Persistent Fever after COVID-19 Vaccination in a Patient with Ulcerative Colitis: A Call for Attention.

The development of vaccinations has been game-changing in the ongoing effort to combat the COVID-19 pandemic. Until now, adverse effects are being reported at low frequency, including thrombocytopenia and myocarditis. Careful monitoring for any suspicious symptoms and signs following vaccination is necessary. We report a case of hemophagocytic lymphohistiocytosis (HLH) after mRNA COVID-19 vaccine in a 23-year-old female with ulcerative colitis. Diagnosis was made according to HLH-2004 criteria and the patient was treated with dexamethasone with response. Our report aimed to draw attention to the potential relation between COVID-19 vaccines and HLH and the necessity of continued surveillance, especially in at-risk populations such as those with underlying immune dysregulation.

O desenvolvimento de vacinas foi um ponto de viragem no combate contra a pandemia da COVID-19. Até ao momento, os efeitos adversos como a trombocitopenia e miocardite têm sido reportados com baixa frequência. A monitorização cuidadosa de qualquer sinal ou sintoma suspeitos é essencial. Reportamos um caso de linfohistiocitose hemofagocítica após vacinação contra a COVID-19 com uma vacina de mRNA, numa jovem de 23 anos com colite ulcerosa. O diagnóstico obedeceu os critérios HLH-2004 e a paciente foi tratada com dexametasona, com resposta. Pretendemos chamar à atenção para a potencial relação entre a vacinação para a COVID-19 e a HLH e a necessária contínua vigilância, especialmente em populações de maior risco, como as portadoras de doenças imuno-mediadas.

The Influence of Subclinical Active Inflammation on IFX Pharmacokinetic Modeling and Disease Progression Assessment: Findings from a Prospective Real-World Study in Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. METHODS: The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. RESULTS: The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in the majority of its definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression. CONCLUSION: In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Thiopurines have no impact on outcomes of Crohn's disease patients beyond 12 months of maintenance treatment with infliximab.

BACKGROUND: The emergence of new treatments the inflammatory bowel diseases (IBD) raised questions regarding the role of older agents, namely thiopurines. AIMS: To clarify the benefits of combination treatment with thiopurines on Crohn's disease (CD) patients in the maintenance phase of infliximab. METHODS: In this analysis of the 2-year prospective multicentric DIRECT study, patients were assessed in terms of clinical activity, faecal calprotectin (FC), C-reactive protein (CRP), and infliximab pharmacokinetics. A composite outcome based on clinical- and drug-related items was used to define treatment failure. RESULTS: The study included 172 patients; of these, 35.5 % were treated with combination treatment. Overall, 18 % of patients achieved the composite outcome, without statistically significant differences between patients on monotherapy and on combination treatment (21.6% vs 11.5 %, p = 0.098). Median CRP, FC, and infliximab pharmacokinetic parameters were similar in both groups. However, in the sub-analysis by infliximab treatment duration, in patients treated for less than 12 months, the composite outcome was reached in fewer patients in the combination group than in the monotherapy group (7.1% vs 47.1 %, p = 0.021). CONCLUSION: In CD patients in maintenance treatment with infliximab, combination treatment does not seem to have benefits over infliximab monotherapy beyond 12 months of treatment duration.

How many biomarker measurements are needed to predict prognosis in Crohn's disease patients under infliximab?-A prospective study.

