Comparison between tofacitinib and ustekinumab as a third-line therapy in refractory ulcerative colitis: A multicenter international study.

BACKGROUND: Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed. METHODS: This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events. RESULTS: One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6 months (q1 -q3, 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p = 0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p < 0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p = 0.11). CONCLUSIONS: Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data.

Analysis of Clinical Trial Screen Failures in Inflammatory Bowel Diseases (IBD): Real World Results from the International Organization for the study of IBD.

BACKGROUND: Recruitment for randomized controlled trials (RCTs) in IBD have substantially dropped over time. This study aimed to assess reasons why IBD patients are not included in sponsored multicenter phase IIb-III RCTs. METHODS: All IOIBD members (n=58) were invited to participate. We divided barriers to participation as follow: 1) reasons patients with active IBD were not deemed appropriate for a RCT; 2) reasons qualified patients did not wish to participate; 3) reasons for screen failure (SF) in patients agreeing to participate. We assess those in a 4-week prospective study including, consecutively, all patients with symptomatic disease for whom a treatment change was required. In addition, we performed a 6-month retrospective study to further evaluate reasons for SF. RESULTS: A total of 106 patients (60 male (56.6%), 63 Crohn's disease [CD] (59.4%)), from 10 centers across the world, were included in the prospective study. A RCT has not been proposed to 65 of them (mainly due to eligibility criteria). Of the 41 patients to whom a RCT was offered, 8 refused (mainly due to reluctance to receive placebo) and 28 agreed to participate. Among these 28 patients, 5 failed their screening and 23 were finally included in a RCT. A total of 107 patients (61 male (57%), 67 CD (62.6%)), from 13 centers worldwide, were included in our retrospective study of SFs. The main reason was insufficient disease activity. CONCLUSION: This first multicenter study analyzing reasons for non-enrollment in IBD RCTs shown that we lose patients at each step. Eligibility criteria, the risk of placebo assignment and insufficient disease activity were part of the main barriers.

Recent Advances in the Optimization of Anti-TNF Treatment in Patients with Inflammatory Bowel Disease.

Despite the evolution in inflammatory bowel disease (IBD) management during the last 20 years owing to the advent of new advanced therapies, anti-TNF agents still remain the cornerstone of therapy for both Crohn's disease and ulcerative colitis. However, this does not only secure favorable outcomes for patients considering the progressive disease character and the high likelihood of primary or secondary loss of response. Therefore, trying to reach a better treatment approach and maximize the benefits anti-TNF agents offer, optimization strategies should be examined. It has been indicated that optimizing treatment with anti-TNF enhances drug efficacy and has been associated with improved disease outcomes and a complication-free disease course. From this perspective, we aim to provide an overview of currently available data and recent advances in the practices of anti-TNF treatment optimization. Special focus has been given to the role of therapeutic drug monitoring (TDM), as well as the utility of combining anti-TNF with an immunomodulator and the treat-to-target approach.

Active smoking is associated with the development of adverse events of biological therapy in patients with inflammatory bowel disease.

INTRODUCTION: Smoking has been associated with lower levels of anti-TNF agents, higher antibodies and a reduced response to anti-TNF in patients with inflammatory bowel disease (IBD). The aim of this study was to investigate the possible association between smoking and adverse events (AEs) of biologics in patients with IBD. MATERIAL AND METHODS: Consecutive IBD patients under biologics from a prospective, longitudinal registry of a tertiary center were included. A specially designed questionnaire including a wide range of AEs associated with biologics was also used. RESULTS: A total of 147 patients with IBD under biologics [median age (IQR) 46 (32.5-56) years, Crohn's disease (CD) 109 (74%), female 51 (35%), under combination with immunosuppressants 60 (41 %), under intensified biologic therapy 50 (34%), under anti-TNF 132 (89%), vedolizumab 11 (7.5%), ustekinumab 3 (2%)] who had completed the questionnaire forms for AEs were included. There were 52 (35%) active smokers and 33 (22.5%) ex-smokers. The prevalence of all AEs was 88% in smokers, 87% in ex-smokers and 79% in nonsmokers. Active smoking was significantly associated with the presence of arthralgias and skin rashes ( P = 0.01 and 0.002, respectively). These correlations were the same for the CD and ulcerative colitis (UC), except for arthralgias where there was a significant correlation only with CD ( P = 0.001). There were no significant associations between smoking and other AEs ( P > 0.05). CONCLUSION: Active smoking is associated with the development of dermatological manifestations (both in UC and CD) and arthralgias (in CD) in IBD patients under biologics.

