Long-term efficacy and safety of ustekinumab in 122 refractory Crohn's disease patients: a multicentre experience.

BACKGROUND: Long-term outcome of ustekinumab in Crohn's disease (CD) has not been evaluated. AIM: To evaluate the long-term efficacy and safety of ustekinumab and identify the predictive factors of ustekinumab failure-free persistence in a cohort of anti-TNF refractory CD patients. METHODS: We performed a retrospective multicentre cohort study including all consecutive CD patients who began subcutaneous ustekinumab and presented a clinical response (defined as a significant improvement of CD-related clinical symptoms assessed by the patient's physician leading to continued ustekinumab) during the first year of treatment. Primary outcome was treatment failure defined as withdrawal of treatment due to loss of response, intolerance or need for surgery. RESULTS: Eighty-eight of the 122 (72%) CD patients beginning ustekinumab from March 2011 to December 2014, responded to ustekinumab and were followed up until November 2016. Median time on ustekinumab was 26.6 (13.4-34.4) months. Forty-seven patients (54%) continued ustekinumab with a clinical response and 38 (43%) stopped treatment (32 for failure, five for remission and one for pregnancy). Endoscopic response was observed in 82% of patients with endoscopic evaluation and mucosal healing in 39%. Ustekinumab failure-free persistence rates were 78% at 12 months, 66% at 24 months and 55% at 36 months. No predictive factor of ustekinumab failure-free persistence was identified. One severe adverse event was observed (anal adenocarcinoma). CONCLUSION: In this cohort of refractory CD patients receiving long-term ustekinumab therapy, more than 50% of patients continued ustekinumab treatment with no loss of response, intolerance or surgery and with a good safety profile.

Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort.

BACKGROUND: The effectiveness of vedolizumab as a treatment for extraintestinal manifestations (EIM) is questionable due to its gut-specificity. AIM: To assess effectiveness of vedolizumab for EIM in patients with inflammatory bowel disease (IBD) in a large real-life experience cohort. METHODS: Between June and December 2014, 173 patients with Crohn's disease and 121 with ulcerative colitis were treated with vedolizumab. Patients were followed until week 54. EIM activity was assessed at weeks 0, 6, 14, 22, 30 and 54 by using a 3-step scale: complete remission, partial response and no response. RESULTS: At baseline, 49 (16.7%) patients had EIMs of which 47 had inflammatory arthralgia/arthritis, four had cutaneous lesions and two had both rheumatologic and skin EIM. At week 54, 21 (44.7%) patients had complete remission for inflammatory arthralgia/arthritis and three (75%) for cutaneous EIM. In multivariate analysis, complete remission of inflammatory arthralgia/arthritis was associated with clinical remission of IBD (OR = 1.89, IC95% [1.05-3.41], P = .03) and recent onset of inflammatory arthralgia/arthritis (OR = 1.99, IC95% [1.12-3.52], P = .02). During the follow-up period, 34 (13.8%) patients without any EIM at baseline, developed incident cases of inflammatory arthralgia/arthritis consisting mostly of peripheral arthralgia without evidence of arthritis and 14 (4.8%) incident cases of paradoxical skin manifestation. CONCLUSION: Vedolizumab therapy is commonly associated with improvement in EIM. This was associated with quiescent IBD and recent EIM. However, paradoxical skin manifestation and inflammatory arthralgia/arthritis may occur upon vedolizumab therapy.

One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multicentre cohort study.

