Meeting News

‘Tight control’ of inflammatory biomarkers improves outcomes in Crohn’s disease

Jean-Frederic Colombel, MD
Jean-Frederic Colombel

A treat-to-target strategy using “tight control” of inflammatory biomarkers in addition to clinical symptom monitoring led to improved outcomes in patients with Crohn’s disease on Humira, according to data from the CALM study presented at UEG Week.

Detailed results were also recently published in The Lancet.

“With this study, we have implemented a new concept of ‘tight control’ of Crohn’s disease, which will change the way that patients will be followed in clinical practice,” Jean-Frederic Colombel, MD, director of The Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at The Mount Sinai Hospital and professor of medicine and gastroenterology at the Icahn School of Medicine at Mount Sinai, said in a press release. “Treatment should be based on objective markers of inflammation and not only on symptoms. A patient with Crohn’s disease may do well clinically, but if biomarkers for the disease remain high, we still need to escalate interventions including drugs. This study shows tight control led to more patients experiencing clinical remission, which will ultimately improve their long-term outcomes.”

In this phase 3 trial comparing the treat-to-target approach with standard clinical management, Colombel and colleagues randomly assigned 244 patients with moderate-to-severe Crohn’s disease (mean age, 31.6 ± 11.7 years; 57.8% women) to one of the two strategies after 8 weeks of prednisone induction therapy, or sooner if their disease was active. Patients were recruited from 74 centers spanning 22 countries, and none had previously used immunomodulators or biologics.

Both groups received stepwise treatment escalation when patients reported increased clinical symptoms, beginning with no treatment, then induction therapy with Humira (adalimumab, AbbVie) every other week, then adalimumab every week, and finally both adalimumab and azathioprine every week. In the treat-to-target group, treatment escalation also occurred when C-reactive protein (CRP) blood levels exceeded 5 mg/L or fecal calprotectin exceeded 250 g/g.

Colombel and colleagues found that 45.9% of the treat-to-target patients achieved mucosal healing after 48 weeks compared with just 30.3% of those who receive standard clinical management (P = .01). Significantly more of these patients also achieved deep remission, defined as a Crohn’s Disease Activity Index score less than 150, no steroids for 8 weeks, no fistula or deep ulcers, and a Crohn’s Disease Endoscopic Index of Severity (CDEIS) score less than 4 (36.9% vs. 23%; P = .014). Further, significantly more of these patients achieved biologic remission, defined as fecal calprotectin less than 250 g/g, CRP less than 5 mg/L, and CDEIS score less than 4 (29.5% vs. 15.6%; P = .006).

The treat-to-target patients advanced more rapidly in the treatment algorithm, and were more often able to de-escalate therapy at 24 and 36 weeks.

Adverse events were comparable, with 86% vs. 82% reporting treatment-emergent adverse events, and 26% vs. 24% discontinuing the study primarily due to adverse events.

A secondary analysis showed the treat-to-target patients also experienced fewer major adverse outcomes, including Crohn’s disease-related hospitalizations (13.2 vs. 28 per 100 patients; P = .021). The rates of Crohn’s disease-related surgical procedures were comparable between groups, but treat-to-target was correlated with a numerically but not statistically significant risk for Crohn’s disease-related hospitalization or serious complication (HR = 0.7; 95% CI, 0.4-1.4).

Colombel and colleagues concluded that this is “the first study to show that timely escalation with an anti-tumor necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn’s disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone, and noted that more research is required to determine whether the tight control strategy can reduce hospitalizations, surgeries, complications and disability in the long-term.

“When patients with Crohn’s disease are making therapeutic decisions about starting a drug, or escalating or de-escalating a drug, they can’t base these decisions on symptoms alone,” Colombel said in the press release. “They need objective data including biomarkers and endoscopy results. Ultimately this will disable their disease from progressing.”

Stephen B. Hanauer, MD
Stephen B. Hanauer

“Like rheumatoid arthritis, assessment of structural damage in CALM, based on mucosal healing, was not assessed as an early endpoint, but rather as a more realistic outcome after almost 1 year of treatment,” Stephen B. Hanauer, MD, of the Feinberg School of Medicine at Northwestern University, Chicago, wrote in a related editorial. “Interim monitoring by the readily available biomarkers CRP and [fecal calprotectin] were used as surrogates to advance therapy.

“Despite not yet achieving disease modification, evidence continues to accrue that treating more than just symptoms and targeting biological disease activity with effective steroid-sparing agents can improve long-term clinical outcomes in Crohn’s disease,” he concluded. – by Adam Leitenberger

References:

Colombel J, et al. Abstract OP225. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Colombel J, et al. Abstract OP227. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Colombel JF, et al. The Lancet. 2017;doi: 10.1016/S0140-6736(17)32641-7.

Hanauer SB. The Lancet. 2017;doi:10.1016/S0140-6736(17)32754-X.

Disclosures: AbbVie funded this trial. Colombel reports financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen, MedImmune, Merck & Co, Pfizer, Protagonist Therapeutics, PPM Services, Second Genome, Seres Therapeutics, Shire, Takeda, Theradiag, Intestinal Biotech Development, and Genfit. Hanauer reports financial relationships with AbbVie, Actavis, Allergan, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Janssen, Eli Lilly, Gilead Sciences, Genentech, GlaxoSmithKline, Hospira, Merck, Novartis, Pfizer, Prometheus Laboratories, Atlantic, Receptos, Salix, Samsung Bioepis, Sanofi-Aventis, Seres Therapeutics, Shire, Takeda, Thetis, TiGenix, UCB Pharma, and VHsquared. Please see the full study for a list of all other authors’ relevant financial disclosures.