BACKGROUND: Timely stratification of Crohn's disease (CD) is essential for patients' management. The use of noninvasive accurate biomarkers is key to monitor treatment and to pursue mucosal healing, the ultimate treatment endpoint in CD. OBJECTIVE: We aimed to evaluate the performance of readily available biomarkers and develop risk matrices to predict CD progression. METHODS: Data from 289 CD patients receiving infliximab (IFX) maintenance therapy for 2 years was collected; those patients were included in DIRECT, a prospective multicenter observational study. Disease progression was evaluated using two composite outcomes incorporating clinical and drug-related factors, the first including IFX dose and/or frequency adjustments. Univariate and multivariable logistic regressions were used to calculate the odds ratios (OR) and to develop risk matrices. RESULTS: The isolated presence of anemia at least once during follow-up was a significant predictor of disease progression (OR 2.436 and 3.396 [p ≤ 0.001] for composite outcomes 1 and 2, respectively) regardless of confounding factors. Isolated highly elevated C-reactive protein (CRP; >10.0 mg/L) and fecal calprotectin (FC; >500.0 µg/g) in at least one visit were also significant predictors, while milder elevations (3.1-10.0 mg/L and 250.1-500.0 µg/g) were only relevant when detected in at least two visits (consecutive or not). The combination of biomarkers in risk matrices had good ability to predict progression; patients simultaneously presenting anemia, highly elevated CRP and FC at least once had 42%-63% probability of achieving the composite outcomes. CONCLUSION: The combined evaluation of hemoglobin, CRP, and FC in at least one time point and their incorporation into risk matrices seems to be the optimal strategy for CD management, as data from additional visits did not meaningfully influence the predictions and may delay decision-making.

Diagnosis of Bowel Endometriosis Using Endoscopic Ultrasound-guided Fine Needle Aspiration.

Endometriosis is a relatively common gynecological condition in women of reproductive age. The rectosigmoid region is the most commonly affected segment when the gastrointestinal tract is involved. A differential diagnosis of colorectal neoplasia is difficult because of the similar clinical, endoscopic, and radiology findings. A 42-year-old female presented with abdominal distention and was subsequently diagnosed with a large bowel obstruction in the rectum. A temporary colostomy was performed, and endoscopy revealed a rectal mass obstructing the rectum. The biopsy showed normal mucosa, and it was difficult to exclude rectal malignancies even after the imaging workup. Endoscopic ultrasound demonstrated a hypoechoic lesion below the rectal mucosa, and fine needle aspiration confirmed the diagnosis of bowel endometriosis. Bowel endometriosis is a challenging diagnosis. Endoscopic ultrasound- guided fine-needle aspiration is useful for acquiring adequate samples for histological confirmation and a definitive diagnosis of bowel endometriosis.

Transmural remission improves clinical outcomes up to 5 years in Crohn's disease.

INTRODUCTION: Evidence supporting transmural remission (TR) as a long-term treatment target in Crohn's disease (CD) is still unavailable. Less stringent but more reachable targets such as isolated endoscopic (IER) or radiologic remission (IRR) may also be acceptable options in the long-term. METHODS: Multicenter retrospective study including 404 CD patients evaluated by magnetic resonance enterography and colonoscopy. Five-year rates of hospitalization, surgery, use of steroids, and treatment escalation were compared between patients with TR, IER, IRR, and no remission (NR). RESULTS: 20.8% of CD patients presented TR, 23.3% IER, 13.6% IRR and 42.3% NR. TR was associated with lower risk of hospitalization (odds-ratio [OR] 0.244 [0.111-0.538], p < 0.001), surgery (OR 0.132 [0.030-0.585], p = 0.008), steroid use (OR 0.283 [0.159-0.505], p < 0.001), and treatment escalation (OR 0.088 [0.044-0.176], p < 0.001) compared to no NR. IRR resulted in lower risk of hospitalization (OR 0.333 [0.143-0.777], p = 0.011) and treatment escalation (OR 0.260 [0.125-0.540], p < 0.001), while IER reduced the risk of steroid use (OR 0.442 [0.262-0.745], p = 0.002) and treatment escalation (OR 0.490 [0.259-0.925], p = 0.028) compared to NR. CONCLUSIONS: TR improved clinical outcomes over 5 years of follow-up in CD patients. Distinct but significant benefits were seen with IER and IRR. This suggests that both endoscopic and radiologic remission should be part of the treatment targets of CD.

