Vedolizumab for the Treatment of Chronic Pouchitis.

BACKGROUND: Approximately half the patients with ulcerative colitis who undergo restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) will subsequently have pouchitis, and among those patients, one fifth will have chronic pouchitis. METHODS: We conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab in adult patients in whom chronic pouchitis had developed after undergoing IPAA for ulcerative colitis. Patients were assigned (in a 1:1 ratio) to receive vedolizumab intravenously at a dose of 300 mg or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All the patients received concomitant ciprofloxacin from weeks 1 to 4. The primary end point was modified Pouchitis Disease Activity Index (mPDAI)-defined remission (an mPDAI score of ≤4 and a reduction from baseline of ≥2 points in the mPDAI total score; scores range from 0 to 12, with higher scores indicating more severe pouchitis) at week 14. The mPDAI is based on clinical symptoms and endoscopic findings. Other efficacy end points included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction from baseline of ≥2 points in the mPDAI score) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of ≤6 and a reduction from baseline of ≥3 points; scores range from 0 to 18, with higher scores indicating more severe pouchitis) at weeks 14 and 34. The PDAI is based on clinical symptoms, endoscopic findings, and histologic findings. RESULTS: Among the 102 patients who underwent randomization, the incidence of mPDAI-defined remission at week 14 was 31% (16 of 51 patients) with vedolizumab and 10% (5 of 51 patients) with placebo (difference, 21 percentage points; 95% confidence interval [CI], 5 to 38; P = 0.01). Differences in favor of vedolizumab over placebo were also seen with respect to mPDAI-defined remission at week 34 (difference, 17 percentage points; 95% CI, 0 to 35), mPDAI-defined response at week 14 (difference, 30 percentage points; 95% CI, 8 to 48) and at week 34 (difference, 22 percentage points; 95% CI, 2 to 40), and PDAI-defined remission at week 14 (difference, 25 percentage points; 95% CI, 8 to 41) and at week 34 (difference, 19 percentage points; 95% CI, 2 to 37). Serious adverse events occurred in 3 of 51 patients (6%) in the vedolizumab group and in 4 of 51 patients (8%) in the placebo group. CONCLUSIONS: Treatment with vedolizumab was more effective than placebo in inducing remission in patients who had chronic pouchitis after undergoing IPAA for ulcerative colitis. (Funded by Takeda; EARNEST ClinicalTrials.gov number, NCT02790138; EudraCT number, 2015-003472-78.).

Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy.

BACKGROUND: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking. OBJECTIVES: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls. METHODS: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection. RESULTS: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases. CONCLUSIONS: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.

Mucosal Healing With Vedolizumab in Patients with Chronic Pouchitis: EARNEST, a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND & AIMS: Vedolizumab is indicated for the treatment of chronic pouchitis in the EU. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements. METHODS: EARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab efficacy and safety in adults with chronic pouchitis. Centrally read endoscopic and histological evaluation was performed at baseline, week (W)14, and W34. Ulcer count, adapted Simple Endoscopic Score for Crohn's Disease (SES-CD) in the pouch, and Pouchitis Disease Activity Index (PDAI) histological component were evaluated. PDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) remission at W14 and W34 were compared by MH status at W14. RESULTS: Following treatment, mean (SD) number of ulcers in vedolizumab-treated patients reduced from 15.1 (16.4) to 5.0 (4.9) at W14 and 2.7 (3.2) at W34 vs placebo-treated patients with corresponding values of 11.8 (11.3), 13.4 (18.4), and 9.7 (13.8) (vedolizumab vs placebo difference [95% CI]: W14:-8.4 [-14.3,-2.6]; W34:-7.0 [-12.0,-2.0]). More patients receiving vedolizumab vs placebo achieved reduction in ulcerated pouch surface area (W14: 52.4% vs 20.0%; difference 32.4p.p [9.7, 51.4]; W34: 52.1% vs 12.9%; difference 40.2p.p [15.6, 60.3]), absence of ulceration (W14: 23.8% vs 7.5%; difference 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference 18.8p.p [-2.0, 39.5]), SES-CD remission (W14: 23.8% vs 7.5%; difference 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference 18.8p.p [-2.0, 39.5]) and MH (W14: 16.7% vs 2.5%; difference 14.2p.p [1.9, 26.4]). Patients with MH at W14 had higher rates of PDAI and IBDQ remission at W14 and W34 than those without. CONCLUSION: Vedolizumab induced endoscopic improvements in patients with chronic pouchitis, which was associated with improved outcomes at W34, particularly in patients achieving MH at W14. CLINICALTRIALS: gov number, NCT02790138.

