Table 1.
Summary of the studies reporting on the management of Crohn’s disease postoperative recurrence.
| Author and Study Year | Outcome | Type of Trial | Drug vs. Placebo/Drug Efficacy Comparison | Number of Patients | Endoscopic Response |
Clinical Response |
Primary Endpoint |
Secondary Endpoint |
Duration of Follow-up | Adverse Events | Comments |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Macaluso et al., 2023 [18] | Endoscopic and clinical response | Real-world observational study | UST | 44 | 50% achieved a reduction of at least one point in RS | 72.7% clinical success | Reduction of at least one point in RS | Clinical success (absence of clinical failure) | 17.8 ± 8.4 months | No adverse events reported | UST initiated for endoscopically documented POR, with significant rates of endoscopic and clinical success |
| Huinink et al., 2023 [28] | Retreatment with anti-TNF therapy for postoperative Crohn’s disease recurrence is valid. Combination therapy is more effective than monotherapy. | Retrospective cohort study | Anti-TNF therapy vs. combination therapy | 364 | Not specified | Not specified | Treatment failure rate (need for reintroduction of corticosteroids, immunosuppressants, or biologicals or need for re-resection) | Treatment failure rate at 1 and 2 years, analysis of preoperative anti-TNF failure, combination therapy vs. monotherapy, retreatment with the same or different anti-TNF agent | 1 and 2 years | Not specified | Retreatment with anti-TNF therapy post-ICR is effective, especially with combination therapy. The study highlights the importance of combination therapy to reduce treatment failure rates |
| Bachour et al., 2023 [19] | Change in Biologic Class Promotes Endoscopic Remission Following Endoscopic Postoperative Crohn’s Disease Recurrence | Retrospective Cohort Study | New Biologic Class vs. Therapy Optimization/Continuation | 81 | Initiation of a new biologic class was associated with a higher rate of endoscopic improvement | 60 patients (74.1%) experienced composite recurrence (persistent ePOR or surgical recurrence) | Composite endoscopic or surgical recurrence | Reduction of modified RS | Median follow-up from ePOR to subsequent endoscopy: 426.5 days | Not specified specifically for each intervention | The study emphasizes the benefit of changing the biologic class after the detection of ePOR despite prophylactic biologic therapy |
| Ueda et al., 2023 [29] | Endoscopic and clinical response | Retrospective cohort study | Biologic era treatments | 267 | Postoperative anastomotic lesions were detected in 61.0% at index ileocolonoscopy and 74.9% at follow-up ileocolonoscopy | Patients with intermediate or severe lesions required significantly more interventions (endoscopic dilation or surgery) | Frequency and severity of postoperative anastomotic lesions | Interventions required (endoscopic dilation or surgery) | ~1 year, follow-up duration not specified | Not reported | Frequent and increasing severity of anastomotic lesions observed, prospective studies needed to evaluate treatment enhancement |
| De Cruz et al., 2022 [30] | Endoscopic and clinical response | Randomized controlled trial | Thiopurine/ADA vs. Placebo | 85 | A combination of ulcer depth and circumference at 6 months was associated with endoscopic recurrence at 18 months | 38% remission at 12 months for patients who stepped up treatment at 6 months, 39% recurrence at 6 months | A combination of ulcer depth and circumference at 6 months was associated with endoscopic recurrence at 18 months | N/A | 18 months | N/A | The combination of ulcer depth and circumference at anastomosis at 6 months was predictive of endoscopic recurrence at 18 months |
| Marques Cami et al., 2022 [31] | Endoscopic and clinical response | Case report | Ruxolitinib | 1 | More than 50% reduction of ulcerated mucosa in both ileocolonic anastomosis and neoileum | Clinical remission for six months, no further budesonide cycles needed | Reduction of ulcerated mucosa, clinical remission | Fecal calprotectin levels, blood test normalization | 6 months | No adverse events reported | Patient showed significant clinical and endoscopic improvement related to ruxolitinib treatment, with satisfactory evolution of polycythemia vera |