 

Jean-Frederic Colombel, MD
Jean-Frederic Colombel

A treat-to-target strategy using “tight control” of inflammatory biomarkers in addition to clinical symptom monitoring led to improved outcomes in patients with Crohn’s disease on Humira, according to data from the CALM study presented at UEG Week.

Detailed results were also recently published in The Lancet.

“With this study, we have implemented a new concept of ‘tight control’ of Crohn’s disease, which will change the way that patients will be followed in clinical practice,” Jean-Frederic Colombel, MD, director of The Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at The Mount Sinai Hospital and professor of medicine and gastroenterology at the Icahn School of Medicine at Mount Sinai, said in a press release. “Treatment should be based on objective markers of inflammation and not only on symptoms. A patient with Crohn’s disease may do well clinically, but if biomarkers for the disease remain high, we still need to escalate interventions including drugs. This study shows tight control led to more patients experiencing clinical remission, which will ultimately improve their long-term outcomes.”

In this phase 3 trial comparing the treat-to-target approach with standard clinical management, Colombel and colleagues randomly assigned 244 patients with moderate-to-severe Crohn’s disease (mean age, 31.6 ± 11.7 years; 57.8% women) to one of the two strategies after 8 weeks of prednisone induction therapy, or sooner if their disease was active. Patients were recruited from 74 centers spanning 22 countries, and none had previously used immunomodulators or biologics.

Both groups received stepwise treatment escalation when patients reported increased clinical symptoms, beginning with no treatment, then induction therapy with Humira (adalimumab, AbbVie) every other week, then adalimumab every week, and finally both adalimumab and azathioprine every week. In the treat-to-target group, treatment escalation also occurred when C-reactive protein (CRP) blood levels exceeded 5 mg/L or fecal calprotectin exceeded 250 g/g.

Colombel and colleagues found that 45.9% of the treat-to-target patients achieved mucosal healing after 48 weeks compared with just 30.3% of those who receive standard clinical management (P = .01). Significantly more of these patients also achieved deep remission, defined as a Crohn’s Disease Activity Index score less than 150, no steroids for 8 weeks, no fistula or deep ulcers, and a Crohn’s Disease Endoscopic Index of Severity (CDEIS) score less than 4 (36.9% vs. 23%; P = .014). Further, significantly more of these patients achieved biologic remission, defined as fecal calprotectin less than 250 g/g, CRP less than 5 mg/L, and CDEIS score less than 4 (29.5% vs. 15.6%; P = .006).

PAGE BREAK

The treat-to-target patients advanced more rapidly in the treatment algorithm, and were more often able to de-escalate therapy at 24 and 36 weeks.

Adverse events were comparable, with 86% vs. 82% reporting treatment-emergent adverse events, and 26% vs. 24% discontinuing the study primarily due to adverse events.

A secondary analysis showed the treat-to-target patients also experienced fewer major adverse outcomes, including Crohn’s disease-related hospitalizations (13.2 vs. 28 per 100 patients; P = .021). The rates of Crohn’s disease-related surgical procedures were comparable between groups, but treat-to-target was correlated with a numerically but not statistically significant risk for Crohn’s disease-related hospitalization or serious complication (HR = 0.7; 95% CI, 0.4-1.4).

Colombel and colleagues concluded that this is “the first study to show that timely escalation with an anti-tumor necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn’s disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone, and noted that more research is required to determine whether the tight control strategy can reduce hospitalizations, surgeries, complications and disability in the long-term.

“When patients with Crohn’s disease are making therapeutic decisions about starting a drug, or escalating or de-escalating a drug, they can’t base these decisions on symptoms alone,” Colombel said in the press release. “They need objective data including biomarkers and endoscopy results. Ultimately this will disable their disease from progressing.”

Stephen B. Hanauer, MD
Stephen B. Hanauer

“Like rheumatoid arthritis, assessment of structural damage in CALM, based on mucosal healing, was not assessed as an early endpoint, but rather as a more realistic outcome after almost 1 year of treatment,” Stephen B. Hanauer, MD, of the Feinberg School of Medicine at Northwestern University, Chicago, wrote in a related editorial. “Interim monitoring by the readily available biomarkers CRP and [fecal calprotectin] were used as surrogates to advance therapy.

“Despite not yet achieving disease modification, evidence continues to accrue that treating more than just symptoms and targeting biological disease activity with effective steroid-sparing agents can improve long-term clinical outcomes in Crohn’s disease,” he concluded. – by Adam Leitenberger

References:

Colombel J, et al. Abstract OP225. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Colombel J, et al. Abstract OP227. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Colombel JF, et al. The Lancet. 2017;doi: 10.1016/S0140-6736(17)32641-7.

Hanauer SB. The Lancet. 2017;doi:10.1016/S0140-6736(17)32754-X.

Disclosures: AbbVie funded this trial. Colombel reports financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen, MedImmune, Merck & Co, Pfizer, Protagonist Therapeutics, PPM Services, Second Genome, Seres Therapeutics, Shire, Takeda, Theradiag, Intestinal Biotech Development, and Genfit. Hanauer reports financial relationships with AbbVie, Actavis, Allergan, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Janssen, Eli Lilly, Gilead Sciences, Genentech, GlaxoSmithKline, Hospira, Merck, Novartis, Pfizer, Prometheus Laboratories, Atlantic, Receptos, Salix, Samsung Bioepis, Sanofi-Aventis, Seres Therapeutics, Shire, Takeda, Thetis, TiGenix, UCB Pharma, and VHsquared. Please see the full study for a list of all other authors’ relevant financial disclosures.