BACKGROUND: We recently showed that vedolizumab is effective in patients with Crohn's disease (CD) and ulcerative colitis (UC) with prior anti-TNF failure in a multicentre compassionate early-access programme before marketing authorisation was granted to vedolizumab. AIMS: To assess effectiveness and safety of vedolizumab at week 54 in patients UC and CD. METHODS: Between June and December 2014, 173 patients with Crohn's disease (CD) and 121 with ulcerative colitis (UC) were treated with vedolizumab induction therapy. Among those 294 patients, 272 completed the induction period and were evaluated at the week 14 visit (161 patients with CD and 111 with UC). Disease activity was assessed using the Harvey-Bradshaw Index for CD and the partial Mayo Clinic score for UC. The primary outcome was steroid-free clinical remission at week 54. RESULTS: At week 54, steroid-free clinical remission rates at week 54 were 27.2% and 40.5% in patients with CD and UC respectively. In addition, the sustained steroid-free clinical remission (from week 14 to week 54) rates were 8.1% and 19.0% respectively. No deaths were observed. Severe adverse events occurred in 17 (7.2%) patients, including six (2.5%) leading to vedolizumab discontinuation. CONCLUSION: Vedolizumab is able to maintain steroid-free clinical remission in up to one-third of patients with UC and CD at week 54 with a reasonable safety profile. A significant number of patients experienced loss of response during the first year of treatment, particularly in patients with CD.

Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.

BACKGROUND: The risk of urinary tract cancers, including kidney and bladder cancers, was increased in transplant recipients receiving thiopurines. AIM: To assess the risk of urinary tract cancers in patients with inflammatory bowel disease (IBD) receiving thiopurines in the CESAME observational cohort. METHODS: Between May 2004 and June 2005, 19 486 patients with IBD, 30.1% of whom were receiving thiopurines, were enrolled. Median follow-up was 35 months (IQR: 29-40). RESULTS: Ten and six patients developed respectively kidney and bladder cancer. The incidence rates of urinary tract cancer were 0.48/1000 patient-years in patients receiving thiopurines (95% CI: 0.21-0.95), 0.10/1000 patient-years in patients who discontinued thiopurines (95% CI: 0.00-0.56) and 0.30/1000 patient-years in patients never treated with thiopurines (95% CI: 0.12-0.62) at entry. The standardised incidence ratio of urinary tract cancer was 3.40 (95% CI: 1.47-6.71, P = 0.006) in patients receiving thiopurines, 0.64 (95% CI: 0.01-3.56, P = 0.92) in patients previously exposed to thiopurines and 1.17 (95% CI: 0.47-12.42, P = 0.78) in patients never treated with thiopurines. The multivariate-adjusted hazard ratio (HR) of urinary tract cancer between patients receiving thiopurines and those not receiving thiopurines was 2.82 (95% CI: 1.04-7.68, P = 0.04). Other significant risk factors were male gender (HR: 3.98, 95% CI: 1.12-14.10, P = 0.03) and increasing age (HR after 65 years (ref <50): 13.26, 95% CI: 3.52-50.03, P = 0.0001). CONCLUSION: Patients with IBD receiving thiopurines have an increased risk of urinary tract cancers. Clinically relevant excess risk is observed in older men.

Adalimumab or infliximab as monotherapy, or in combination with an immunomodulator, in the treatment of Crohn's disease.

BACKGROUND: The comparative efficacy of adalimumab (ADA) and infliximab (IFX) in Crohn's disease, and the benefit of initial combotherapy with an immunomodulator, are debated. AIM: To assess the best anti-TNF treatment regimens in Crohn's disease. METHODS: We included 906 biologic-naïve Crohn's disease patients [median age, 31 years (24-41)] and performed a retrospective analysis of 1284 therapeutic exposures to ADA (n = 521) or IFX (n = 763) between 2006 and 2015. An immunomodulator was associated during the first 4-6 months (initial combotherapy) during 706 therapeutic exposures (55%). Median duration of anti-TNF therapy was 39 months (IQR 17-67). Primary outcomes were 6-month and 2-year response rates and drug survival. Logistic regression with propensity scoring and Cox proportional hazard analysis determined variables associated with outcomes. RESULTS: The response rates at 6 months and 2 years were 64% and 44% on ADA mono, 86% and 70% on ADA combo, 72% and 45% on IFX mono, and 84% and 68% on IFX combotherapy, respectively. Differences between ADA and IFX were not significant, whereas combotherapy was superior to monotherapy (P < 0.001). Drug survival was longer with combotherapy vs. monotherapy [adjusted hazard ratio 2.17 (1.72-2.70)] and not significantly different between ADA and IFX. During subsequent anti-TNF exposures, IFX combotherapy fared better than other groups regarding response rates, drug survival, disease activity, hospitalisations and abdominal surgery. CONCLUSION: In this retrospective analysis of a large tertiary centre cohort of Crohn's disease patients, ADA and IFX had similar efficacy as first line treatment, while initial combotherapy with an immunomodulator improved all outcome measures.

