Y-ECCO Literature Review: Radha Gadhok
Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: retrospective long-term follow-up of the LIR!C trial
Stevens TW, Haasnoot ML, D’Haens GR, Buskens CJ, De Groof EJ, Eshuis EJ, Gardenbroek TJ, Mol B, Stokkers PCF, Bemelman WA, Ponsioen CY on behalf of the LIR!C study group
Lancet Gastroenterol Hepatol 2020 Jun 30;S2468-1253(20)30117-5. doi: 10.1016/S2468-1253(20)30117-5. Online ahead of print.
© Radha Gadhok
The positioning of medical therapies in the management of Crohn’s Disease (CD) continues to be debated  whilst surgery is reserved for cases with disease complications or failure of medical therapy. The LIR!C trial  provided evidence for surgical resection as an alternative to infliximab (IFX) in the management of localised terminal ileitis, a common presentation of CD .
Briefly, the LIR!C trial reported quality of life scores (IBDQ) among 143 adult patients with terminal ileitis (<40 cm) who underwent randomisation to IFX induction/maintenance or ileocaecal resection. Patients were recruited from 29 secondary and tertiary Dutch and British centres. Exclusion criteria included non-inflammatory disease, prestenotic dilatation, abscess and previous surgery. Inclusion criteria included failing at least three months of conventional therapy [immunomodulator (IM) and/or corticosteroid (CS)] 
At 12 months, IBDQ scores were similar in the two groups (IFX and resection). In the IFX group (n=70, with 65 starting IFX), 21 patients discontinued treatment, including 13 undergoing ileocaecal resection. In the resection group (n=73, with 70 undergoing resection), three patients started IFX. Follow-up data (median 4 years) revealed that an additional 13 patients in the IFX group underwent resection, and an additional 16 patients in the resection group started anti-TNF. In the IFX group (with no surgery), 84% (38/45) of patients achieved endoscopic remission, while in the resection group (with no IFX), 79% (42/53) achieved endoscopic remission .
In this study, Toer Stevens and colleagues retrospectively collected data from medical charts from the time of patient enrolment in the LIR!C trial to 2.5 years after trial completion. They sought to extend the follow-up data originally reported and to provide additional clinical outcome data, namely first additional medical or surgical intervention, the time to the first additional intervention (“duration of treatment effect”) and any associated baseline factors. Factors included age, CD duration, smoking status, perianal modifier, baseline CS use, IM use after randomisation and baseline CRP.
The median duration of follow-up was 63 months [IQR 34–92] among 69 patients in the resection group and 65 months [IQR 41–97] among 65 patients in the IFX group. In the resection group, 18 (26%) patients started anti-TNF treatment at a median 26 months [IQR 13–47], 22 (32%) required additional treatment with IM/CS, 15 (22%) did not require additional treatment, 14 (20%) continued prophylactic IM and no patients underwent additional surgery. In the IFX group, 31 (48%) patients had a resection for CD at a median of 17 months [IQR 6–34], 25 (38%) continued on IFX (or data were censored) and 9 (14%) required another biologic, IM or CS for active disease or drug intolerance/immunogenicity. Thus, patients in the resection group were less likely to “switch group” than patients in the resection group (log rank 0.01).
Duration of treatment effect was similar between the resection group (33 months [95% CI 15–50]) and the IFX group (34 months [95% CI 0–69], log rank p=0.5). Post hoc analysis of the IFX group (redefining additional first treatments to include only those for active CD/flare) demonstrated reduced risk of additional treatment in the IFX group, but no emergent difference between IFX and resection groups (log rank p=0.25). The indications for first additional treatment were endoscopic and/or radiological in 79% of patients in the resection group and in 65% of those in the IFX group.
Considering factors associated with duration of treatment effect by univariate regression: In the resection group, prophylactic IM treatment was associated with decreased risk of additional therapy (0.39 [95% CI 0.20–0.79], p=0.009) and this association was sustained in multivariate analysis (0.34 [95% CI 0.16–0.69], p=0.003); in the IFX group, the use of IM showed a similar association (0.49 [95% CI 0.26–0.93], p=0.028) in univariate analysis (no multivariate analysis required). A combined model showed no difference in the protective effect of IM between the treatment groups. When post hoc analysis was carried out as above, the results suggested that the protective effect of IM in the IFX group is mainly an effect of reduced immunogenicity.
Early surgery in newly diagnosed ileocaecal CD has been shown in cohort studies to impact on clinical outcomes, including by reducing the requirement for biologics . The LIR!C trial  (the only RCT in this area) selected patients often escalated to biologics and demonstrated a similar duration of treatment effect between resection and IFX groups.
Meta-analysis of 11 studies showed a 5-year risk of second surgery of 24.2% . Although reported second surgery rates vary, it is recognised that they are decreasing over time. This study found that no patients in the resection group required further surgery at five years. The authors suggest that increased postoperative surveillance and early timing of surgery may be contributing to this improvement.
Debate around the impact of biologics on surgical rates in CD continues . In this study the authors found a 48% rate of surgery in the IFX group. If patients with limited benefit from biologics could be identified and early surgery offered, exposure to potentially toxic drugs could be avoided. Although some progress is being made in this area , this is yet to translate to clinical practice.
The authors acknowledge study limitations, including lack of algorithms for follow-up. Although length of follow-up was similar between the groups, the frequency and type of follow-up was not reported. While the type of evidence for active CD is summarised, further details of disease flare, including the site of disease recurrence, are not described. The focus of this study was limited to the first additional therapy, resection and anti-TNF treatment, and as a consequence neither multiple additional treatments received during follow-up nor interventions such as endoscopic dilatation were reported. In the multivariate analysis, it was not possible to include faecal calprotectin or radiological or endoscopic data. Finally, evolving practices in optimising medical treatment (e.g. drug monitoring and concomitant IM) [8, 9] were not uniformly employed .
Overall, this study adds support for including surgery in the treatment options for limited terminal ileitis. Individual patient-level decision-making remains multifactorial and may include discussion around surgical vs drug risks : for “surgery-averse” patients, it is significant that half of all IFX patients avoided surgery at five years; on the other hand, for “drug-averse” patients it is significant that three-quarters of surgical patients avoided an anti-TNF and one-fifth managed to avoid any further treatment. To help patients further, research to develop predictors of benefit from medical and surgical treatments is urgently needed.
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Radha Gadhok – Short Biography
Radha Gadhok is a gastroenterology trainee at The Royal London Hospital and is undertaking a PhD at The Blizard Institute, Queen Mary University of London. She is exploring the development, differentiation and function of intestinal monocyte-derived cells in Crohn’s Disease and has an interest in predicting treatment response in IBD.