Inflammatory bowel disease and thromboembolic events: a c'lot to learn.

Background: Inflammatory bowel disease (IBD) is associated with a variety of extraintestinal manifestations including arterial and venous thromboembolism. Research evidences that IBD patients have about a 2- to 3-fold increase in the risk of venous thromboembolism when compared with the general population. Objectives: We intended to evaluate the coagulation parameters and the prevalence of thromboembolic events (TE) in IBD patients. It was also our aim to investigate the correlation between coagulation parameters and disease phenotype and activity in this population. Methods: This single center prospective observational study was performed between November 2016 and April 2020. The cohort included patients with 18 years of age or older, diagnosed with IBD and followed at a gastroenterology consultation, during a follow-up period of 36 months. Patients were evaluated in terms of IBD type, extent and disease behavior, clinical scores of IBD activity, medication, smoking history, family and personal history of TE, coagulation parameters, fecal calprotectin levels, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hospitalization due to TE, IBD-related hospitalization or surgery, pregnancy, or diagnosis of malignancy. Results: The study included 149 IBD patients (67 males and 82 females). Coagulation parameters were similar in CD and UC patients and only plasminogen was increased in CD patients [97.4 (17.0) versus 91.6 (13.3), p = 0.035], when comparing with UC patients. The determined values were in the range of the reference values described in literature for the standard population. During the follow-up period, none of the patients experienced a TE that demanded hospitalization. Conclusion: In our study, acquired and inherited risk factors for TE and changes in coagulation parameters did not show to influence prothrombotic predisposition in IBD patients. As such, the clinical relevance of measuring coagulation parameters in this population is questionable. Trial Registry: NCT05162339 (ClinicalTrials.gov ID).

Composite outcomes in observational studies of Crohn's disease: a systematic review and meta-analysis.

Background: This systematic review and meta-analysis aims to assess composite and aggregate outcomes of observational studies in Crohn's disease and to evaluate whether the number and type of variables included affect the frequency of the outcome. Methods: MEDLINE [via PubMed], Scopus and Web of Science were searched to identify observational studies that enrolled patients with Crohn's disease and evaluated a composite or aggregate outcome. The proportion of patients achieving the outcome was determined and a random-effects meta-analysis was performed to evaluate how the frequency of each outcome varies according to the reporting of predefined variables. Results: From 10,257 identified records, 46 were included in the qualitative analysis and 38 in the meta-analysis. The frequency for composite and aggregate outcomes was 0.445 [95% confidence interval (CI): 0.389-0.501] and 0.140 (95% CI: 0.000-0.211), respectively. When comparing composite outcomes by number of included variables, the frequency was 0.271 (95% CI: 0.000-0.405) and 0.698 (95% CI: 0.651-0.746), for one and six variables, respectively. The frequency of the composite outcome varied according to the identity of the variables being reported. Specific pairs of predefined variables had a significant effect in the frequency of composite outcomes. Conclusion: Composite outcomes with increasing number of predefined variables show an increase in frequency. Outcomes including variables such as 'Surgery' and 'Steroids' had higher frequencies when compared with the ones that did not include these variables. These results show that the frequency of composite outcomes is dependent on the number and type of variables being reported.

Incidence Trends of Inflammatory Bowel Disease in a Southern European Country: A Mirror of the Western World?