Mental Health, Work Presenteeism, and Exercise in Inflammatory Bowel Disease.

BACKGROUND: Chronic diseases, such as IBD, can lead to anxiety and depression which can have a significant impact on productivity at work [presenteeism]. The aim of this study was to assess the prevalence of depression/anxiety, presenteeism and exercise levels among IBD patients. METHODS: This was a multicentre study whereby adult IBD patients, in clinical remission, were asked to answer a questionnaire anonymously. Hospital Anxiety and Depression Score [HADS], Stanford Presenteeism Scale [SPS-6] and Godin Exercise Score were also collected. RESULTS: A total of 585 patients were recruited. The majority had Crohn's disease [CD, 62.2%] and were male [53.0%], with a median age of 39 years [IQR 30-49]. A psychiatric diagnosis was present in 10.8% of patients prior to their IBD diagnosis. A further 14.2% of patients were psychiatrically diagnosed after IBD diagnosis, this being commoner in CD patients [41.6% of CD, p <0.01]. A raised HADS-Anxiety or a HADS-Depression score ≥8 was present in 46.1% of patients, with 27.4% having a score ≥11. Low presenteeism at work was present in 34.0%. Patients diagnosed with depression/anxiety had a more sedentary lifestyle [p <0.01], lower presenteeism at work [p <0.01] and a higher rate of unemployment [p <0.01]. CONCLUSIONS: A significant percentage of IBD patients in remission suffer from anxiety and/or depression. Risk factors for these are CD, female gender, use of biologic medications, long-standing and/or perianal disease. Depression/anxiety was associated with a sedentary lifestyle, lower presenteeism at work and unemployment. Validated screening tools and appropriate referrals to psychologists and/or psychiatrists should be employed within IBD clinics.

Effect of antinuclear antibodies on pharmacokinetics of anti-TNF therapy in patients with inflammatory bowel disease.

PURPOSE: The detection of antinuclear antibodies (ANA) in serum of patients with inflammatory bowel disease (IBD) has been associated with a worse response to anti-TNF therapy and the development of cutaneous or arthritic manifestations. The aim of this study was to investigate a possible association of serum ANA with infliximab (IFX) and adalimumab (ADA) trough levels (TLs) and anti-drug antibodies in IBD patients treated with IFX or ADA. METHODS: Consecutive IBD patients under maintenance therapy with IFX or ADA in whom there was at least one available measurement of anti-TNF TLs, antibodies to IFX or ADA, and ANA in serum were included. The correlation of ANA positivity with demographics, clinical characteristics, treatment, TLs and anti-drug antibodies, of all patients was analyzed. RESULTS: One hundred two IBD patients under maintenance therapy with IFX or ADA were enrolled. Of these, 53 (52%) were ANA positive with 28 (27.5%) positive also to anti-ds-DNA in serum. In the univariate analysis ANA positivity was found to be correlated with age (P = 0.008), female gender (P = 0.03), duration of treatment (P = 0.06), arthralgias (P = 0.04) and TLs (P = 0.005). However, in multivariate logistic regression analysis only age and TLs remained significantly associated with the presence of ANA positivity (P = 0.04 and P = = 0.006, respectively). No significant association of ANA positivity with the development of cutaneous or rheumatological manifestations was found. CONCLUSIONS: In IBD patients under maintenance therapy with anti-TNF ANA positivity is associated with lower TLs. The clinical significance of this finding remains to be defined in future larger prospective studies.

