Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. METHODS: This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. RESULTS: Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. CONCLUSIONS: The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

Immunomodulator Withdrawal From Anti-TNF Therapy Is Not Associated With Loss of Response in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The benefit of concomitant immunomodulators (thiopurines or methotrexate) in patients with inflammatory bowel disease (IBD) on anti-tumor necrosis factor α (anti-TNF) (infliximab or adalimumab) maintenance therapy is debated. We compared outcomes after immunomodulator withdrawal vs continuation of combination therapy. METHODS: This was a retrospective cohort study in a general hospital and a tertiary referral center. We included adult IBD patients, receiving anti-TNF therapy for ≥4 months, plus an immunomodulator at baseline, between January 1, 2011, and January 1, 2019. The primary endpoints were loss of response (LOR) (ie, anti-TNF discontinuation because of disease activity) and anti-drug antibodies. Adjusted hazard ratios (aHRs) were calculated by mixed-effects Cox regression analysis. RESULTS: We included 614 treatment episodes of combination therapy in 543 individuals, yielding 1664 patient-years of follow-up. The immunomodulator was withdrawn in 296 (48.2%) episodes after 0.9 (interquartile range, 0.6-2.1) years, which was not associated with a higher risk of LOR (aHR, 1.08; 95% confidence interval [CI], 0.72-1.61), although anti-drug antibodies were detected more frequently (aHR, 2.14; 95% CI, 1.17-3.94), compared with continuation. Clinical remission at the time of withdrawal reduced the risk of LOR (aHR, 0.48; 95% CI, 0.25-0.93), while longer duration of combination therapy before withdrawal decreased the risk of anti-drug antibodies (HR per year, 0.56; 95% CI, 0.32-0.91). Higher prewithdrawal infliximab trough levels reduced the subsequent risks of anti-drug antibodies and LOR. Infliximab trough levels were lower after immunomodulator withdrawal (P = .01). CONCLUSIONS: Patients who withdrew the immunomodulator in this retrospective cohort were not at increased risk of LOR within the following 1-2 years, but an increase in anti-drug antibodies was observed. Our findings require prospective validation, preferably in adequately powered randomized controlled trials.

Loss of response to anti-TNFα agents depends on treatment duration in patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α therapy (anti-TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%-21% per patient-year). AIMS: To assess whether the incidence of loss of response decreases with longer treatment duration METHODS: This was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti-TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation. RESULTS: We included 844 anti-TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti-drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three-fold higher than after four years of treatment (17.2% vs 4.8% per patient-year, P < 0.001). The incidence of anti-TNFα discontinuation (28.6% vs 14.0% per patient-year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient-year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10-2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15-2.46) and male sex (aHR 0.55, 95% CI 0.38-0.78). Immunomodulators were protective against loss of response with anti-drug antibodies (aHR 0.42, 95% CI 0.24-0.74). CONCLUSIONS: Patients with sustained benefit to anti-TNFα after 2 years are at low risk of subsequent loss of response.

Surveillance and management of colorectal dysplasia and cancer in inflammatory bowel disease: Current practice and future perspectives.

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). Current guidelines recommend frequent surveillance colonoscopies for patients with at least left-sided ulcerative colitis, or Crohn's disease involving more than 30% of the colon. Surveillance allows for early detection and treatment of colorectal dysplasia and cancer. The first colonoscopy should be performed 8 to 10 years after onset of disease symptoms. European and British guidelines employ a risk-stratification algorithm that assigns patients to surveillance intervals of one, three or five years, whereas American guidelines recommend to perform surveillance every 1 to 3 years based on the (combined) presence of risk factors. Patients with concomitant primary sclerosing cholangitis are at an additionally increased risk, and should undergo annual surveillance starting immediately after the diagnosis. The current practice of surveillance is based on limited evidence, is resource intensive and cannot preclude the occurrence of interval carcinomas. Fortunately, advances in endoscopic techniques for mucosal visualisation, along with better control of inflammation, have resulted in a declining incidence of CRC in patients with IBD. Furthermore, advanced endoscopic resection techniques can be expected to result in a shift from surgical to endoscopic management of dysplastic lesions. In this review, we provide an up-to-date overview of colitis-associated CRC pathophysiology, epidemiology, surveillance practices, and management of dysplasia.