INTRODUCTION: Inflammatory bowel disease (IBD) affects people from all age categories worldwide. Although the incidence of the disease is stabilizing or decreasing in most Western world countries, its prevalence is still increasing because of the rise in life expectancy and better disease management. This work intends to identify the trends related to IBD incidence nationwide, analyzing regional, sex, and age distributions. METHODS: Data were provided by the Portuguese Shared Services of the Ministry of Health. This study consisted of a retrospective analysis of all first consultations coded for "Chronic enteritis/ulcerative colitis" (D94) in a primary healthcare setting, between 2017 and 2020, in Portugal. The primary outcome measure was the IBD incidence rate per 100,000 inhabitants. We also calculated the incidence rate per person-year and forecasted incidence until 2024. RESULTS: Between 2017 and 2019, the incidence rate of IBD in Portugal decreased from 54.9 to 48.6 per 100,000 inhabitants. The average incidence was 20 new cases of IBD per 1,000 person-year. It was predicted that, in December 2023, IBD incidence would reach 305.4 new cases (95% Prediction Interval 156.6-454.3), a similar result to the values forecasted for December 2021 (305.4, 95% Prediction Interval 197.3-413.6). DISCUSSION: The incidence of IBD slightly declined from 2017 to 2019, and it is posed to stabilize in the future. The presented data are of the utmost importance for the characterization of IBD in Southern European countries and the establishment of future health policies in the setting of compounding prevalence in the Western world.

The Magnitude of Crohn's Disease Direct Costs in Health Care Systems (from Different Perspectives): A Systematic Review.

BACKGROUND: The prevalence of inflammatory bowel disease (IBD) has been increasing worldwide, causing high impact on the quality of life of patients and an increasing burden for health care systems. In this systematic review, we reviewed the literature concerning the direct costs of Crohn's disease (CD) for health care systems from different perspectives: regional, economic, and temporal. METHODS: We searched for original real-world studies examining direct medical health care costs in Crohn's disease. The primary outcome measure was the mean value per patient per year (PPY) of total direct health care costs for CD. Secondary outcomes comprised hospitalization, surgery, CD-related medication (including biologics), and biologics mean costs PPY. RESULTS: A total of 19 articles were selected for inclusion in the systematic review. The studies enrolled 179 056 CD patients in the period between 1997 and 2016. The pooled mean total cost PPY was €6295.28 (95% CI, €4660.55-€8503.41). The pooled mean hospitalization cost PPY for CD patients was €2004.83 (95% CI, €1351.68-€2973.59). The major contributors for the total health expenditure were biologics (€5554.58) and medications (€3096.53), followed by hospitalization (€2004.83) and surgery (€1883.67). No differences were found between regional or economic perspectives, as confidence intervals overlapped. However, total costs were significantly higher after 2010. CONCLUSIONS: Our review highlighted the burden of CD for health care systems from different perspectives (regional, economic, and temporal) and analyzed the impact of the change of IBD treatment paradigm on total costs. Reducing the overall burden can depend on the increase of remission rates to further decrease hospitalizations and surgeries.

Subclinical Persistent Inflammation as Risk Factor for Crohn's Disease Progression: Findings From a Prospective Real-World Study of 2 Years.

BACKGROUND AND AIMS: Subclinical intestinal inflammation is common in Crohn's disease (CD). We aimed to explore its impact in the disease progression of infliximab-treated patients and the usefulness of fecal calprotectin (FC) and C-reactive protein (CRP) as surrogate minimally invasive biomarkers. METHODS: The registry-based, prospective, observational, multicenter DIRECT (study to investigate the correlation of fecal calprotectin with serum Drug levels and development of an antI-dRug antibodiEs among adult patients with inflammatory bowel disease reCeiving anti-TNF-alfa treatment or vedoluzimab treatment) study followed infliximab-treated CD patients for 2 years in a tertiary care setting. Persistent inflammation definition was based on FC (>150 µg/g, >250 µg/g, or >350 µg/g) or serum CRP (>3 µg/mL) concentrations over 2 consecutive or at least 3 visits. Patients were categorized according to a composite outcome reflecting disease progression that incorporated surgery; hospitalizations; new fistulae, abscess, or stricture; and treatment escalation. RESULTS: Of 322 DIRECT study patients, 180 asymptomatic, infliximab treated on maintenance regimen were included in the analysis. Patients developing the composite endpoint (n = 96) presented higher median levels of FC (205 [interquartile range, 98-515] µg/g; P = .045) but not of CRP (2.50 [interquartile range, 0.80-6.00] µg/mL; P = .895). Biomarker-defined persistent subclinical inflammation prevalence ranged from 24% to 81%. Considering FC >250 µg/g in 2 consecutive visits, prevalence was 50%, odds of achieving the endpoint were increased 3-fold (odds ratio, 2.996 [95% confidence interval, 1.557-5.776]), and time-to-outcome occurrence was significantly lower among subjects with persistent inflammation (median time: 11 months). Both clinical-related and treatment-related components were significantly associated with persistent inflammation. Definitions based on CRP >3 µg/mL, FC >150 µg/g, FC >350 µg/g, double biomarkers (FC >250 µg/g and/or CRP >3 µg/mL), or more visits did not improve predictive ability. CONCLUSIONS: Persistent inflammation, defined simply and readily by FC >250 µg/g over 2 consecutive visits, was associated with a significantly higher risk and shorter time to occurrence of a composite outcome reflecting disease progression in asymptomatic infliximab-treated CD patients.