Impact of the diagnosis and treatment of cancer on the course of inflammatory bowel disease.

BACKGROUND: The effects of extra-intestinal cancer on the course of inflammatory bowel disease (IBD) are poorly understood. AIM: To evaluate the impact of cancer and its management on IBD outcomes. METHODS: A total 80 IBD patients (51 Crohn's disease, 29 ulcerative colitis; 33 men, median age at cancer diagnosis 48yrs) diagnosed with extra-intestinal cancer were selected from a prospective database. IBD activity and therapeutic requirements (assessed year-by-year) were compared before and after cancer diagnosis, with a control group of patients without cancer matched for gender, birth date, date of IBD diagnosis and IBD phenotype. RESULTS: Paired comparisons of the consecutive periods before and after cancer diagnosis did not show significant changes in median (IQR) percentages of years with active disease (27% [0-50] vs. 19% [0-53]), while the proportion of patient-years on any immunosuppressant remained stable (26% vs. 28%). Chemotherapy had no significant effect on IBD activity. Compared to controls, patients with cancer had a similar IBD activity and use of anti-TNF, but less use of immunomodulators (19% vs. 25%, p<0,001) and an increased rate of surgery (4% vs. 2.5%, p<0,05). Individual variations in IBD activity after cancer diagnosis were not significantly different in patients with cancer and their matched controls. CONCLUSION: Occurrence of extra-intestinal cancer impacts IBD therapeutic management, with a trend towards less use of immunomodulators and more surgery. In the long-term, cancer diagnoses and treatments do not modify IBD outcomes.

The impact of cytomegalovirus reactivation and its treatment on the course of inflammatory bowel disease.

BACKGROUND: Consequences of latent cytomegalovirus (CMV) infection reactivation on inflammatory bowel disease (IBD) flare, as a flare-worsening factor or simple bystander, are debated. Impact of anti-viral treatment on IBD course is poorly known. AIM: To assess the impact of CMV reactivation on patients hospitalised for IBD flare and the effect of anti-viral treatment on IBD flare in patients with CMV reactivation. METHODS: First, a population of UC patients from Saint-Antoine hospital, in flare with positive blood CMV PCR without anti-viral treatment (n = 26), were compared to matched patients with negative blood CMV PCR in a case-control study. Secondly, a total of 110 hospitalisations between October 2003 and May 2012 for IBD flare-up with CMV reactivation (80 diagnosed on blood PCR, 33 on tissue PCR) were identified in three French referral centres. Evolution following CMV reactivation diagnosis was compared between patients receiving anti-viral treatment and those who did not. RESULTS: In the case-control study, no differences were observed between the two groups regarding length of hospital stay and colectomy rate. Comparing treated and untreated patients, no differences were observed at inclusion regarding age, gender, IBD type, immunosuppressant, CRP and haemoglobin level. No differences were observed regarding CRP level decrease at 10 days and colectomy rate at 3 months. Anti-viral treatment was associated with lower serum albumin level at inclusion and longer hospitalisation. CONCLUSIONS: CMV reactivation does not appear to alter the course of IBD flare. CMV treatment does not seem to impact the course of IBD. These results should be confirmed prospectively.