Gastroenteropancreatic Neuroendocrine Neoplasms in Patients with Inflammatory Bowel Disease: An ECCO CONFER Multicentre Case Series.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms [GEP-NENs] have rarely been reported in association with inflammatory bowel diseases [IBDs]. METHODS: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collects cases of GEP-NENs diagnosed in patients with IBD. RESULTS: GEP-NEN was diagnosed in 100 IBD patients; 61% female, 55% Crohn's disease, median age 48 years (interquartile range [IQR] 38-59]). The most common location was the appendix [39%] followed by the colon [22%]. Comprehensive IBD-related data were available for 50 individuals with a median follow-up of 30 months [IQR 11-70] following NEN diagnosis. Median duration of IBD at NEN diagnosis was 84 months [IQR 10-151], and in 18% of cases NEN and IBD were diagnosed concomitantly. At diagnosis, 20/50 were stage-I [T1N0M0], and 28/50 were graded G1 [ki67 ≤2%]. Incidental diagnosis of NEN and concomitantly IBD diagnosis were associated with an earlier NEN stage [p = 0.01 and p = 0.02, respectively]. Exposure to immunomodulatory or biologic therapy was not associated with advanced NEN stage or grade. Primary GEP-NEN were more frequently found in the segment affected by IBD [62% vs 38%]. At the last follow-up data, 47/50 patients were alive, and only two deaths were related to NEN. CONCLUSIONS: In the largest case series to date, prognosis of patients with GEP-NEN and IBD seems favourable. Incidental NEN diagnosis correlates with an earlier NEN stage, and IBD-related therapies are probably independent of NEN stage and grade. The association of GEP-NEN location and the segment affected by IBD may suggest a possible role of inflammation in NEN tumorigenesis.

Effectiveness of Third-Class Biologic Treatment in Crohn's Disease: A Multi-Center Retrospective Cohort Study.

BACKGROUND: Multiple studies have described the effectiveness of ustekinumab (UST) and vedolizumab (VDZ) in patients with Crohn's disease (CD) failing anti- Tumor necrosis factors (TNFs); however, the effectiveness of VDZ or UST as a third-class biologic has not yet been described. AIMS AND METHODS: In this retrospective multicenter cohort study, we aimed to investigate the effectiveness of VDZ and UST as a third-class biologic in patients with CD. RESULTS: Two-hundred and four patients were included; 156/204 (76%) patients received VDZ as a second- and UST as a third-class therapy (group A); the remaining 48/204 (24%) patients received UST as a second- and VDZ as a third-class therapy (group B). At week 16-22, 87/156 (55.5%) patients and 27/48 (56.2%) in groups A and B, respectively, responded to treatment (p = 0.9); 41/156 (26.2%) and 15/48 (31.2%) were in clinical remission (p = 0.5). At week 52; 89/103 (86%) patients and 25/29 (86.2%) of the patients with available data had responded to third-class treatment in groups A and B, respectively (p = 0.9); 31/103 (30%) and 47/29 (24.1%) were in clinical remission (p = 0.5). CONCLUSION: Third-class biological therapy was effective in more than half of the patients with CD. No differences in effectiveness were detected between the use of VDZ and UST as a third-class agent.

Real-life utility and diagnostic accuracy of a home-performed fecal calprotectin test to predict endoscopic activity in patients with inflammatory bowel disease under maintenance treatment with adalimumab.

AIMS: The home-performed fecal calprotectin (FC) test has been proposed for the remote management of inflammatory bowel disease (IBD) patients. We present our real-world experience on the use of FC home testing in IBD patients under maintenance treatment with adalimumab. METHODS: Consecutive IBD patients on maintenance treatment with adalimumab were studied retrospectively on the basis of prospectively recorded data. FC calprotectin home test (IBDoc, Βühlmann Laboratories AG, Schönenbuch, Switzerland) was analyzed alongside sufficient information on baseline characteristics, follow-up data and treatment modifications, as well as serum biomarkers and endoscopic assessment data on the basis of validated endoscopic scores. RESULTS: From a total of 72 IBD patients under maintenance treatment with adalimumab, 65 (90%) showed compliance with performing the home FC test. FC values were significantly higher in patients who finally needed treatment modification (37%) compared with those who were maintained on stable treatment (63%) (761 µg/g [537-1000] vs. 108 [41-335], P < 0.0001). In the logistic regression analysis FC and erythrocyte sedimentation rate (ESR) were independently correlated with endoscopically active disease (odds ratio: 1.003; 95% confidence interval, 1.001-1.006, P < 0.01 and odds ratio: 1.058; 95% confidence interval, 1.013-1.105, P < 0.05). FC identified patients with endoscopically active disease more effectively than other biomarkers with an area under the receiver operating characteristic curve of 0.78. FC levels >413 µg/g had a sensitivity of 75% and a specificity of 76% in predicting active disease in endoscopy. CONCLUSIONS: These first real-life results indicate that in IBD patients under maintenance treatment with adalimumab FC home test is a valuable tool with high compliance rates that performs better than the other biomarkers in predicting disease endoscopic activity.