Composite outcomes in observational studies of ulcerative colitis: A systematic review and meta-analysis.

BACKGROUND: Ulcerative colitis (UC) has been the focus of numerous observational studies over the years and a common strategy employed in their design is the use of composite and aggregate outcomes. OBJECTIVE: This systematic review and meta-analysis aims to identify composite and aggregate outcomes of observational studies in UC and to evaluate how the number and type of variables included and the length of follow-up affect the frequency of patients that achieve these outcomes. METHODS: A systematic literature search was carried out using MEDLINE [via PubMed], Scopus, and Web of Science online databases. Observational studies that included UC patients and reported composite or aggregate outcomes were identified. A set of variables considered to be representative of progressive or disabling UC was defined, the proportion of patients attaining the outcomes was determined and a random-effects meta-analysis was performed by dividing the identified studies into subgroups according to different criteria of interest. RESULTS: A total of 10,264 records were identified in the systematic search, of which 33 were retained for qualitative analysis and 20 were included in the meta-analysis. The mean frequency for composite outcomes was 0.363 [95% confidence interval (CI) 0.323-0.403]. The frequency of composite outcome for the subgroup of studies that included the variable "Biologics" was significantly higher than for those in which this variable was not reported [0.410; 95% CI 0.364-0.457 versus 0.298; 95% CI 0.232-0.364; p = 0.006]. Composite outcomes were also more frequent as the follow-up duration increased. CONCLUSION: The frequency of composite outcomes in observational studies of UC is dependent on the specific identity of the variables being reported. Moreover, longer follow-up periods are associated with higher frequencies of composite outcomes. The evidence provided here is useful for the design of future observational studies of UC that aim to maximize the frequency of patients that achieve composite outcomes.

A survey on the impact of IBD in sexual health: Into intimacy.

Patients with Inflammatory Bowel Disease (IBD) are at increased risk of psychological and physical burden, including sexual dysfunction (SD). This study aimed to assess the prevalence of SD and to identify its predictive factors, in IBD patients. This unicentric cross-sectional case-control survey (ratio 2:1) included patients followed at the day hospital IBD consultation, in the Gastroenterology department of a tertiary referral center, for 2 years. Participants received anonymous questionnaires, concerning basic characteristics and sexual function, and a questionnaire on anxiety and depression, body image, fatigue, and IBD-specific health-related quality of life (QoL). We analyzed data from 120 IBD patients and 60 healthy controls. Forty-two female (56.8%) and 6 male (14.6%) IBD patients, and 6 women (15%) and 2 males (10%) of the control group presented SD. SD was significantly higher in IBD patients with age between 18 and 30 and 51 and 60 than in healthy controls (P < .05) Regarding multivariate analysis, age was a predictive factor for SD in males (P = .014), and anxiety and depression (P = .002) and fatigue (P = .043) in females. SD is a predictor of lower QoL among IBD patients, considering the last 15 (P < .001) and 60 days (P = .001), regarding univariate analysis. SD (P = .007), body image distortion (P < .001), and fatigue (P = .004) were predictors of low QoL (last 15 days, multivariate analysis). SD was more prevalent in IBD patients than in the control group and impacted negatively the QoL of patients. Age was a predictive factor for SD in men while anxiety and depression, and fatigue were predictive of SD in women.

