Attitudes, perceptions and barriers in implementing therapeutic drug monitoring for anti-TNFs in inflammatory bowel disease: a survey from the Middle East.

Background: A growing body of evidence underscores the beneficial impact of therapeutic drug monitoring (TDM) on the efficacy and cost-effectiveness of anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD). Objectives: We surveyed clinician attitudes, perceptions and barriers related to TDM in IBD in the Middle East. Design: A 15-question survey was distributed through national gastroenterological societies in five Middle Eastern countries (UAE, Saudi Arabia, Kuwait, Lebanon and Egypt). Methods: Data on clinician characteristics, demographics, utilization patterns and obstacles related to the adoption of TDM with anti-TNFs were gathered. Logistic regression analysis was used to predict factors influencing the utilization of TDM. Results: Among 211 respondents (82% male), 82% were consultants, 8% were physicians with an interest in gastroenterology (GI), and 6% were GI trainees. Of these, 152 met inclusion criteria, treating >5 IBD patients per month and ⩾1 with an anti-TNF per month. TDM was used in clinical practice by 78% (95% CI: 71-85) of respondents. TDM was utilized following the loss of response (LOR) in 93%, for primary non-response (PNR) in 40% and before restarting anti-TNF therapy after a drug holiday in 33% of respondents, while 34% used TDM proactively. No specific factors were associated with the use of TDM. Barriers to TDM use included cost (85%), time lag to results (71%) and lack of insurance reimbursement (65%). Overall knowledge of TDM (70%), interpretation and actioning of results (76%) or awareness of clinical guidelines (57%) were not perceived as barriers. If barriers were removed, 95% would use TDM more frequently; 93% for LOR, 60% for PNR, 50% when restarting after a drug holiday, and 54% would use TDM proactively. Conclusion: Most gastroenterologists use TDM for LOR, with cost, time lag and insurance reimbursement being significant barriers. Addressing these barriers would increase the judicious use of reactive and proactive TDM to optimize anti-TNF therapy in IBD.

Attitudes, perceptions, and barriers in implementing therapeutic drug monitoring for anti-TNFs in inflammatory bowel disease: a survey from Middle East Anti-TNF therapies are perhaps the most widely used and available biological therapies for the treatment of inflammatory bowel disease globally even though other agents have been licensed in recent years. The role of therapeutic drug monitoring to optimise outcomes and mitigate against immunogenicity with anti-TNF agents are now being appreciated. Our study investigates clinician attitudes, perceptions, and barriers related to therapeutic drug monitoring (TDM) in the context of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD) through a comprehensive survey distributed from five Middle Eastern countries. Among 211 respondents (82% male), 82% were consultants, 8% physicians with an interest in gastroenterology (GI), and 6% GI trainees. TDM was utilised following loss of response (LOR) in 93%, for primary non-response (PNR) in 40%, and before restarting anti-TNF therapy after a drug holiday by 33% of respondents, while 34% used TDM proactively. No specific factors were associated with the use of TDM. Barriers to TDM use included cost (85%), time lag to result (71%), and lack of insurance reimbursement (65%). Overall knowledge of TDM (70%), interpretation and actioning of results (76%), or awareness of clinical guidelines (57%) were not perceived as barriers. If barriers were removed, 95% would use TDM more frequently; 93% for LOR, 60% for PNR, 50% when restarting after a drug holiday and 54% would use TDM proactively. Most gastroenterologists use TDM for LOR, with cost, time lag, and insurance reimbursement being significant barriers. Addressing these barriers would increase judicious use of reactive and proactive TDM to optimise anti-TNF therapy in IBD.

Rare case of rectal perforation by an intrauterine device: Case report and review of the literature.

INTRODUCTION AND IMPORTANCE: Intrauterine devices (IUDs) are safe, highly effective and reversible forms of contraception. Reliance on IUD has been increasing and as such, it is the responsibility of the healthcare provider to be aware of the complications associated with it. IUD rectal migration is one of the rare but serious complications that may lead to detrimental sequelae. CASE PRESENTATION: A 30-year-old asymptomatic woman presented to the gynaecology clinic two months after a difficult insertion of an IUD. On examination, the device was not localised in utero with transvaginal sonography. Computed tomography scan and colonoscopy revealed the position of the IUD within the rectum. It was successfully retrieved with a combined laparoscopic-colonoscopic approach. Follow-up flexible sigmoidoscopy showed a well-healed rectal wall. CLINICAL DISCUSSION: IUD perforation can increase the risk of morbidity and necessitates early surgical intervention even if the patient is asymptomatic. Combined laparoscopic-colonoscopic approach allows for safe retrieval of IUD that has perforated the intraperitoneal rectal segment or is firmly embedded within the mucosa. Recognising the risk factors and adhering to the principles of IUD insertion could significantly lower the risk of perforation. CONCLUSION: This case report highlights the importance of a physician's vigilance regarding a perforating IUD in a patient with a history of a difficult insertion. It is imperative to undertake additional steps to rule out such a complication in these cases. Uterine perforation can be avoided with implementation of safe IUD insertion practice.

