Y-ECCO Literature Review: Omer Serhan Omer

Although CALM highlighted the benefits of a TC approach in early CD, there are currently no data on the impact of achievement of these targets on long-term disease progression. In the current study, follow-up data from CALM participants were utilised to evaluate the impact of achieving early deep and endoscopic remission on long-term disease outcomes in patients with CD.

Methods

A retrospective cohort observational study was conducted on participants of the CALM study. In brief, CALM was a multicentre, randomised, open-label, active-controlled, 48-week, phase 3 trial to assess TC versus conventional management (CM) algorithms in adults with moderate to severe CD. Patients in the TC arm had medical therapy (adalimumab) escalation in response to clinical symptoms (CDAI) or elevation in faecal calprotectin or CRP, whereas patients in the CM arm had therapy (adalimumab) escalation in response to symptoms alone (CDAI). The primary endpoint in CALM was Crohn’s Disease Endoscopic Index of Severity (CDEIS) of <4 and no deep ulcers on ileo-colonoscopy at 48 weeks after randomisation. To evaluate long-term outcomes, the original CALM study sites were contacted and patient records reviewed. Data were collected on patient follow-up and disease progression. The primary outcome was a composite of major adverse outcomes reflecting disease progression: new internal fistula/abscess, stricture, perianal fistula/abscess, CD hospitalisation or CD surgery since end of CALM. Secondary outcomes included the individual components of the composite primary outcome and the proportion of patients still receiving adalimumab therapy at the end of follow-up. Patients were then stratified by level of remission obtained at the end of CALM compared to long-term outcomes. The primary variable of interest for this stratification was deep remission (defined as CDAI of <150, CDEIS of <4 with no deep ulcers and no steroids for ³8 weeks).

Key findings

A total of 122 patients who participated in CALM were included in the present long-term follow-up study, representing 50% (122/244) of the original CALM population. The median follow-up duration since the end of the CALM study was 3.02 years. Half of the patients in the current study were in the TC arm of CALM. Disease progression had occurred in 34 patients (27.9%) since the end of the CALM study. The risk of disease progression during follow-up was not significantly different when comparing patients in clinical remission (n=64) at the end of the CALM study with those who were not. In contrast, patients in endoscopic (n=49) and deep remission (n=36) had a significantly lower risk of disease progression compared to those not in remission. On univariate Cox regression analysis, deep remission (HR 0.28; 95% CI 0.10–0.80) was associated with reduced risk of CD disease progression. Endoscopic remission and clinical remission were also associated with decreased progression but with more modest hazard ratios. Of note, there was no significant difference in risk of disease progression in the TC and CM treatment arms after the end of the CALM study (HR 0.89; 95% CI 0.45–1.75).

In multivariate models, deep remission (aHR 0.19; 95% CI 0.07–0.31) was associated with a decreased risk of progression. Again, deep remission had the most marked decrease in risk. Both endoscopic remission and clinical remission were associated with a decreased risk of CD disease progression after adjusting for confounders. Patients achieving deep remission were more likely to remain on adalimumab at the end of follow-up. Among patients in deep remission at the end of CALM, 61.1% were still receiving adalimumab compared to 34.9% of those not in deep remission (p=0.001). Following the CALM study, patients in deep remission had lower rates of cessation of adalimumab due to loss of response or adverse effects. Among patients in deep remission, the most common reasons for stopping adalimumab were cost or logistical factors (36%) and patient preference (29%).

Discussion

Prior studies have shown that patients with CD have improved clinical response and remission rates following the early introduction of immunomodulator and anti-TNF therapy. A similar impact of early intervention has also been noted in a large paediatric cohort [4]. However, these studies mostly reported shorter-term outcomes and did not examine the long-term impact of achieving early deep remission. For the first time, Ungaro et al. examine long-term outcomes of achieving early deep remission in CD. The present study showed that deep remission was associated with an 81% decrease in risk of adverse outcomes over a median of 3 years. Endoscopic remission was also significantly associated with decreased risk of disease progression but to a lower effect size than deep remission. These data validate the current recommended CD treatment strategies of early therapeutic intervention, TC and treat to target by highlighting the impact of early deep remission on long-term disease modification.

References

1. Berg DR, Colombel JF, Ungaro R. The role of early biologic therapy in inflammatory bowel disease. Inflamm Bowel Dis. 2019;25:1896–1905.
2. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324–38.
3. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2017;390:2779–89.
4. Walters TD, Kim M-O, Denson LA, et al. Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children wi

Omer Serhan Omer - Short Biography

Omer Serhan Omer is an MRC Clinical Research Training Fellow based at the IBD Centre, Guy’s & St Thomas’ NHS Foundation Trust, London, UK and the School of Immunology and Microbial Sciences at King’s College London. He is currently undertaking translation research to evaluate the effect of CDK inhibition on the transcriptional landscape of colonic CD4⁺ T cells and its utility as a novel therapeutic strategy for treatment-resistant IBD.