Thiopurines: Use them or lose them? International survey on current and future use of thiopurines in inflammatory bowel disease.

BACKGROUND AND AIMS: The role of thiopurines in therapeutic algorithms of Crohn's disease (CD) and Ulcerative colitis (UC) is being questioned. This work aimed to investigate current practice and future perspectives of Inflammatory Bowel Disease (IBD) physicians regarding the efficacy, safety, and role of precision medicine with thiopurines in IBD. METHODS: A 29-questions web-based survey was developed and distributed to IBD physicians worldwide. RESULTS: We collected the complete answers of 408 physicians from 50 countries. Most participants were experienced physicians in IBD; 26.0% met our definition of "IBD expert". Four physicians reported to not use thiopurines in clinical practice. Most respondents used thiopurines in monotherapy and in combination therapy, both in CD and UC. Respondents tended to consider thiopurines as drugs with a good safety profile, with the agreement of 61.5% of the overall cohort. A minority of physicians (~6%) considered that thiopurines will not be used in the future in IBD patients, while 57.8% believed that these drugs will still be used, in mono and combination therapy. CONCLUSION: Despite the many emerging treatments in IBD, according to the beliefs of most physicians surveyed, thiopurines will still be an important part of the treatment algorithm of both CD and UC.

Age at Diagnosis Is Determinant for the Outcome of Inflammatory Bowel Disease: Is It a Myth?

INTRODUCTION: Patients with elderly-onset inflammatory bowel disease were previously associated with a less aggressive course of the disease. However, there are conflicting data that need further validation. We aimed to determine the association between age at diagnosis and the development of progressive disease in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: This cohort study included patients with CD and UC followed in 6 secondary and tertiary care centers in mainland Portugal. Patients were divided into a derivation (80%) cohort and a validation (20%) cohort. The primary outcome was progressive disease. Logistic regression analysis, receiver operating characteristic curves, and the areas under the curve (AUC) were performed. Odds ratios with 95% confidence intervals (CIs) were estimated. RESULTS: The derivation cohorts included 1245 patients with CD (68% with progressive disease) and 1210 patients with UC (37% with progressive disease), whereas the validation cohorts included 302 patients with CD and 271 patients with UC, respectively, with similar outcome proportions. In our final model, age at diagnosis older than 60 years was significantly associated with a lower risk of developing progressive disease (odds ratio 0.390, 95% CI 0.164-0.923, P = 0.032), with a high discriminative power (AUC 0.724, 95% CI 0.693-754) in patients with CD. However, according to this model, no significant associations were found between age at diagnosis and the risk of developing progressive disease in patients with UC. No differences were observed in the AUC values between the validation and the derivation cohorts. DISCUSSION: Patients with elderly-onset CD, but not patients with UC, were associated with a less progressive course of the disease.

Clinical, Endoscopic and Histological Outcomes in Induction of Moderate-to-Severe Ulcerative Colitis: A Systematic Review with Meta-Analysis.