Continuation of Anti-TNF in Patients With Ulcerative Colitis in Remission Is Not Cost-effective Compared With Treatment Withdrawal: A Markov Model.

BACKGROUND AND AIMS: Anti-tumour necrosis factor alpha [anti-TNF] treatment accounts for 31% of health care expenditures associated with ulcerative colitis [UC]. Withdrawal of anti-TNF in patients with UC in remission may decrease side effects and infections, while promoting cost containment. Approximately 36% of patients relapse within 12-24 months of anti-TNF withdrawal, but reintroduction of treatment is successful in 80% of patients. We aimed to evaluate the cost-effectiveness of continuation versus withdrawal of anti-TNF in patients with UC in remission. METHODS: We developed a Markov model comparing cost-effectiveness of anti-TNF continuation versus withdrawal, from a health care provider perspective. Transition probabilities were calculated from literature, or estimated by an expert panel of 11 gastroenterologists. Deterministic and probabilistic sensitivity analyses were performed to account for assumptions and uncertainty. The cost-effectiveness threshold was set at an incremental cost-effectiveness ratio of €80,000 per quality-adjusted life-year [QALY]. RESULTS: At 5 years, anti-TNF withdrawal was less costly [-€10,781 per patient], but also slightly less effective [-0.04 QALY per patient] than continued treatment. Continuation of anti-TNF compared with withdrawal costs €300,390/QALY, exceeding the cost-effectiveness threshold. Continued therapy would become cost-effective if the relapse rate following anti-TNF withdrawal was ≥43% higher, or if adalimumab or infliximab [biosimilar] prices fell below €87/40 mg and €66/100 mg, respectively. CONCLUSIONS: Continuation of anti-TNF in UC patients in remission is not cost-effective compared with withdrawal. A stop-and-reintroduction strategy is cost-saving but is slightly less effective than continued therapy. This strategy could be improved by identifying patients at increased risk of relapse.

Association Between Indefinite Dysplasia and Advanced Neoplasia in Patients With Inflammatory Bowel Diseases Undergoing Surveillance.

BACKGROUND & AIMS: Little is known about the clinical significance of indefinite dysplasia (IND) in patients with inflammatory bowel diseases (IBD) undergoing colonoscopic surveillance for colorectal neoplasia. METHODS: We conducted a retrospective cohort analysis of 492 patients with colonic IBD for 8 or more years or concomitant primary sclerosing cholangitis, with no history of advanced colorectal neoplasia (high-grade dysplasia or colorectal cancer) or colectomy, undergoing colorectal neoplasia surveillance at a tertiary IBD referral center from 2001 through 2017. Subjects received consistent histopathologic grading of dysplasia. We collected data on time to development of (advanced) colorectal neoplasia or colectomy using Kaplan Meier methods. We identified factors independently associated with (advanced) colorectal neoplasia with multivariable Cox regression analysis. RESULTS: After 2149 person-years of follow-up, 53 patients (10.8%) received a diagnosis of IND without prior or synchronous low-grade dysplasia (LGD). Compared to patients without dysplasia, patients with IND had a significantly higher risk of advanced colorectal neoplasia (adjusted hazard ratio, 6.85; 95% CI, 1.78-26.4) and colorectal neoplasia (adjusted hazard ratio, 3.25; 95% CI, 1.50-7.05), but not colectomy (P = .78). Compared to IND, LGD was associated with a significantly higher risk of advanced colorectal neoplasia (P = .05). Following a diagnosis of no dysplasia, IND only, or LGD, the incidence rates of advanced colorectal neoplasia were 0.4% per patient-year, 3.1% per patient-year, and 8.4% per patient-year, respectively. CONCLUSIONS: In a retrospective analysis of patients with IBD undergoing colorectal neoplasia surveillance with consistent histopathologic grading of dysplasia, IND was independently associated with a significant increase in risk of advanced colorectal neoplasia. These findings require validation and if confirmed, a reappraisal of the colorectal neoplasia surveillance guidelines.

