Almost two thirds of patients with Crohn's disease (CD) and symptomatic small bowel stricture respond to the tumor necrosis factor (TNF) inhibitor adalimumab after 24 weeks of treatment, according to results from the multicenter, observational, GETAID CREOLE study. In addition, nearly half the patients who respond remain surgery-free 4 years later.

"There have been concerns regarding the use of anti-TNFs in patients with established strictures," lead author Yoram Bouhnik, MD, PhD, Gastroentérologie, MICI et Assistance Nutritive, Hôpital Beaujon, Clichy, France, and colleagues explain. "Indeed, several reports have suggested that they increase the risk of intestinal obstruction."

"We were surprised both for the fact that two thirds of patients achieved success at week 24 and for the maintenance of this effect over time, as the majority of [successful responders] were free of surgery after a median follow-up of 4 years," Dr Bouhnik added in an email to Medscape Medical News.

The study was published online January 24 in Gut.

Ninety-seven patients with a diagnosis of Crohn's disease were included in the analysis. Patients also had to have either a single or several small bowel strictures located in the duodenum, jejunum, or ileum accompanied by obstructive symptoms within the last 8 weeks before enrolment. All patients underwent magnetic resonance enterography (MRE) before study entry.

"Adalimumab was administered subcutaneously at baseline (week 0) at a dose of 160 mg, followed by 80 mg at week 2, and then 40 mg every other week," Dr Bouhnik and colleagues write. Importantly, 42% of patients were also receiving either a thiopurine or methotrexate at baseline and immunosuppression was maintained throughout the study. Steroids, however, could be tapered if the treating physician felt patients could do well without them.

At 24 weeks, treatment was deemed a success and adalimumab continued if the patient had not required any type of prohibited treatment, including the use of corticosteroids after the eighth week of the study, or had not required either endoscopic dilation or bowel surgery to alleviate small bowel stricture.

"In total, 62 out of the 97 patients (64%) reached success at week 24," the authors write. Among this group of patients, 88% achieved a Crohn's Disease Activity Index of less than 150.

At a median follow-up of 3.8 years, 45.7% of patients were still receiving adalimumab and had required neither dilation nor surgery at the end of follow-up, indicating that 29% of the original cohort responded successfully to adalimumab, as defined by the CREOLE investigators.

Commenting further on findings, Dr Bouhnik says the results suggest that adalimumab not only delays the need for surgery but may also modify the natural history of the disease, even for patients with long-standing Crohn's disease.

"Our results are in accordance with studies showing that anti-TNFs are able to reverse strictures which are thought to be nonreversible according to the Lemann Index in some Crohn's disease patients," he observed.

He noted that it may not be adalimumab alone that has this effect. "It's probably a class effect, but for the homogeneity of the cohort, we always used the same anti-TNF agent, and it's difficult to extrapolate these results to infliximab," he added.

Prognostic Score

The Lemann Index is used to measure cumulative structural bowel damage in patients with Crohn's disease and helps clinicians better judge both disease progression and the efficacy of treatment.

In this study, the investigators also arrived at a prognostic score to better predict who might respond to adalimumab. Factors that contributed to a patient's prognostic score included both clinical and radiological features of the disease.

"The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes," the investigators observe. Among patients in either the good or intermediate prognostic group, almost 78% achieved success on adalimumab at week 24.

Table. Independent Factors Associated With a High Rate of Success (Each Factor Is Worth 1 Point)

Factors OR of Success P Value Immunosuppressive treatment (yes) 3.42 .040 Crohn's disease obstructive score >4 3.48 .046 Duration of obstructive symptoms (<5 weeks) 6.00 .016 Length of stricture (<12 cm) 6.04 .0042 Maximal small bowel diameter proximal to stricture or strictures (18 - 29 mm) 7.32 .0013 Enhancement on delayed T1-weighted sequence/marked 5.92 .0034 Fistula (n0) 4.72 .035

In contrast, almost 95% of patients in the poor prognostic group failed to respond to the same treatment regimen. "This is the first demonstration that a score is able to clearly distinguish patients who will have benefit from medical treatment from those who won't," Dr Bouhnik explained to Medscape Medical News.

"Of course, this score needs to be validated in an independent cohort, which is ongoing, but already, this score has changed our practice," he added. "When the sum of items is 2 out of 7 or below, we usually go directly to surgery."

Asked by Medscape Medical News to comment on the study, Sunanada Kane, MD, from the Mayo Clinic, Rochester, Minnesota, noted that the CREOLE study set out to answer an important clinical question; namely, in patients with active symptoms and a known stricture, will an anti-TNF agent prevent surgery?

"The results are very encouraging and point out that patients need to be evaluated using several modalities to assess the amount of active inflammation that may be present prior to treatment," she added. Although the majority of patients enrolled in CREOLE had elevated C-reactive protein levels, "they were not high risk for surgery," Dr Kane observed, "and had a good chance of having therapeutic success."

"Thus, just because a stricture is present, it does not mean that the stricture is the driver of all symptoms, and it's therefore important to take a good history and use MRE results in the context of a patient's symptoms," she emphasized.

Peter Higgins, MD, PhD, director of the inflammatory bowel disease center at the University of Michigan in Ann Arbor, agreed with Dr Kane. He added that the most important part of the CREOLE study was not the fact that an anti-TNF agent worked in this particular setting, but that clinicians are getting closer to being able to predict which patients with Crohn's disease and strictures should go to surgery without delay and which may well respond to treatment and deserve a chance at medical therapy first.

"Up until now, people have thrown their hands up and said, 'Let's just treat everybody, and if they get readmitted to the hospital 3 times in 6 months, we'll send them to surgery,'" he told Medscape Medical News. "So it's been a fairly nihilist approach, and patients suffer a lot," he added.

"The key thing coming out of this study is that you can risk-stratify patients — you don't have to treat every stricture the same — because there are markers that can tell you you're better off going to surgery right away, whereas there are other patients who are much more likely to respond to treatment, and it really is worth taking a shot at therapy," he added.

Indeed, Dr Higgins and colleagues published a similar paper in 2016. Whereas several of their prognostic markers overlap with those used by Dr Bouhnik and colleagues, some did not. For example, they found that having a narrowing with a big upstream dilation was a very powerful predictor of a patient's need to proceed to surgery within the next 2 years, as was a platelet:albumin ratio of 125 or greater.

"I think a lot of people are working on this because it has been such a difficult problem," he concluded.

The study was funded by AbbVie. The CREOLE authors declared the following conflicts of interest: consultancies: BMS, Shire, Sanofi, Norgine Pharma, MSD, AbbVie, Astra Zeneca, Roche, Takeda Millenium, Janssen Cilag, Pfizer; stock ownership: Inception IBD; USA Honoraria: BMS, MSD, AbbVie, Teva, Ferring, Vifor Pharma, HAC, Mayoli-Spindler; paid expert testimony: AbbVie; and travel grants: AbbVie; MSD, Ferring, Takeda, Vifor Pharma. Both Dr Kane and Dr Higgins report that they have been consultants for AbbVie but were not involved in the CREOLE study.

Gut. Published online January 24, 2017. Full text

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