A new meta-analysis has given fresh insights into the optimal sequence of first- and second-line therapies in moderate-to-severe Crohn’s disease, gastroenterologists say.
The systematic review and network meta-analysis included 31 clinical trials of TNF inhibitors (infliximab, adalimumab, and certolizumab pegol), anti-integrins (vedolizumab), anti-IL-12/23p40 agents (ustekinumab), and anti-IL-23p19 agents (risankizumab).
The latest evaluation found infliximab alone or with azathioprine, adalimumab and ustekinumab were more likely to induce remission in biologic-naive patients than certolizumab pegol (odds ratio [OR]: 4.53, 95% CI: 1.49–13.79; 7.49, 2.04–27.49; 3.01, 1.25–7.27; and 2.63, 1.10–6.28, respectively), as was infliximab-azathioprine versus vedolizumab (OR: 3.76, 95% CI: 1.01–14.03).
Meanwhile, adalimumab (after loss of response to infliximab) and risankizumab were better for induction of remission than vedolizumab in patients with previous biologic exposure, (OR: 2.82, 95% CI: 1.20–6.62; 2.10. 95% CI: 1.12–3.92, respectively).
Infliximab-azathioprine ranked highest for remission maintenance, however, no single agent achieved superiority, lead author and University of California San Diego Health gastroenterologist Assistant Professor Siddharth Singh and colleagues wrote in The Lancet Gastroenterology and Hepatology.
Risks for adverse events appeared similar across treatments, though, clinical trials are underpowered to detect rare side effects and clinicians should consider registry data, long-term pharmacovigilance and real-world data when evaluating drug safety, they warned.
“Although biologic treatment choices in patients with moderate-to-severe Crohn’s disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission,” they wrote.
The finding contrasts with Assistant Professor Singh’s 2018 study which suggested “infliximab or adalimumab may be preferred first-line agents and ustekinumab a preferred second-line agent, for induction of remission in patients with moderate-to-severe [Crohn’s]”, based on indirect comparisons.
Several important changes have occurred in the Crohn’s disease landscape over the last three years, not least being the 2021-reported head-to-head trial of adalimumab and ustekinumab, Assistant Professor Singh’s latest paper read.
Recent studies have also fleshed out IL-23’s role in Crohn’s pathogenesis, with some showing that a “specific IL-23p19 blockade is more effective than anti-IL-12/IL-23p40 for other immune-mediated disorders, including psoriasis and psoriatic arthritis”.
Finally, “landmark treatment strategy trials have confirmed that early combined immunosuppression with a TNF antagonist and azathioprine, as well as escalating to combination therapy to maintain tight control of inflammatory activity, results in better long-term outcomes”, Assistant Professor Singh and colleagues wrote.
These updates necessitated a re-evaluation of the optimal sequence of biologic therapies in Crohn’s disease, they said.
They hope the new findings will help inform treatment guidelines, risk-benefit conversations between clinicians and patients and ultimately, therapeutic decisions.
Gastroenterologists respond
The work has already been well-received by University of Colorado and Weill Cornell Medicine-based gastroenterologists, Assistant Professor Waseem Ahmed and Associate Professor Dana Lukin, who “applaud[ed]” the study in an accompanying editorial.
The findings “can serve as a tool for health-care providers in positioning therapies and re-emphasise the role of TNF antagonist therapies for the treatment of patients with biologic-naive, moderate-to-severe Crohn’s disease, particularly in combination with thiopurines for patients with an aggressive phenotype”, they wrote.
They also supported Assistant Professor Singh and colleagues suggestion that anti-IL-23s may be a preferred second-line therapy, though they advised that, while adalimumab might be prescribed after infliximab intolerance or failure, it “is likely to be of limited use in primary TNF non-responders”.
They weren’t quite ready to dismiss ustekinumab as a first-line therapy either, noting that adalimumab and ustekinumab had “similar clinical and endoscopic remission rates and safety outcomes” in biologic-naive Crohn’s patients and that recent trials found the latter’s safety profile was “comparable to placebo”.
The authors suggested keeping vedolizumab in mind as a first-line therapy for patients “without poor prognostic features and for whom safety is a priority,” despite its relatively lacklustre performance among other therapies.
They recommend that Assistant Professor Singh’s findings could “serve as a primer to clinicians when choosing from an increasing range of therapeutic options”, but more “head-to-head studies are needed before any formal conclusions are made on the therapeutic positioning of Crohn’s disease”.