mRNA-1273 vaccinated inflammatory bowel disease patients receiving TNF inhibitors develop broad and robust SARS-CoV-2-specific CD8+ T cell responses.

SARS-CoV-2-specific CD8+ T cells recognize conserved viral peptides and in the absence of cross-reactive antibodies form an important line of protection against emerging viral variants as they ameliorate disease severity. SARS-CoV-2 mRNA vaccines induce robust spike-specific antibody and T cell responses in healthy individuals, but their effectiveness in patients with chronic immune-mediated inflammatory disorders (IMIDs) is less well defined. These patients are often treated with systemic immunosuppressants, which may negatively affect vaccine-induced immunity. Indeed, TNF inhibitor (TNFi)-treated inflammatory bowel disease (IBD) patients display reduced ability to maintain SARS-CoV-2 antibody responses post-vaccination, yet the effects on CD8+ T cells remain unclear. Here, we analyzed the impact of IBD and TNFi treatment on mRNA-1273 vaccine-induced CD8+ T cell responses compared to healthy controls in SARS-CoV-2 experienced and inexperienced patients. CD8+ T cells were analyzed for their ability to recognize 32 SARS-CoV-2-specific epitopes, restricted by 10 common HLA class I allotypes using heterotetramer combinatorial coding. This strategy allowed in-depth ex vivo profiling of the vaccine-induced CD8+ T cell responses using phenotypic and activation markers. mRNA vaccination of TNFi-treated and untreated IBD patients induced robust spike-specific CD8+ T cell responses with a predominant central memory and activated phenotype, comparable to those in healthy controls. Prominent non-spike-specific CD8+ T cell responses were observed in SARS-CoV-2 experienced donors prior to vaccination. Non-spike-specific CD8+ T cells persisted and spike-specific CD8+ T cells notably expanded after vaccination in these patient cohorts. Our data demonstrate that regardless of TNFi treatment or prior SARS-CoV-2 infection, IBD patients benefit from vaccination by inducing a robust spike-specific CD8+ T cell response.

Implementation of 'IBD-Specific Cognitive Behavioural Therapy' for Patients with Inflammatory Bowel Diseases with Poor Mental Quality of Life, Anxiety and Depression.

This paper describes the implementation of inflammatory bowel disease (IBD)-specific cognitive behavioural therapy (CBT) for IBD patients with poor quality of life (QoL), anxiety and depression, in four hospitals in the Netherlands. Treatment outcomes were compared with those of a previously published randomized control trial (RCT) of 'IBD-specific CBT', following a benchmark strategy. Primary outcome was IBD-specific QoL (IBDQ) completed before and after CBT, secondary outcomes were anxiety and depressive symptoms (HADS, CES-D). Semi-structured interviews were conducted among a pilot of gastroenterologists, nurse specialists and psychologists to evaluate 'IBD-specific CBT'. 94 patients started treatment (280 screened). At follow-up, 63 participants (67% compared to 81% in the RCT benchmark) completed the IBDQ. Treatment effect sizes of the implementation study were comparable and slightly larger than those of RCT benchmark. Gastroenterologists, IBD nurses and psychologists found CBT necessary for IBD patients with poor QoL, depression and/or anxiety disorders. 'IBD-specific CBT' can be successfully implemented. Regular supervision of psychologists performing 'IBD-specific CBT' treatment is needed.

Intestinal Ultrasound Is Accurate to Determine Endoscopic Response and Remission in Patients With Moderate to Severe Ulcerative Colitis: A Longitudinal Prospective Cohort Study.

