Spotlight on treatment response in Crohn's disease

Recent studies evaluated early versus late response to biologic therapy, treatment response and infection risk, and endoscopic outcomes.

Three recent studies looked at aspects of treatment response in patients with Crohn's disease.

In the first study, a post hoc analysis of patient-level data from a clinical trial in Canada, researchers evaluated whether one-year outcomes differed in patients who were first-time recipients of biologic therapies and had early or delayed response to ustekinumab or adalimumab. Early response was defined as a reduction in Crohn's Disease Activity Index (CDAI) score of at least 100 points from baseline or a CDAI score below 150 at week 8. Those who had not responded at week 8 but did respond by week 16 were considered to have a delayed response. Clinical remission at week 56 was the primary outcome. The results were published Jan. 18 by the American Journal of Gastroenterology.

Of the 373 participants included in the analysis, 187 received ustekinumab and 186 received adalimumab. The rate of delayed clinical response overall was 13.1%. Two hundred fifty-three patients (67.8%) had early response, 49 (13.1%) had delayed response, and 71 (19.0%) did not respond to treatment. At week 56, patients with early or delayed response did not differ in clinical remission or in any of the secondary outcomes, including corticosteroid-free remission, clinical response, endoscopic remission, or endoscopic healing. Those with delayed response had a significantly greater decrease in C-reactive protein (CRP) level at week 8 versus those who did not respond.

The researchers noted that their study looked only at biologic-naive patients, among other limitations, and called for additional studies to confirm their findings. They concluded that among biologic-naive patients with moderate to severe Crohn's disease, those who responded early and those with delayed response had similar clinical outcomes at one year.

“Using CRP, fecal calprotectin, and clinical symptom response over the first 8 weeks of response can help differentiate a patient who is likely to have non response by week 16 compared to those who will be delayed responders,” the authors wrote. “For patients with no improvement in CRP, fecal calprotectin, and lack of clinical symptom response by week 8, persisting with additional dosing may not be of high yield. Ultimately, waiting for delayed response is not without risk, and informing the decision with use of early biomarker trajectory may help clinicians deem where persisting with additional therapy may be of benefit.”

The second study, a secondary analysis of real-world data from the international PYRAMID registry, looked at the effect of treatment response on risk for serious infections in patients with Crohn's disease. Patients who began taking adalimumab were classified as responding (steroid-free clinical remission based on patient-reported outcomes) or not responding (no steroid-free clinical remission) to treatment at six months, and risk for serious infection six to 36 months after treatment initiation was compared. The results were published Jan. 10 by Clinical Gastroenterology and Hepatology.

The study included 1,515 patients, 763 (50.4%) who responded to treatment at six months and 752 (49.6%) who did not. Mean age was 37 years, and 56% were women. Those who responded to treatment were less likely than those who did not to have moderate to severe symptoms (55.6% vs. 33%) and to require steroids (45.5% vs. 17.3%) or opiates (6.6% vs. 1.3%) at baseline. The two groups did not differ in disease location, perianal disease, or previous complications of Crohn's disease. During follow-up, in a stabilized inverse probability of treatment-weighted Cox proportional hazards model, those who responded to treatment were 34% less likely to have a serious infection than those who did not respond (hazard ratio [HR], 0.66; 95% CI, 0.46 to 0.96). Risk for GI and extra-intestinal infections was also lower in those who responded to treatment than in those who did not (HRs, 0.61 [95% CI, 0.38 to 0.99] and 0.61 [95% CI, 0.46 to 1.30], respectively).

The researchers noted that they defined response and nonresponse according to symptoms, not endoscopic or biochemical remission, and that they only considered treatment with adalimumab, among other limitations. “In summary, in a real-world prospective observational registry of adalimumab-treated patients with [Crohn's disease], we observed that treatment response is independently associated with risk of serious infections,” they wrote. “Patients who achieve corticosteroid-free symptomatic remission on adalimumab within 6m experience a 34% lower risk of serious infections compared with non-responders, over the next 36 months. This study highlights that effective therapies may lower the risk of serious infections through effective disease control and avoidance of corticosteroids.”

The third study, published Jan. 5 by Clinical Gastroenterology and Hepatology, was a network meta-analysis that compared the efficacy of advanced therapies in adults with moderate to severely active Crohn's disease. Phase 2 and 3 randomized controlled trials published through Aug. 2, 2023, were included if they compared tumor necrosis factor (TNF) antagonists, etrolizumab, vedolizumab, anti-interleukin (IL)-12/23p40 agents, anti-IL23p19 agents, or Janus kinase-1 (JAK1) inhibitors with placebo or active comparator for induction and/or maintenance of remission and reported outcomes of endoscopy. Endoscopic response after induction therapy and endoscopic remission after maintenance therapy were the primary outcomes.

Twenty trials involving 5,592 patients were included in the analysis. Of these, 12 reported endoscopic outcomes for the induction phase, five reported them for the maintenance phase, and three reported them for both phases. JAK1 inhibitors (relative risk [RR], 3.49; 95% CI, 1.48 to 8.26) and anti-IL23p19 agents (RR, 2.30; 95% CI, 1.02 to 5.18) were more efficacious than etrolizumab (moderate certainty of evidence), while JAK1 inhibitors were more efficacious than anti-IL12/23p40 agents for inducing endoscopic response (RR, 2.34; 95% CI, 1.14 to 4.80; moderate certainty of evidence). Induction of endoscopic response was most common with JAK1 inhibitors and anti-IL-23p19 agents. Few randomized controlled trials of TNF antagonists reported endoscopic outcomes with induction therapy. A network meta-analysis of six randomized controlled trials found that all agents except vedolizumab (RR, 1.89; 95% CI, 0.61 to 5.92) effectively maintained endoscopic remission versus placebo, with TNF antagonists, anti-IL12/23p40 agents, and JAK1 inhibitors ranking highest.

The researchers said that the lack of data on TNF antagonists for induction and on vedolizumab for induction and maintenance are important caveats to their findings, among other limitations. They concluded that JAK1 inhibitors and anti-IL23p19 agents may be superior to other non-TNF-targeting biologics for favorable endoscopic outcomes, especially among patients in whom biologic therapy had previously failed. “Whilst there is paucity of data on endoscopic outcomes with TNF antagonists in [randomized controlled trial] settings, real-world evidence would suggest high effectiveness with these agents,” they wrote. “Future head-to-head trials with clinical and endoscopic outcomes will inform positioning of different therapies for the management of moderate to severely active [Crohn's disease].”