BACKGROUND AND AIMS: Interest in histology for ulcerative colitis [UC] has increased recently. This systematic review and meta-analysis aims to assess, for the first time, whether histological outcomes are more informative than endoscopic and clinical outcomes in distinguishing the impact of intervention over placebo in induction trials. METHODS: MEDLINE, ScienceDirect and Cochrane Central Register of Controlled Trials were searched to identify randomized placebo-controlled trials [RCTs] enrolling moderate-to-severe UC patients. Studies were assessed using the Quality Assessment Tool for Studies with Diverse Designs. We analysed the pooled proportion of patients achieving clinical, endoscopic and histological remission and response after a pharmacological intervention and compared the results with those of placebo-treated patients by using a random-effects model. RESULTS: From 889 identified records, 13 RCTs were included. The odds ratio [OR] for remission was higher in patients receiving intervention than in those under placebo for clinical (OR 2.13, 95% confidence interval [CI] 1.33-3.43), endoscopic [OR 1.46, 95% CI 0.19-11.18] and histological remission [OR 1.85, 95% CI 1.20-2.84]. Significant differences were observed for all response outcomes [clinical: OR 2.27, 95% CI 1.84-2.85; endoscopic: OR 2.16, 95% CI 1.51-3.10; histological: OR 3.63, 95% CI, 1.41-9.36]. No significant heterogeneity existed; no subgroup effects were found for duration of the induction or histological scale [p > 0.05]. Clinical and histological remission and endoscopic response were concordant in discriminating interventions from placebo. CONCLUSION: Histological outcomes are informative in trials of moderate-to-severe UC. Further studies analysing histology at the end of induction are needed to confirm its relevance in distinguishing the efficacy of an intervention over placebo in comparison to clinical and endoscopic outcomes and to explore its prognostic value.

Histologic Features of Colon Biopsies (Geboes Score) Associated With Progression of Ulcerative Colitis for the First 36 Months After Biopsy.

BACKGROUND & AIMS: In addition to findings from endoscopy, histologic features of colon biopsies have been associated with outcomes of patients with ulcerative colitis (UC). We investigated associations between Geboes scores (a system to quantify structural changes and inflammatory activity in colon biopsies) and UC progression, and the time period over which this association is valid. METHODS: We analyzed data from 399 asymptomatic patients with UC enrolled in the ACERTIVE study, followed at 13 inflammatory bowel disease (IBD) centers in Portugal through 31 December 2019. Blood and stool samples were collected and analyzed, and all patients underwent sigmoidoscopy within 24 h of sample collection. We assessed baseline endoscopic status (Mayo endoscopic subscore), histologic features of 2 sigmoid and 2 rectal biopsies (Geboes score), and concentration of fecal calprotectin (FC). The primary outcome was UC progression (surgical, pharmacologic, and clinical events). We generated survival curves for 36 months or less and more than 36 months after biopsy according to Geboes score using the Kaplan-Meier method and compared findings with those from a log rank test. Cox regression was adjusted for Mayo endoscopic subscore, Geboes score, and level of FC; results were expressed as adjusted hazard ratios (HR) with 95% CIs. RESULTS: Patients with Geboes scores >2B.0, Geboes scores >3.0, or Geboes scores >4.0 had a higher frequency of, and a shorter time to UC progression, than patients with Geboes scores ≤2B.0, Geboes scores ≤3.0, or Geboes score ≤4.0 (P < .001). Disease progression occurred earlier in patients with Geboes scores >2B.0, Geboes scores >3.0, or Geboes scores >4.0 compared with patients with Geboes scores ≤2B.0 (HR, 2.021; 95% CI, 1.158-3.526), Geboes scores ≤3.0 (HR, 2.007; 95% CI, 1.139-3.534), or Geboes scores ≤4.0 (HR, 2.349; 95% CI, 1.269-4.349), respectively, in the first 36 months after biopsy. Similar results were found for patients with concentrations of FC below 150 µg/g. CONCLUSIONS: We found histologic features of colon biopsies (Geboes score) to be an independent risk factor for progression of UC in the first 36 months after biopsy.

Rapid test detection of anti-infliximab antibodies: performance comparison with three different immunoassays.