BACKGROUND & AIMS: Intestinal ultrasound (IUS) is noninvasive, cost-effective, and accurate to determine disease activity in ulcerative colitis (UC). In this study, we prospectively evaluated IUS for treatment response in a longitudinal cohort by using endoscopy and histology as gold standards. METHODS: Consecutive patients with moderate to severe UC (endoscopic Mayo score [EMS] ≥2) starting tofacitinib treatment were included. Patients were evaluated at baseline and after 8 weeks of tofacitinib induction by means of clinical, biochemical, endoscopic (EMS and UC endoscopic index for severity), histologic (Robarts Histopathologic Index) and IUS assessments. Readers of IUS, endoscopy, and histology were blinded for all other outcomes. The primary outcome was difference in bowel wall thickness (BWT) for endoscopic improvement vs no endoscopic improvement. Endoscopic remission was defined as EMS = 0, improvement as EMS ≤1, and response as a decrease of EMS ≥1. RESULTS: Thirty patients were included, with 27 patients completing follow-up. BWT correlated with EMS (ρ = 0.68, P < .0001), UC endoscopic index for severity (ρ = 0.73, P < .0001) and Robarts Histopathologic Index (ρ = 0.49, P = .002) at both time points. BWT in the sigmoid was lower in patients with endoscopic remission (1.4 mm vs 4.0 mm, P = .016), endoscopic improvement (1.8 mm vs 4.5 mm, P < .0001) and decrease in BWT was more pronounced in patients with endoscopic response (-58.1% vs -13.4%, P = .018). The most accurate cutoff values for BWT were 2.8 mm (area under the curve [AUC] 0.87) for endoscopic remission, 3.9 mm (AUC 0.92) for improvement, and decrease of 32% (AUC 0.87) for response. The submucosa was the most responsive wall layer. CONCLUSION: IUS, importantly BWT as the single most important parameter, is highly accurate to detect treatment response when evaluated against endoscopic outcomes.

I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators. METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia. CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations.

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity.

Risk factors associated with short-term adverse events after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases.

BACKGROUND: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). METHODS: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. RESULTS: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). CONCLUSIONS: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. TRIAL REGISTRATION: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.

Breakthrough infections with the SARS-CoV-2 omicron (B.1.1.529) variant in patients with immune-mediated inflammatory diseases.

OBJECTIVES: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. METHODS: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. RESULTS: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. CONCLUSIONS: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections.

Performance measures for colonoscopy in inflammatory bowel disease patients: European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative.

The European Society of Gastrointestinal Endoscopy (ESGE) presents a short list of performance measures for colonoscopy in inflammatory bowel disease (IBD) patients. Current performance measures for colonoscopy mainly focus on detecting (pre)malignant lesions. However, these performance measures are not relevant for all colonoscopy indications in IBD patients. Therefore, our aim was to provide endoscopy services across Europe and other interested countries with a tool for quality monitoring and improvement in IBD colonoscopy. Eight key performance measures and one minor performance measure were recommended for measurement and evaluation in daily endoscopy practice.

Assessment of endoscopic response using pan-enteric capsule endoscopy in Crohn's disease; the Sensitivity to Change (STOC) study.

BACKGROUND: The potential use of pan-enteric capsule endoscopy (pan-CE) to evaluate mucosal changes during treatment has not been evaluated. We aimed to assess the ability of pan-CE to measure changes in mucosal disease activity before and after starting biologic treatment in Crohn's disease patients. METHODS: In this two-center prospective study, patients with clinical and biochemical signs of active Crohn's disease underwent pan-CE before and 8 to 12 weeks after treatment initiation with infliximab, adalimumab or vedolizumab. Endoscopic disease activity was assessed using the simple endoscopic score for Crohn's disease (SES-CD) and the Crohn's disease endoscopic index of severity (CDEIS), expanded with two segments (i.e., the jejunum and pre-terminal ileum). Occurrence of endoscopic remission (i.e., absence of ulcers) and endoscopic response (i.e., 50% decrease in SES-CD and CDEIS scores compared to baseline) was assessed and the standardized effect size was calculated. RESULTS: Twenty-two patients (50% females) completed the study. Endoscopic remission was observed in 6 out of 22 (27%) patients and 13/22 patients (59%) showed an endoscopic response for both the SES-CD and CDEIS score. Median SES-CD and CDEIS scores decreased from 16.0 (IQR 10.0 - 24.0) to 6.0 (IQR 2.8 - 12.0, p = .001) and from 7.1 (IQR 4.6 - 11.2) to 3.0 (IQR 0.9 - 6.0, p = .001), respectively. The standardized effect size was 1.44 and 1.24 for the SES-CD and CDEIS, respectively. No adverse events related to pan-CE were reported. CONCLUSION: Pan-CE was a useful technique to assess changes in mucosal disease activity in Crohn's disease patients.

Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial.

OBJECTIVES: Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients. METHODS: In this multicentre 1:1 'PRECISION' trial, we randomized IBD patients in clinical remission (Harvey Bradshaw Index ≤4 for Crohn's disease (CD) or a partial Mayo score ≤2 for ulcerative colitis (UC)) receiving IFX maintenance treatment. The precision group (PG) received IFX dosing guided by a Bayesian pharmacokinetic model, aiming to achieve and maintain a TL of 3 µg/ml by treatment (de)escalation as indicated by the dashboard. Patients in the control group (CG) continued treatment without dose adaptations. The primary endpoint was the proportion of patients in sustained clinical remission after 1 year. RESULTS: Eighty patients were enrolled (66 CD, 14 UC), and the median [interquartile range] age was 37 years [27-51]). After one year, 28/32 (88%) of patients in the PG were in sustained clinical remission versus 25/39 (64%) in the CG (p = .017). PG patients had lower median faecal calprotectin levels after 1 year (p = .031), whereas no significant differences in median CRP levels were found. CONCLUSION: We demonstrated that the use of a Bayesian dashboard for IFX dosing in maintenance treatment for IBD reduced the incidence of LOR compared to standard dosing. Precision dosing also resulted in lower FCP levels. CLINICALTRIALS.GOV NUMBER: NCT02453776.

Impaired Quality of Working Life in Inflammatory Bowel Disease Patients.

BACKGROUND: Work-related aspects are important determinants of health for inflammatory bowel disease (IBD) patients. AIMS: We aimed to describe quality of working life (QWL) in IBD patients and to assess variables that are associated with QWL. METHODS: Employed IBD patients of two tertiary and two secondary referral hospitals were included. QWL (range 0-100) was measured using the Quality of Working Life Questionnaire (QWLQ). Work productivity (WP), fatigue, and health-related quality of life (HRQL) were assessed using the Work Productivity and Activity Impairment questionnaire, Multidimensional Fatigue Inventory, and Short Inflammatory Bowel Disease Questionnaire, respectively. Active disease was defined as a score > 4 for the patient-reported Harvey-Bradshaw index in Crohn's disease (CD) or Simple Clinical Colitis Activity Index in ulcerative colitis patients. RESULTS: In total, 510 IBD patients were included (59% female, 53% CD, mean age 43 (SD 12) years). The mean QWLQ score was 78 (SD 11). The lowest subscore (54 (SD 26)) was observed for "problems due to the health situation": 63% reported fatigue-related problems at work, 48% agreed being hampered at work, 46% had limited confidence in their body, and 48% felt insecure about the future due to their health situation. Intermediate/strong associations were found between QWL and fatigue (r = - 0.543, p < 0.001), HRQL (r = 0.527, p < 0.001), WP loss (r = - 0.453, p < 0.001) and disease activity (r = - 0.331, p < 0.001). Independent predictors of impaired QWL in hierarchical regression analyses were fatigue (B = - 0.204, p < 0.001), WP loss (B = - 0.070, p < 0.001), and impaired HRQL (B = 0.248, p = 0.001). CONCLUSIONS: IBD-related problems at work negatively influence QWL. Fatigue, reduced HRQL, and WP loss were independent predictors of impaired QWL in IBD.