The burden and management of anemia in Greek patients with inflammatory bowel disease: a retrospective, multicenter, observational study.

BACKGROUND: Anemia is a common extraintestinal manifestation of Inflammatory Bowel Disease (IBD) affecting negatively the patients' quality of life. The aim of this study was to determine the frequency and real-life management of anemia in IBD patients in Greece. METHODS: This study was conducted in 17 Greek IBD referral centers. Demographic, clinical, laboratory, IBD and anemia treatment data were collected and analyzed retrospectively. RESULTS: A total of 1394 IBD patients [560 ulcerative colitis (UC), 834 Crohn's disease (CD)] were enrolled. Anemia at any time was reported in 687 (49.3%) patients of whom 413 (29.6%) had episodic and 274 (19.7%) had recurrent/persistent anemia. Anemia was diagnosed before IBD in 45 (6.5%), along with IBD in 269 (39.2%) and after IBD in 373 (54.3%) patients. In the multivariate analysis the presence of extraintestinal manifestations (p = 0.0008), IBD duration (p = 0.026), IBD related surgeries and hospitalizations (p = 0.026 and p = 0.004 accordingly) were risk factors of recurrent/persistent anemia. Serum ferritin was measured in 839 (60.2%) IBD patients. Among anemic patients, 535 (77.9%) received treatment. Iron supplementation was administered in 485 (90.6%) patients, oral in 142 (29.3%) and intravenous in 393 (81%). CONCLUSIONS: The frequency of anemia in IBD patients, followed at Greek referral centers, is approximately 50%. Development of recurrent/persistent anemia may be observed in 20% of cases and is independently associated with the presence of extraintestinal manifestations, IBD duration, IBD related surgeries and hospitalizations. Anemia treatment is administered in up to [Formula: see text] of anemia IBD patients with the majority of them receiving iron intravenously.

First case of Whipple's disease successfully treated with tigecycline.

INTRODUCTION: Whipple's disease is a rare chronic infectious disease caused by Tropheryma whipplei. The infection mainly affects the small intestine of middle-aged patients, approximately three times more often in males than in females causing malabsorption and excessive weight loss but other organs may be affected as well. CASE REPORT: We describe a case of a 42-year-old woman with a history of chronic diarrhea and weight loss evolving for at least the last 6 years. The diagnosis of Whipple's disease was confirmed by histopathological examination of duodenal biopsy samples with Periodic acid-Schiff positive macrophages and by polymerase chain reaction technique detecting the DNA of Tropheryma whipplei. The patient was commenced on several antimicrobials including beta-lactams and co-trimoxazole but she did not improve. Finally, after-long lasting i.v. tigecycline 100 mg BID she was commenced on p.o. doxycycline along with hydroxychloroquine 200 mg TID for one year and after by p.o. doxycycline alone. DISCUSSION: The intriguing thing with this case was not only the natural resistance to co-trimoxazole but that the infection was controlled empirically with long-lasting i.v. tigecycline since several failed attempts to discontinue i.v. treatment followed. This might be due to erratic absorption of oral drugs due to gut inflammation. CONCLUSIONS: To our knowledge, this is the first case of Whipple's disease successfully treated with long-lasting induction parenteral tigecycline followed by p.o. doxycycline along with hydroxychloroquine for one year and after by p.o. doxycycline alone.

Mucocutaneous manifestations in patients with inflammatory bowel disease: a decade study from a Greek cohort.