BACKGROUND AND AIMS: Therapeutic drug monitoring (TDM) of infliximab (IFX) and anti-infliximab antibodies (ATIs) is essential for treatment optimisation in inflammatory bowel disease (IBD) patients. The aim of this study was to estimate and compare the agreement and accuracy between a new rapid test and three established enzyme-linked immunosorbent assays (ELISAs) to quantify ATIs levels, and to evaluate the impact of exogenous IFX on the performance of these assays. METHODS: We analysed 200 serum samples from 57 IBD outpatients in IFX induction or maintenance therapy at six IBD centres in Portugal. ATI levels were quantified using the rapid test Quantum Blue® (QB) Anti-Infliximab (Bühlmann) and three established ELISAs: In-House, Theradiag (Lisa Tracker Anti-Infliximab), and Immundiagnostik (IDKmonitor Infliximab). ATIs were quantified in patients' serum samples and spiked samples with exogenous IFX, based on analytical and clinical cutoffs. Qualitative agreement and accuracy were estimated by Cohen's kappa (k) with 95% confidence intervals. RESULTS: ATIs quantification with clinical cutoffs showed a slight agreement between QB rapid test and In-House [k = 0.163 (0.051-0.276)] and Immundiagnostik [k = 0.085 (0.000-0.177)]. Regarding IFX/ATIs status, the QB rapid test showed a substantial agreement with Theradiag [k = 0.808 (0.729-0.888)] and a fair agreement with In-House [k = 0.343 (0.254-0.431)] and Immundiagnostik [k = 0.217 (0.138-0.297)]. The QB rapid test could not detect ATI-positive levels in samples with exogenous IFX at 5-300 µg/ml. Interference on ATIs detection was observed at exogenous IFX ⩾30 µg/ml for In-house and Immundiagnostik assays. CONCLUSION: QB rapid test is only suitable to detect ATI-positive levels in the absence of IFX.

Inflammatory Bowel Disease Reoperation Rate Has Decreased Over Time If Corrected by Prevalence.

INTRODUCTION: Despite the recent emergence of expensive biologic therapies, hospitalization and surgery remain important contributors for the overall costs of inflammatory bowel disease (IBD). In this study, we aimed to describe the burden of reoperations in patients with IBD by evaluating reoperation rates, charges, and risk factors over 16 years. METHODS: We performed a retrospective analysis of all hospital discharges, with focus on reoperations and with a primary diagnosis of IBD, in public hospitals between 2000 and 2015 in mainland Portugal from the Central Administration of the Health System's national registry. We collected data on patient, clinical, and healthcare charges. We used multivariate regressions to estimate the risk factors of IBD-related reoperations. RESULTS: We found that 5% of IBD-related hospitalizations were related to reoperations. The number of reoperations per year increased by approximately 200%. However, when corrected by the prevalence of the disease, IBD reoperation rates decreased. Mean IBD-related charges per hospitalization were 7,780 &OV0556; in 2000 and 10,592 &OV0556; in 2015, with total charges reaching 6.7 million euros by the end of the study. Risk factors for reoperation include urgent hospitalization, in patients with ulcerative colitis (odds ratio 1.94, 95% confidence interval 1.19-3.17, P = 0.008), and colic disease, in patients with Crohn's disease (odds ratio 1.57, 95% confidence interval 1.06-2.34, P = 0.025). DISCUSSION: To obtain an accurate scenario of reoperations among patients with IBD, it is mandatory to adjust the number of reoperations to the prevalence of the disease. Reoperation and its risk factors should be closely monitored to decrease the burden of IBD to the healthcare system.

Thiopurines' Metabolites and Drug Toxicity: A Meta-Analysis.

Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines' metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines' metabolites and drug toxicity. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 108 RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 108 RBC), and lower in patients with hepatotoxicity (MD -40.6 pmol × 108 RBC). We established a significant correlation between 6-TGN and leukocytes (r = -0.21), neutrophils (r = -0.24) and alanine aminotransferase levels (r = -0.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95%CI 2.24; 9.57). An optimal cut-off of 135 pmol/8 × 108 RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 108 RBC; OR 4.28; 95%CI 3.20; 5.71). Levels of 6-MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines' toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.