Immunogenicity of the Currently Recommended Pneumococcal Vaccination Schedule in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of invasive pneumococcal infections. Therefore, vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 2 months later is recommended. However, the level of immunogenicity induced by this vaccination schedule in IBD patients with and without immunosuppressive medication remains unclear. METHODS: We prospectively assessed the immunogenicity of PCV13 followed by PPSV23 in IBD patients by measuring serotype-specific pneumococcal immunoglobulin G antibody concentrations at baseline and 4-8 weeks postvaccination. Response to vaccination was defined as a postvaccination antibody concentration ≥1.3 µg/mL for 70% of the measured serotypes. We analyzed the immunogenic effect of 4 different medication regimens: (1) conventional immunomodulators (ie, oral prednisolone >10 mg/day, thiopurines, methotrexate); (2) anti-tumor necrosis factor agents; (3) combination therapy; and (4) no treatment with immunosuppressive agents (control group). RESULTS: One hundred forty-one IBD patients were included, of whom 37 were controls. Adequate response to vaccination was 59% (61/104) in patients using immunosuppressive agents (groups 1-3) vs 81% (30/37) in controls (odds ratio, 0.33 [95% confidence interval, .13-.82]). A combination of different immunosuppressive drugs most severely impaired the immune response to pneumococcal vaccination (response, 52% [15/29]). CONCLUSIONS: Although the sequential vaccination schedule of PCV13 followed by PPSV23 is safe, immunogenic, and thus beneficial in the majority of IBD patients, those receiving immunosuppressive agents, and especially those receiving combination therapy, have an impaired immune response compared to controls. Therefore, preferably, vaccinations should be administered before the initiation of immunosuppressive therapy. CLINICAL TRIALS REGISTRATION: Dutch trial register #6315.

Reliability of Endoscopic Evaluation of Postoperative Recurrent Crohn's Disease.

Endoscopic evaluation for postoperative recurrence of Crohn's disease (CD) is routinely integrated into clinical practice. The Rutgeerts score (RS) was developed to grade the severity of endoscopic postoperative CD recurrence and has been integrated into clinical practice guidelines and utilized as an endpoint in interventional trials.1,2 However, the operating properties of the RS have not been fully assessed. Furthermore, the RS i2 grade groups purely anastomotic ulcerations with those in the neoterminal ileum, whereas the modified Endoscopic Postoperative Recurrence Score (mEPRS) distinguishes lesions limited to the ileocolic anastomosis (i2a) from those in the neoterminal ileum (i2b). Accurate characterization of endoscopic recurrence is an important determinant for initiating postoperative medical therapy. Therefore, variability in endoscopic scoring may result in inappropriate therapeutic decisions.3 We evaluated the reliability of endoscopic assessment of postoperative CD recurrence among independent blinded central readers.

No Superiority of Tacrolimus Suppositories vs Beclomethasone Suppositories in a Randomized Trial of Patients With Refractory Ulcerative Proctitis.

BACKGROUND & AIMS: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP. METHODS: We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test. RESULTS: Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups. CONCLUSIONS: In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.

Vedolizumab Induces Endoscopic and Histologic Remission in Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the ability of vedolizumab to induce endoscopic and histologic remission in patients with Crohn's disease (CD). METHODS: We performed a prospective study of 110 patients with active CD, based on CD activity index (CDAI) scores >220 and mucosal ulcerations, who received open-label vedolizumab (300 mg) infusions at weeks 0, 2, and 6, and every 8 weeks thereafter through week 52 at tertiary centers in Europe. Patients received an additional infusion at week 10 if their CDAI score had not decreased by 70 points. Patients underwent ileocolonoscopy with collection of biopsies at baseline and weeks 26 and 52; a local and central reader determined simple endoscopic index for CD (SES-CD) scores. Histologic features were assessed by a blinded pathologist at week 26. Serum concentrations of vedolizumab were measured at serial time points. The primary outcome was endoscopic and histologic remission in patients with active CD treated with vedolizumab for 52 weeks. RESULTS: At weeks 26 and 52, 36 patients (29%) and 34 patients (31%), respectively, were in corticosteroid-free clinical remission (CDAI score <150), respectively. Based on intent-to-treat analysis, endoscopic remission (SES-CD score <4) was achieved by 36 patients (33%) and 40 patients (36%) at weeks 26 and 52. Endoscopic responses (decrease in SES-CD score ≥50%) occurred in 44 patients (40%) at week 26 and 5 patients (45%) at week 52. Serum concentrations of vedolizumab were higher at weeks 2, 10, and 22 in patients with lower SES-CD scores. Histologic remission at week 26 was observed in 43 (64%) of 67 patients based on Geboes Score and 37 (66%) of 56 patients based on Robarts Histopathology Index scores in analyses of paired biopsies with inflammation at baseline. Serum concentrations of vedolizumab above 10 mg/L at week 22 were associated with endoscopic remission at week 26. CONCLUSIONS: In a prospective trial, we found that approximately one-third of patients with CD achieve endoscopic remission after 52 weeks of treatment with vedolizumab and two-thirds achieve histologic remission at week 26. Higher serum concentrations of vedolizumab were associated with better outcomes. EUDRACT no: 2014-005376-29.

