Y-ECCO Literature Review: Patrick Dawson
Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn's disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial
Schulberg JD, Wright EK, Holt BA, et al.
Lancet Gastroenterol Hepatol. 2022;7:318–31. doi: 10.1016/S2468-1253(21)00393-9.
© Patrick Dawson
Crohn’s Disease (CD) is a chronic gastrointestinal inflammatory condition  that commonly causes strictures, with more than 50% of patients developing at least one stricture in the first decade after diagnosis . Management options include biologics, endoscopic dilatation and surgery. Dilatation requires that the stricture be endoscopically accessible and medical therapy has limited benefit in fibrostenosing disease; therefore, surgery often remains the initial treatment of choice . MRI and ultrasound can provide detailed assessment but cannot always definitively quantify active inflammation [4, 5].
This open label, randomised control trial was carried out at a specialist IBD unit in Australia with the aim of establishing whether medical therapy is an effective treatment of stricturing CD and, if so, whether intensive medical therapy is more effective than standard therapy. The primary end point was an improvement in the 14-day obstructive symptom score by one or more points compared to baseline at 12 months. Secondary outcomes included: improvement in the Crohn’s Disease Activity Index (CDAI), C-reactive protein (CRP), faecal calprotectin (FCP), stricture morphology on MRI, small bowel ultrasound (SBUS) or endoscopy, and correlation of serum adalimumab concentration with any improvement.
Between September 2017 and September 2019, 77 patients over the age of 18 with a diagnosis of CD and with evidence of an inflammatory stricture on MRI and/or endoscopy were enrolled to either intensive medical therapy (52) or standard therapy (25). Active inflammation was defined as a CRP >5 mg/L, FCP >100 µg/g, increased small bowel thickness on MRI with contrast enhancement or oedema based on the MRI Index of Activity Score (MaRIA).
Both groups were able to undergo balloon dilatation at study entry if deemed necessary and prior biologic use was permitted; however, adalimumab could not have been used within the preceding year or have been ceased due to treatment failure. Patients underwent stratified block randomisation to distribute these factors between the groups.
Steroids were stopped within four weeks of study entry but two courses of steroids were permitted during the study. Exclusion criteria included: acute small bowel obstruction not responding to conventional treatment, patients needing urgent surgery, active perianal sepsis, internal fistulae, anal/rectal strictures, dysplasia/malignancy and a contraindication to MRI.
The intensive group patients commenced an escalated loading dose of adalimumab in addition to a thiopurine. If thiopurines were not tolerated, adalimumab monotherapy was continued. The standard group commenced standard dose adalimumab monotherapy.
Follow up occurred at 4 and 8 months with SBUS, CRP and FCP. If there was active inflammation, the dose of adalimumab was escalated to a maximum of 80 mg weekly in the intensive group. The standard group maintained the same dose. Final assessment was at 12 months with MRI, endoscopy, SBUS, CRP and FCP.
Obstructive symptom score at 12 months improved in both groups compared to baseline (5 from 17 in the intensive group and 6 from 17 in the standard group, p=<0.0001) but without a significant difference between the two groups: 79% of patients showed improvement in the intensive group vs 64% in the standard group (OR 2.1 [0.73–6.01]; p=0.17).
There was a significant difference in treatment failure between the two groups, with failure occurring in 10% of the intensive group vs 28% of the standard group (OR 0.27 [0.08–0.97]; p=0.045), but no significant difference was observed in the need for surgery (OR 0.44 [0.10–1.92]; p=0.27).
There was an improvement in CDAI but there was no significant difference between the groups with respect to a CDAI of <150 at 12 months, which was observed in 69% of the intensive group and 60% of the standard group (OR 1.5 [0.56–4.05]; p=0.42).
There was a significant difference between the intensive group (61%) and the standard group (28%) in terms of stricture severity assessed by the MaRIA score (OR 3.99 [1.41–11.26]; p=0.0091). However, significance was not achieved with regard to either complete resolution of strictures on MRI (20% in the intensive group vs 16% in the standard group: OR 1.28 [0.36–4.57]; p=0.70) or improvement in small bowel thickness on SBUS (51% in the intensive group vs 31% in the standard group: OR 0.15 [0.71–6.21]; p=0.18).
CRP and FCP both normalised in 62% of the intensive group vs 44% of the standard group, with no significant difference (OR 0.15 [0.77–5.36]; p=0.15).
Higher serum adalimumab concentrations were achieved in the intensive group and were less associated with active inflammation or dose escalation.
There was no significant difference between the intensive group (71%) and the standard group (56%) with regard to steroid-free clinical remission at 12 months (OR 1.94 [0.72–5.22]; p=0.19).
Quality of life scores and adverse events were similar in the two groups.
The authors conclude that the study findings provide a clear strategy for the management of stricturing CD with biologic treatment and that intensive therapy is the preferred option. Previous evidence from the CREOLE study and the SONIC study demonstrated symptomatic benefit from treating CD strictures with biologics and higher rates of steroid-free remission when using combination therapy [6, 7]; however, longer term data series have shown that 50% of patients still require surgery over a four-year period .
The results of this study met the primary and secondary end points but did not determine a significant difference between the two groups with the exception of improvement in MaRIA score at 12 months and a lower chance of treatment failure in the intensive group. The rate of surgical intervention did not differ significantly between the groups.
There were limitations to this study. The sample size was relatively small, with patients coming from a single centre, making it difficult to achieve significant results. Only the reporting radiologists in the study were blinded, which presents an opportunity for bias. As the follow-up period was only 12 months, the longevity of any response could not be assessed.
Although the results of the study showed an improvement in symptoms and inflammatory activity in stricturing CD with medical therapy, the absence of a comparison with surgical management and the limited length of the follow-up period mean that a clear strategy for the management of CD strictures cannot be proposed on the basis of the study data. Nevertheless, it is evident that medical management can play a role in the management of certain patient groups, particularly those unable to undergo surgery.
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- Bouhnik Y, Carbonnel F, Laharie D, et al. Efficacy of adalimumab in patients with Crohn’s disease and symptomatic small bowel stricture: a multicenter, prospective, observational cohort (CREOLE) study. Gut. 2018;67:53–60.
- Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.
- Schulberg JD, Wright EK, Holt BA, et al. Magnetic resonance enterography for predicting the clinical course of Crohn’s disease strictures. J Gastroenterol Hepatol. 2020;35:980–7.
Patrick Dawson - Short Biography
Patrick Dawson is a UK Gastroenterology Registrar currently working as a research fellow at Guys and St Thomas’ NHS Foundation Trust. His current interests include the pathophysiology of Inflammatory Bowel Disease and he has just started a laboratory-based research project to explore this further.