| Macaluso et al., 2022 [32] | Endoscopic and clinical response | Cohort study | VDZ | 58 | Endoscopic success in 47.6% (reduction of at least one point of RS) | Clinical failure in 19.0% at one year, 32.8% at the end of follow-up, 12.1% required new resection | Endoscopic success (reduction of at least one point RS) | Clinical failure, need for new resection | Mean 24.8 ± 13.1 months | Not reported | VDZ shows potential effectiveness in treating POR of CD |
| Orlando et al., 2020 [20] | Endoscopic and clinical response | Randomized double-blind double-dummy trial | AZA vs. High-dose 5-aminosalicylic acid (5-ASA) | 46 | AZA: 6 (27.3%) with RS decrease ≥ 2 points, 8 (36.4%) with decrease ≥ 1 point; 5-ASA: 2 (8.3%) with RS decrease ≥ 2 points, 2 (8.3%) with decrease ≥ 1 point | AZA: 3 (13.6%) clinical recurrence; 5-ASA: 5 (20.8%) clinical recurrence | Therapeutic failure (clinical recurrence or drug discontinuation due to adverse events) at 12 months | 10-year post-trial analysis of clinical and endoscopic outcomes | 12 months | AZA: 3 adverse events leading to drug discontinuation (fever, hyperamylasemia, mild pancreatitis) | No significant difference in treatment failure between 5-ASA and AZA, AZA has a less favorable safety profile but may be more effective in preventing clinical recurrence |
| Canete et al., 2020 [21] | Endoscopic and clinical response | Multicenter retrospective observational study | IFX vs. ADA | 179 | Endoscopic improvement in 61%, endoscopic remission in 42% | 59% clinical remission in patients with clinical POR at the start of therapy | Effectiveness of anti-TNF agents in improving mucosal lesions | Endoscopic improvement, clinical remission | Median 31 months (IQR 13–54) | Not specified | IFX showed higher rates of endoscopic response and remission compared to ADA; concomitant thiopurine use increased efficacy |
| Riviere et al., 2021 [33] | Clinical and surgical recurrence | Retrospective cohort study | Immunosuppressants and biologics | 365 | RS ≥ i2 associated with increased risk of clinical and surgical recurrence | 48% clinical POR, 26% modified surgical POR within a median follow-up of 88 months | Clinical POR rates, surgical POR rates | Impact of endoscopy-guided therapy modification | Median 88 months | Not reported | RS ≥ i2 patients more likely to receive new therapy; modest decrease in clinical POR for RS i3 and i4 with immunosuppressants or biologics; no benefit for RS i2 |
| Hu et al., 2016 [34] | Endoscopic and clinical response | Case report | Thalidomide | 1 | Mucosal healing achieved at 9 months; RS declined from i2 to i1 | Clinical remission at 15 months | Mucosal healing (MH) of anastomotic ulcers | Endoscopic and clinical improvement | 15 months | No adverse effects reported | Thalidomide is effective in inducing mucosal healing in postoperative CD endoscopic recurrence |
| De Cruz et al., 2015 [22] | Endoscopic and clinical response | Randomized controlled trial | Thiopurine/ADA vs. Metronidazole alone | 174 | 60 (49%) in the active care group had endoscopic recurrence at 18 months vs. 35 (67%) in standard care | 33 (27%) in the active care group had clinical recurrence (CDAI > 200) vs. 21 (40%) in standard care | Endoscopic recurrence at 18 months | Clinical recurrence, C-reactive protein levels, need for further surgery | 18 months | No significant differences between active care and standard care groups | Early colonoscopy and treatment step-up for recurrence is better than conventional drug therapy alone |