Monitoring of Adalimumab Concentrations at Home in Patients with Inflammatory Bowel Disease Using Dried Blood Samples.

BACKGROUND: Adalimumab (ADL) is a subcutaneously administered anti-tumor necrosis factor (TNF) agent used in the treatment of patients with inflammatory bowel disease. Higher ADL trough concentrations are associated with improved clinical and endoscopic outcomes. Therapeutic drug monitoring (TDM) of ADL might be facilitated by using dried blood samples (DBSs) from capillary blood obtained at home. The study aimed to compare serum ADL concentrations obtained through venipuncture to ADL concentrations in DBSs. METHODS: Patients with Crohn's disease and ulcerative colitis receiving induction or maintenance ADL therapy were enrolled in this prospective cohort study. Blood was obtained through venipuncture and through DBSs during a regular outpatient visit (time point 1). Just before the next ADL administration, patients performed DBSs at home (time point 2). For this time point, serum ADL concentrations were estimated by Bayesian analysis. RESULTS: Thirty-three patients with inflammatory bowel disease were enrolled. During the outpatient visit, samples were obtained after a median (interquartile range) of 6 (4-10) days after the last ADL dose. A high correlation was found between DBSs and venipuncture results (Pearson correlation: ≥0.96), without any clinically relevant bias. For DBSs performed by patients at home, initial comparison showed a moderate correlation between DBS results and predicted ADL serum concentrations (Pearson correlation: 0.51), although no bias was present. In addition, DBS eluate results compared with predicted ADL serum concentrations showed a mean absolute percentage error (ie, accuracy) of 45%. CONCLUSIONS: High correlations were found between ADL serum concentrations obtained through conventional venipuncture and DBSs, which indicates that this home-based test can facilitate therapeutic drug monitoring-based ADL dose adjustments in daily practice.

Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn's disease patients.

Objectives: Anti-TNF agents are effective to treat perianal Crohn's disease (CD). Evidence suggests that Crohn's disease patients with perianal fistulas need higher infliximab (IFX) serum concentrations compared to patients without perianal CD to achieve complete disease control. Our aim was to compare anti-TNF serum concentrations between patients with actively draining and closed perianal fistulas. Methods: A retrospective survey was performed in CD patients with perianal disease treated with IFX or adalimumab (ADL). Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging. Results: We identified 66 CD patients with a history of perianal fistulas treated with IFX (n = 47) and ADL (n = 19). Median IFX serum trough concentrations ([interquartile range]) were higher in patients with closed fistulas (n = 32) compared to patients with actively draining fistulas (n = 15): 6.0 µg/ml [5.4-6.9] versus 2.3 µg/ml [1.1-4.0], respectively (p < .001)). A similar difference was seen in patients treated with ADL: median serum concentrations were 7.4 µg/ml [6.5-10.8] in 13 patients with closed fistulas versus 4.8 µg/ml [1.7-6.2] in 6 patients with producing fistulas (p = .003). Serum concentrations of ≥5.0 µg/ml for IFX (area under the curve of 0.92; 95% CI: 0.82-1.00)) and 5.9 µg/ml for ADL (area under the curve of 0.89; 95% CI 0.71-1.00) were associated with fistula closure. Conclusion: Cut-off serum concentrations ≥5.0 µg/ml for IFX and ≥5.9 µg/ml for ADL were associated with perianal fistula closure. Hence, patients with producing perianal fistulas may benefit from anti-TNF dose intensification to achieve fistula closure.