No Association Between Pseudopolyps and Colorectal Neoplasia in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases who have postinflammatory polyps (PIPs) have an increased risk of colorectal neoplasia (CRN). European guidelines propose that patients with PIPs receive more frequent surveillance colonoscopies, despite limited evidence of this increased risk. We aimed to define the risk of CRN and colectomy in patients with inflammatory bowel diseases and PIPs. METHODS: We conducted a multicenter retrospective cohort study of patients with inflammatory bowel diseases who underwent colonoscopic surveillance for CRN, from January 1997 through January 2017, at 5 academic hospitals and 2 large nonacademic hospitals in New York or the Netherlands. Eligible patients had confirmed colonic disease with duration of at least 8 years (or any duration, if they also had primary sclerosing cholangitis) and no history of advanced CRN (high-grade dysplasia or colorectal cancer) or colectomy. The primary outcome was occurrence of advanced CRN according to PIP status; secondary outcomes were occurrence of CRN (inclusive of low-grade dysplasia) and colectomy. RESULTS: Of 1582 eligible patients, 462 (29.2%) had PIPs. PIPs were associated with more severe inflammation (adjusted odds ratio 1.32; 95% confidence interval [CI] 1.13-1.55), greater disease extent (adjusted odds ratio 1.92; 95% CI 1.34-2.74), and lower likelihood of primary sclerosing cholangitis (adjusted odds ratio 0.38; 95% CI 0.26-0.55). During a median follow-up period of 4.8 years, the time until development of advanced CRN did not differ significantly between patients with and those without PIPs. PIPs did not independently increase the risk of advanced CRN (adjusted hazard ratio 1.17; 95% CI 0.59-2.31). The colectomy rate was significantly higher in patients with PIPs (P = .01). CONCLUSIONS: In a retrospective analysis of data from 2 large independent surveillance cohorts, PIPs were associated with greater severity and extent of colon inflammation and higher rates of colectomy, but were not associated with development of any degree of CRN. Therefore, intervals for surveillance should not be shortened based solely on the presence of PIPs.

Reporting of patient characteristics and stratification factors in phase 3 trials investigating first-line systemic treatment of metastatic colorectal cancer: A systematic review.

BACKGROUND: Patient characteristics and stratification factors are important factors influencing trial outcomes. Uniform reporting on these parameters would facilitate cross-study comparisons and extrapolation of trial results to clinical practice. In 2007, standardisation on patient characteristics reporting and stratification in metastatic colorectal cancer (mCRC) trials was proposed. We investigated the reporting of prognostic factors and implementation of this proposal in mCRC trials published from 2005 to 2016. METHODS: We searched PubMed and Embase (January 2005 - June 2016) for first-line phase 3 mCRC trials. Patient characteristics reporting and use of stratification factors were extracted and analysed for adherence to the proposal from 2007. RESULTS: Sixty-seven trials (35,315 patients) were identified, reporting 48 different patient characteristics (median: 9 [range: 5-18] per study). Age, gender, performance status (PS), primary tumour site and adjuvant chemotherapy were frequently reported (87%-100%), in contrast to laboratory values, such as alkaline phosphatase, lactate dehydrogenase and white blood cell count (10%-25%). We identified 29 different stratification factors (median: 3 [range: 1-9] per study). The most common strata were PS and treatment centre (>60%). A median of 8/12 (range: 4-11) of the proposed parameters was reported. Although the percentage of studies reporting each factor slightly increased over time, there was no significant correlation between publication year and adherence to the proposal from 2007. CONCLUSIONS: We observed persistent heterogeneity in the reporting of patient characteristics and use of stratification factors in first-line mCRC trials. The proposal from 2007 has not led to increased uniformity of patient characteristics reporting and use of stratification over time. There is an urgent need to address this issue to improve the interpretation of trial results.