| Zabana et al., 2014 [35] | Endoscopic and clinical response | Case-control study | Thiopurines with mesalamine vs. Thiopurines alone | 37 | Endoscopic improvement in 49%, no difference between groups | 32% clinical recurrence in cases, 11% in controls (p = 0.2) | Development of clinical recurrence | Change in RS, mucosal lesions | Median 59 months (IQR 22–100) | No specific adverse effects reported for mesalamine | Mesalamine addition showed no benefit over thiopurine alone for endoscopic improvement or clinical recurrence rates |
| Reinisch et al., 2013 [36] | Clinical recurrence | Follow-up survey of randomized double-blind double-dummy trial | AZA vs. Mesalamine | 46 | N/A | 36% clinical recurrence with AZA, 25% with mesalamine within 24 months post-treatment | Clinical recurrence within 24 months post-treatment | Long-term prevention of clinical recurrence | Approximately 4 years | N/A | No significant difference in time to clinical recurrence between AZA and mesalamine |
| Yamamoto et al., 2013 [37] | Endoscopic and clinical response | Prospective cohort study | Enteral nutrition (EN) vs. Control | 40 | 56% (EN) vs. 82% (control) endoscopic recurrence | 30% (EN) vs. 60% (control) clinical recurrence | Recurrence requiring biologic therapy or reoperation | Clinical recurrence rate, reoperation rate | 5 years | Diarrhea and abdominal distension in the EN group | EN significantly reduced the incidence of recurrence requiring biologic therapy, though compliance issues noted |
| Papamichael et al., 2012 [3] | Endoscopic and clinical response | Prospective, single-center, open-label, two-year pilot study | ADA | 23 | 60% (9/15) achieved complete (RS-i0) or near-complete (RS-i1) mucosal healing at 24 months | 56% (5/9) of patients with clinical relapse at study enrolment achieved and maintained clinical and serological remission | Prevention of early (at 6 months) and late (at 24 months) PO-ER (Group I) and rate of complete mucosal healing (Group II) | Endoscopic and clinical improvement (Group II) | 24 months | No serious adverse events reported | ADA is effective in preventing and treating PO-ER and PO-CR in high-risk CD patients |
| Sorrentino et al., 2012 [23] | Endoscopic and clinical response | Prospective open-label multicenter pilot study | IFX vs. Mesalamine | 24 | IFX: 54% endoscopic remission, 69% improvement in endoscopic score; Mesalamine: 0% endoscopic remission, no improvement in endoscopic score | IFX: 0% clinical recurrence; Mesalamine: 18% clinical recurrence at 8 and 9 months | Proportion of patients with endoscopic remission (score < 2) after 54 weeks | Improvements in endoscopic scores, clinical recurrence at 54 weeks | 54 weeks | Flu-like symptoms in 3 patients in the IFX group, new positivity for anti-DNA and lupus anticoagulant antibodies in 2 patients | IFX is superior to mesalamine in treating postoperative endoscopic recurrence of CD, though prophylactic use of IFX may be more effective |
| Reinisch et al., 2010 [24] | Clinical and endoscopic recurrence | Randomized double-blind double-dummy multicenter trial | AZA vs. Mesalamine | 78 | 63.3% of AZA patients showed ≥1 point reduction RS vs. 34.4% of mesalamine patients | 22.0% therapeutic failure in the AZA group vs. 10.8% in the mesalamine group; clinical recurrence: 0% (AZA) vs. 10.8% (mesalamine) | Therapeutic failure during 1 year (CDAI ≥ 200 and increase of ≥60 points from baseline or drug discontinuation due to lack of efficacy/adverse reaction) | Endoscopic improvement at month 12, CDAI score change, IBDQ score change, CRP level change, mucosal healing | 12 months | Adverse drug reactions led to discontinuation in 22.0% of AZA patients (e.g., pancreatitis, leucopenia) | AZA showed superior endoscopic improvement but higher adverse event-related discontinuations compared to mesalamine |
| Regueiro et al., 2010 [25] | Endoscopic and clinical response | Long-term follow-up of randomized controlled trial | IFX vs. Placebo | 24 | 71% remission in the placebo group switched to INF at 2 years; recurrence in all INF patients who stopped at 1 year | Not specified | Long-term endoscopic remission and recurrence rates after surgery | Effectiveness of INF beyond the first postoperative year, response to INF after recurrence | Up to 4.5 years | Infusion reactions leading to switch to (ADA) in some patients | INF maintains remission with ongoing infusions; recurrence if stopped; effective in treating endoscopic recurrence in anti-TNF naive patients post-surgery |