NOD2/CARD15 polymorphisms (P268S, IVS8+158, G908R, L1007fs, R702W) among Kuwaiti patients with Crohn's disease: A case-control study.

Background: Nucleotide-binding oligomerization domain-containing two (NOD2/CARD15) gene polymorphisms are implicated in the pathogenesis of Crohn's disease (CD). Aim: To describe the allelic frequency of NOD2/CARD15 gene variants among Kuwaiti patients with CD and investigate potential genotype/phenotype associations. Methods: Adult Kuwaiti citizens with an established diagnosis of CD and healthy controls were enrolled from October 2018 to May 2020. Three common NOD2/CARD15 polymorphisms (R702W, G908R, and L1007fs) and P268S and IVS8+158 polymorphisms were screened by polymerase chain reaction/restriction analysis length polymorphism (PCR/RFLP). Results: Ninety adult Kuwaiti patients with CD and 210 healthy subjects (as controls) were recruited. P268S, IVS8+158, G908R, and R702W minor alleles were identified in 38.9%, 21.1%, 12.2%, and 4.4% of CD patients, respectively. NOD2/CARD15 polymorphisms coexisted in 35 healthy controls (16.7%) and 21 CD patients (23.3%). Individuals with either a single or multiple polymorphism were approximately two times more likely to have CD than those with no polymorphism. Patients with multiple polymorphisms had significantly more stricturing and penetrating disease. Conclusion: NOD2/CARD15 gene polymorphisms were significantly associated with an increased risk of disease and aggressive phenotypes among the Kuwaiti CD population.

Clinical characteristics of coronavirus disease 2019 (COVID-19) patients in Kuwait.

This is a retrospective single-center study of 417 consecutive patients with coronavirus disease 2019 (COVID-19) admitted to Jaber Al-Ahmad Hospital in Kuwait between February 24, 2020 and May 24, 2020. In total, 39.3% of patients were asymptomatic, 41% were symptomatic with mild/moderate symptoms, 19.7% were admitted to the intensive care unit (ICU). Most common symptoms in cohort patients were fever (34.3%) and dry cough (32.6%) while shortness in breath was reported in (75.6%) of ICU admissions. Reported complications requiring ICU admission included Sepsis (68.3%), acute respiratory distress syndrome (95.1%) and heart failure (63.4%). ICU patients were more likely to have comorbidities, in comparison to non-ICU patients, including diabetes (35.4% vs 20.3%) and hypertension (40.2% vs 26.9%). Mortality rate of cohort was 14.4% and mean age of death was 54.20 years (± 11.09) and 90% of death cases were males. Chest high-resolution computed tomography for ICU cases reveled multifocal large patchy areas of ground glass opacification mixed with dense consolidation. Cases admitted to ICU showed abnormal levels of markers associated with infection, inflammation, abnormal blood clotting, heart problems and kidney problems. Mean hospital stay for asymptomatic cases was 20.69 days ±8.57 and for mild/moderate cases was 21.4 days ±8.28. Mean stay in ICU to outcome for survivors was 11.95 days ±8.96 and for death cases 13.15 days ±10.02. In this single-center case series of 417 hospitalized COVID-19 patients in Kuwait 39.3% were asymptomatic cases, 41% showed mild/moderate symptoms and 18.7% were admitted to ICU with a mortality rate of 14.4%.

Concordance between tuberculin skin test and interferon-gamma release assay for latent tuberculosis screening in inflammatory bowel disease.