BACKGROUND: We sought to investigate the prevalence of mucocutaneous manifestations (MCM) and potential associations with clinical characteristics in Greek patients with IBD. METHODS: This was a retrospective observational single-center study. Patients with IBD diagnosis attending a tertiary referral hospital in Heraklion, Crete, from January 2010 to January 2020 were included. Data were extracted with relevant medical information from the IBD registry. Standard statistical tests, descriptive statistics tests, chi-square, Pearson correlation and multivariate analysis tests were performed, using IBM SPSS Statistics 25. RESULTS: A total of 806 IBD patients were included in the study: 463 (57.4%) males, 441 (54.7%) Crohn's Disease, 352 (43.7%) ulcerative colitis and 13 (1.6%) IBD unclassified (IBD-U). Mean age was 50.67 ± 17.67 years, mean age of IBD diagnosis 36.67 ± 16.53 years and mean disease duration 13.65 ± 9.89 years. The prevalence of MCM was 171/806 (21.2%), 9.65% in ulcerative colitis and 30.84% in CD. The presence of MCM was significantly correlated with younger age of IBD diagnosis, longer IBD duration, CD diagnosis, inflammatory behavior and ileal or ileocolonic location of CD, extensive colitis in ulcerative colitis, intestinal manifestations (EIMs) and treatment with immunosuppressant or anti-TNFa. The development of MCM was independently associated with the presence of other EIMs odds ratio (OR), 4.03 [95% confidence interval (CI), 2.60-6.24; P < 0.001] and treatment with immunosuppressant (OR, 1.87; 95% CI, 01.14-3.07; P = 0.013) or anti-TNFa (OR = 2.47; 95% CI, 1.59-3.84; P < 0.01). CONCLUSIONS: In our study, about one-fifth of IBD patients developed MCM that was more frequently present in CD than in ulcerative colitis.

Solid extraintestinal malignancies in patients with inflammatory bowel disease.

Malignancies constitute the second cause of death in patients with inflammatory bowel diseases (IBD), after cardiovascular diseases. Although it has been postulated that IBD patients are at greater risk of colorectal cancer compared to the general population, lately there has been evidence supporting that this risk is diminishing over time as a result of better surveillance, while the incidence of extraintestinal cancers (EICs) is increasing. This could be attributed either to systemic inflammation caused by IBD or to long-lasting immunosuppression due to IBD treatments. It seems that the overall risk of EICs is higher for Crohn's disease patients and it is mainly driven by skin cancers, and liver-biliary cancers in patients with IBD and primary sclerosing cholangitis. The aims of this review were first to evaluate the prevalence, characteristics, and risk factors of EICs in patients with IBD and second to raise awareness regarding a proper surveillance program resulting in early diagnosis, better prognosis and survival, especially in the era of new IBD treatments that are on the way.

Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?

BACKGROUND/AIMS: The measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX. METHODS: A retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared. RESULTS: Of a total of 83 IBD patients (61 Crohn's disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 µg/ mL [1.32-9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 µg/mL (1.36- 10.25), higher than the median IFX-TL of patients without AEs (3.40 µg/mL [1.30-5.92]), but the difference was not significant (P= 0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P= 0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 µg/ mL and patients with IFX-TLs < 15 µg/mL. CONCLUSIONS: IFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.

Infliximab trough levels are decreasing over time in patients with inflammatory bowel disease on maintenance treatment with infliximab.

BACKGROUND: Infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATIs) have been suggested as useful markers for the optimization of treatment in inflammatory bowel disease (IBD). We aimed to estimate the patterns over time of IFX-TLs and ATIs in IBD patients on maintenance treatment with IFX. METHODS: Two different measurements of IFX-TLs and ATIs were performed (ELISA; Eagle BioSciences) at a 10-month interval using serum samples of consecutive patients on maintenance treatment with IFX. Certain biomarkers [hemoglobin, erythrocyte sedimentation rate, C-reactive protein (CRP), platelets, albumin] measured at the same time as well as clinical disease activity and quality of life were assessed. RESULTS: Among a total of 86 IBD patients under maintenance treatment with IFX, 64 [49 Crohn's disease, 15 ulcerative colitis (UC), 42 men, mean age 44.2±15.2 years, 41 in combination therapy with immunomodulator, six in intensified dose], with two available measurements of IFX-TLs and ATIs (A and B), were included in the study. The median levels of IF-TLs were 5.07 (interquartiles range: 1.60-12.73) µg/ml in measurement A and 4.68 (1.19-7.83) µg/ml in measurement B (P<0.0001). Patients whose dose was intensified after the first measurement showed an increase in their median IFX-TLs from 1.47 to 8.5 µg/ml, whereas patients with stable IFX dose showed a significant reduction in the median IFX-TLs from 5.65 to 3.8 µg/ml (P<0.0001). In the logistic regression analysis, the decrease in IFX-TL was correlated significantly and independently with the increase in CRP [odds ratio 5.2 (1.4-19.0), P=0.01]. CONCLUSION: IBD patients on maintenance treatment with IFX show decreasing patterns of IFX-TLs over time associated with increasing patterns of CRP levels.