| Yamamoto et al., 2009 [10] | Endoscopic and clinical response | Prospective pilot study | IFX vs. Mesalamine vs. AZA | 26 | 75% endoscopic improvement with IFX, 38% with AZA, 0% with mesalamine | 0% clinical recurrence with IFX, 38% with AZA, 70% with mesalamine | Clinical recurrence (CDAI > 150) at 6 months | Endoscopic improvement, changes in mucosal cytokine levels | 6 months | No serious adverse events reported | IFX significantly reduced clinical and endoscopic recurrence and mucosal cytokine levels compared to AZA and mesalamine |
| Biancone et al., 2006 [38] | Endoscopic and clinical response | Pilot open-label study | Local injection of IFX | 8 | Endoscopic score improved in 3/8 patients, reduced number and extent of lesions in 7/8 patients | No clinical relapse observed during the follow-up period | Feasibility and safety of local iIFXnfliximab injection for CD recurrence | Clinical remission, histologic score, and assessment of local side effects | Median 20 months (range 14–21 months) | No local or systemic side effects reported | IFX injections were feasible and safe, with reduced lesion extent in most patients; further placebo-controlled studies needed to assess efficacy |
| Alves et al., 2004 [39] | Clinical recurrence | Retrospective cohort study | Immunosuppressive (IS) drugs (AZA, 6-mercaptopurine, or methotrexate) vs. Control (salicylates or no treatment) | 26 | N/A | Clinical recurrence rate at 3 years: IS group 25%, Control group 60% | Clinical recurrence rate at 3 years | Recurrence rate at follow-up, third intestinal resection rate | Mean follow-up of 80 ± 46 months | No specific IS complications reported | IS drugs lowered clinical recurrence and third resection rates after the second resection for ileocolonic anastomotic recurrence in CD patients |
| Dejaco et al., 2004 [40] | Endoscopic and clinical response | Open-label pilot study | (rhG-CSF) | 5 | Complete mucosal healing in 2 patients (40%); Partial response in 4 patients (80%) | All patients remained in clinical remission for 12 months | Complete mucosal healing (RSi0) | Intestinal permeability, cytokine levels, quality of life (IBDQ) | 12 months | Transient headache, mild bone and muscle pain observed in 2 patients | rhG-CSF was well tolerated and demonstrated potential efficacy in treating severe endoscopic POR in CD patients |
| De Cruz et al., 2013 [41] | Endoscopic and clinical response | Multicenter randomized controlled trial | Immediate postoperative ADA vs. Step-up ADA at 6 months | 60 | 43% endoscopic recurrence with immediate Adalimumab, 59% with step-up Adalimumab | 32% complete mucosal normality with immediate ADA, 22% with step-up ADA | Endoscopic recurrence at 18 months | Severe disease recurrence rates, mucosal healing | 18 months | Not specifically reported | No significant difference in recurrence; step-up anti-TNF therapy based on endoscopic findings viable for high-risk patients |
| Reinisch et al., 2008 [42] | Clinical and endoscopic response | Randomized double-blind double-dummy multicenter trial | AZA vs. Mesalamine | 78 | 46.3% endoscopic improvement with AZA vs. 29.7% with mesalamine (ITT); 63.3% vs. 34.4% (completer analysis) | Not specified | Therapeutic failure (CDAI ≥ 200 or drug discontinuation due to lack of efficacy or intolerable adverse reaction) | Endoscopic improvement (≥ 1 point drop in RS) | 52 weeks | Not specified | No significant difference in therapeutic failure rates; higher endoscopic improvement with AZA |
Abbreviations: CD—Crohn’s disease, RS—Rutgeerts score, POR—postoperative recurrence, rhG-CSF—granulocyte colony-stimulating factor, AZA—azathioprine, IFX—infliximab, ADA—adalimumab, UST—Ustekinumab, VDZ—vedolizumab.