to conventional treatments, the path forward can feel uncertain. A growing number of specialist IBD centres are exploring "advanced combination therapy" (ACT): pairing two biological or advanced drugs simultaneously, rather than using either alone. A June 2026 systematic review and meta-analysis published in BMJ Open Gastroenterology by Radford and colleagues has produced the most comprehensive synthesis of available evidence on this practice to date, pooling data from 52 studies involving 2,022 adults (Radford et al., 2026).

The headline from this review is cautiously encouraging on safety but carries a critical caveat: the certainty of evidence is rated very low across all analyses.

What Is Advanced Combination Therapy?

Biological drugs for IBD work by targeting specific parts of the immune system. Anti-TNF agents (such as infliximab or adalimumab), integrin inhibitors (such as vedolizumab), and interleukin-12/23 or interleukin-23 inhibitors each use a distinct mechanism. ACT means giving two of these advanced agents together rather than one. This is not the same as the well-established practice of pairing a single biologic with a traditional immunosuppressant such as azathioprine; that combination has decades of evidence behind it. ACT is a newer and less well-studied approach.

Because using two advanced drugs simultaneously raises obvious questions about safety, and because people with refractory IBD (disease that persists despite standard treatments) often have fewer remaining options, understanding the risk profile of ACT matters.

What the Review Found

Radford and colleagues searched Embase, MEDLINE, and PubMed for studies published between January 2015 and March 2026. The 52 included studies enrolled 2,022 adults with IBD. The most frequently studied combination was an anti-TNF drug paired with an integrin inhibitor; the second most common pairing was an interleukin-23 inhibitor combined with an integrin inhibitor (Radford et al., 2026).

On safety, the key pooled results were:

• Serious adverse event (SAE) rate for the anti-TNF plus integrin inhibitor combination: 2.7% (95% CI 0.22% to 6.86%)
• Treatment discontinuation rate across all ACT groups: 6.38% (95% CI 2.36% to 11.58%)

The wide confidence intervals on both figures reflect how much the results varied from study to study. Subgroup analyses by drug class produced similar patterns.

The review also gathered efficacy data (clinical remission and response rates) but framed these as exploratory. Because the primary aim was safety, and because the evidence quality was insufficient for conclusions, no efficacy recommendation is made.

A Critical Limitation: Very Low Certainty of Evidence

The authors assessed certainty using the GRADE framework (Grading of Recommendations, Assessment, Development and Evaluations). Their conclusion is direct: GRADE certainty is very low across all pooled analyses. This is the lowest rating in the GRADE system. It means the true safety profile of ACT could look substantially different as better evidence accumulates.

Several factors explain the low rating:

• The majority of included studies were observational rather than randomised controlled trials, making it harder to separate the drug effect from characteristics of the patients who received it.
• Sample sizes across individual studies were often small.
• Heterogeneity (statistical variation between studies) was substantial: patient populations, drug doses, disease types, and follow-up lengths differed considerably.

The authors are explicit: "robust conclusions regarding safety and efficacy cannot be made." A finding of low SAE rates in a collection of small, predominantly observational studies is not the same as a clean safety signal from a large, well-controlled trial. It is a starting point for understanding, not a settled answer.

The review authors disclosed financial relationships with pharmaceutical companies active in the IBD space, which is common among academic IBD researchers. Competing interests spanned multiple companies rather than a single sponsor, and the protocol was pre-registered on PROSPERO (CRD420251025883), which reduces the risk of selective outcome reporting.

ACT in Practice

ACT is not a first-line or widely available treatment. It tends to be considered in specialist centres for patients whose IBD has failed multiple prior therapies. Several randomised controlled trials of combination approaches are currently underway; the results of those trials will be necessary before any clinical guidance for or against ACT can be issued.

For people in the IBD and ostomy community who have navigated refractory disease, including those for whom surgery became part of the path, research into options for people who have not responded to existing treatments is an active and clinically important area. This review is one step in building that evidence base.

What to Take Away

This 2026 systematic review and meta-analysis offers an early map of the ACT safety landscape. The pooled SAE rates are not alarming, but the very low GRADE certainty means these figures are preliminary. As the authors note, the field needs properly powered randomised controlled trials before clinical recommendations become possible.

For now, ACT remains a specialist-only discussion, not a self-directed option.

This article is an AI-assisted curation of published research. It is not medical advice. If you are living with IBD or an ostomy and your current treatment is not working as well as you hoped, please speak with your gastroenterologist or IBD nurse specialist before making any changes to your treatment plan.