BACKGROUND/AIMS: Latent tuberculosis screening is mandatory prior to initiating anti-tumor necrosis factor (anti-TNF) medications. Guidelines recommend interferon-gamma release assays (IGRA) as first line screening method for the general population. Studies provided conflicting evidence on IGRA and tuberculin skin test (TST) performance in inflammatory bowel disease (IBD) patients. We assessed test concordance and the effects of immunosuppression on their performance in IBD patients. METHODS: We searched MEDLINE, Embase and Cochrane databases (2011-2018) for studies testing TST and IGRA in IBD. Primary outcome was TST and IGRA concordance. Secondary outcomes were effects of immunosuppressive therapy on performance. Immunosuppression defined as either steroids, thiopurine, methotrexate or cyclosporine use. We used the pooled random effects model to adjust for heterogeneity analyzed using (I2-Q statistics). We compared the fixed model to exclude smaller study effects. RESULTS: Sixteen studies (2,488 patients) were included. Pooled TST and IGRA concordance was 85% (95% confidence interval [CI], 81%-88%; P=0.01). Effects of immunosuppression were reported in 8 studies (814 patients). The odds ratio of testing positive by IGRA decreased to 0.57 if immunosuppressed (95% CI, 0.31-1.03; P=0.06). The odds ratio of testing positive by TST if immunosuppressed was 1.14 (95% CI, 0.61-2.12; P=0.69). The fixed model yielded similar results, however the negative effect of immunosuppression on IGRA reached statistical significance (P=0.01). CONCLUSIONS: While concordance was 85% between TST and IGRA, the performance of IGRA seems to be negatively affected by immunosuppression. Given the importance of detecting latent tuberculosis prior to anti-TNF initiation, further randomized controlled trials comparing the performance of TST and IGRA in IBD patients are needed.

Rare Benign Large Lymphoid Colonic Polyp.

Benign lymphoid polyps are uncommon lesions of the small bowel and the colon to a lesser degree that are mostly found in children. There are only few reported cases in adults in which the lesions were predominantly polypoid and described as lymphonodular hyperplasia. We present a case of a large benign lymphoid polyp in the transverse colon of a 64-year-old lady who was referred to our care for a history of alteration in her bowel habit and anemia. Colonoscopy showed a 3 cm (Paris 1p) friable polyp which was excised and retrieved. Histopathology examination confirmed its benign nature supported by immunohistochemical studies. Benign lymphoid polyp is a rare condition posing a diagnostic challenge as it can be misinterpreted as a malignant lesion.

A Study of Optimal Screening for Latent Tuberculosis in Patients with Inflammatory Bowel Disease.

BACKGROUND: Reactivation of LTBI in patients with IBD on anti-TNF-α agents can lead to serious life-threatening illness. No gold standard exists for the detection of LTBI. We examined whether a dual testing strategy with TST and IGRA would improve the detection of LTBI. METHODS: Consecutive IBD patients being considered for anti-TNF-α treatment underwent testing with a TST, IGRA and CXR. All patients completed a self-administered questionnaire. The association of both tests with demographic factors, LTBI risk factors, BCG vaccination, IS therapy and agreement between the TST and IGRA were evaluated. RESULTS: One-hundred and fifty-five IBD patients were included, 6% were TST positive and 5% were IGRA positive. Concordance between TST and IGRA was fair (κ = 0.21, 95% CI - 0.081-0.498). Neither test was affected by age, gender or BCG vaccination. The presence of risk factors for LTBI was found to be positively associated with TST (OR 19.8, 95% CI 3.9-102.1), but not IGRA. IGRA was negatively associated with IS therapy (OR 0.06, 95% CI 0.007-0.5), but not TST. Four patients who were IGRA positive but TST negative were treated for LTBI by a respirologist. CONCLUSION: An IGRA result was negatively associated with IS therapy, while the presence of risk factors for LTBI was found to be positively associated with TST results. There was fair agreement between positive TST and IGRA results. The addition of IGRA to the standard practice of TST and CXR increased the number of cases that were initiated on LTBI therapy.

Comparative Effectiveness of Infliximab Versus Adalimumab in Patients with Biologic-Naïve Crohn's Disease.

BACKGROUND: Direct head-to-head studies comparing the long-term outcomes of infliximab (IFX) to adalimumab (ADA) in Crohn's disease (CD) are sparse. AIMS: We compared the short-term and long-term efficacy and safety of IFX and ADA in CD. METHODS: We performed a single-center retrospective study including biologic-naïve adult patients with CD who were started on IFX or ADA at the McGill University Health Center. The primary end points were clinical response and remission at 12 months. Secondary end points included corticosteroid-free remission at 12 months, durable remission, and treatment failure with need for steroids, hospitalization or surgery. Safety was also assessed. RESULTS: Two hundred and twenty patients were included (143 IFX, 77 ADA). Patients on IFX had a higher prevalence of fistulizing or perianal disease and corticosteroid treatment at baseline. Rates of clinical remission and corticosteroid-free remission at 12 months were similar between both groups: 63.8 versus 76.3% (p = 0.139) and 54.1 versus 44.7% (p = 0.354), respectively, for IFX and ADA. Combination therapy led to significantly higher remission rates at 12 months compared to monotherapy for patients on IFX (81.2 vs. 52.1%, p = 0.008), but not for those on ADA. Higher rates of adverse events were reported with IFX compared to ADA (p = 0.006). CONCLUSIONS: Our real-life experience in biologic-naïve CD patients demonstrated that patients started on IFX were more likely to have a harder-to-treat phenotype. Despite that, efficacy end points were similar between both groups. Clinical remission was higher in patients with combination therapy for IFX, but not for those on ADA. This warrants further investigation.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

BACKGROUND: It is important to minimize placebo rates in randomised controlled trials (RCTs) to efficiently detect treatment differences between interventions. Historically, high placebo rates have been observed in clinical trials of ulcerative colitis (UC). A better understanding of factors influencing placebo rates may lead to more informed clinical trial design. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate placebo response and remission rates in RCTs evaluating UC treatments in adult patients. SEARCH METHODS: Electronic databases (i.e. MEDLINE, EMBASE, and CENTRAL) were searched from inception to 1 March 2017 with no language restrictions applied. Reference lists and conference proceedings of major gastroenterology meetings were also handsearched to identify additional studies. SELECTION CRITERIA: Placebo-controlled RCTs of adult patients with UC treated with corticosteroids, aminosalicylates, immunosuppressives or biologics were eligible, provided enrolment and outcome assessment was conducted using the Ulcerative Colitis Disease Activity Index (UCDAI) or the Mayo Clinic Score. The minimum trial duration was two weeks for induction trials and four months maintenance trials. DATA COLLECTION AND ANALYSIS: Pairs of authors independently determined study eligibility and extracted data with any disagreements resolved through consensus. Outcomes of interest included the proportion of patients with clinical response and remission. Trial characteristics such as the design, participant demographics and disease history, interventions, and enrolment and assessment criteria were also recorded. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool. Pooled placebo response and remission rates and 95% confidence intervals (95% CI) were calculated using a binomial normal model for proportions. Induction of remission and maintenance studies were pooled separately. The impact of study-level characteristics on placebo response and remission rates was investigated using mixed-effects meta-regression analyses with logits of event rates as the outcome variables. An assessment of pooled placebo rates over time was conducted using a cumulative meta-analysis based on date of publication. Publication bias was examined using funnel plots. MAIN RESULTS: The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%).Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score ≥1 versus ≥ 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01).Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). AUTHORS' CONCLUSIONS: Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.

Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

BACKGROUND AND AIMS: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.

Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn's disease: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Combination therapy with infliximab and azathioprine has been shown to be superior to either treatment alone in Crohn's disease (CD). However, the benefit of combining adalimumab with an immunomodulator remains controversial. The aim of this study was to compare the efficacy of adalimumab monotherapy with combination therapy for induction and maintenance of response and remission in CD using a meta-analysis of the current literature. METHODS: We performed a systematic literature search using Medline, Embase, Cochrane and several other databases. Prospective randomized controlled trials, retrospective cohort and case-controlled studies were included. The primary outcomes included induction of response and remission (up to week 12), maintenance of clinical response and remission (1 year) and the need for dose escalation. Several subgroup and sensitivity analyses were performed. RESULTS: Eighteen out of 2743 retrieved studies were included. A meta-analysis of 7 studies assessing induction of remission (n=1984) showed that ADA monotherapy was inferior to combination therapy [OR=0.78 (0.64-0.96), p=0.02]. A meta-analysis of 4 studies revealed that combination therapy was not statistically different from ADA for maintenance of remission [OR=1.08 (0.79-1.48), p=0.48]. Combination therapy was also not different from ADA monotherapy in terms of requirement for dose escalation [OR=1.13 (0.69-1.85), p=0.62]. CONCLUSIONS: Combination therapy with ADA and immunomodulator was mildly superior to ADA monotherapy for induction of remission in CD. The rate of remission at 1 year and the need for dose escalation were similar in both groups. These findings should be interpreted with caution in view of possible confounders and should be further validated by randomized controlled trials.

State-of-the-art management of acute bleeding peptic ulcer disease.

The management of patients with non variceal upper gastrointestinal bleeding has evolved, as have its causes and prognosis, over the past 20 years. The addition of high-quality data coupled to the publication of authoritative national and international guidelines have helped define current-day standards of care. This review highlights the relevant clinical evidence and consensus recommendations that will hopefully result in promoting the effective dissemination and knowledge translation of important information in the management of patients afflicted with this common entity.