Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.11) [corrected] higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD.

Real-World Outcomes of Dual Advanced Therapy in Children and Young Adults with Inflammatory Bowel Disease.

BACKGROUND: Data are limited on the safety and efficacy of combining advanced therapies for refractory patients with IBD. AIM: To evaluate the real-world efficacy and safety of dual advanced therapy (DAT), combining 2 biologics or a biologic with a small molecule, in children and young adults with refractory IBD. METHODS: Primary outcome of this single IBD center cohort was DAT remission (clinical and biomarker remission) at first assessment (T1). Secondary outcomes included remission at T2, if DAT de-intensification (De-I) occurred and T3, if T2 DAT re-intensification (Re-I) occurred. Efficacy and safety outcomes were described. RESULTS: Of the 30 patients [43% female, 30% CD, median age of 18.3 [15.1-19.8] years], all 11 UST + TOFA achieved T1 remission; 6/10 De-I failed at T2; and 4/4 Re-I achieved T3 remission. Of 9 VDZ + TOFA, 6 achieved T1 remission; 5/6 De-I failed at T2; and 1/1 failed T3 Re-I. Of 4 UST + VDZ, 3 achieved T1 remission; 2/3 De-I failed at T2; and 0 had Re-I. Of 5 UST + UPA, 4 achieved T1 remission; 1/5 De-I failed at T2 but recaptured T3 remission post-Re-I. One VDZ + OZA achieved T1 remission and maintained T2 remission post-De-I to OZA monotherapy. At last follow-up, 43% were on original DAT, 17% on one of original DAT, and 40% neither. One UST + TOFA patient developed mild leukopenia and another developed septic arthritis and venous thromboembolism on VDZ + TOFA and prednisone. CONCLUSION: Most children and young adults treated with DAT achieved remission with minimal safety events; however, de-intensification had limited success.

Corrigendum: Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

[This corrects the article DOI: 10.3389/fimmu.2024.1342477.].

Determining the Accuracy of Intestinal Ultrasound Scores as a Prescreening Tool in Crohn's Disease Clinical Trials.

INTRODUCTION: High rates of screen failure for the minimum Simple Endoscopic Score for Crohn's Disease (SES-CD) plague Crohn's disease (CD) clinical trials. We aimed to determine the accuracy of segmental intestinal ultrasound (IUS) parameters and scores to detect segmental SES-CD activity. METHODS: A single-center, blinded, cross-sectional cohort study of children and young adult patients with CD undergoing IUS and ileocolonoscopy, comparing segmental IUS bowel wall thickness (BWT), hyperemia (modified Limberg score [MLS]), and scores to detect segmental SES-CD activity: (i) SES-CD ≤2, (ii) SES-CD ≥6, and (iii) SES-CD ≥4 in the terminal ileum (TI) only. Primary outcome was accuracy of BWT, MLS, and IUS scores to detect SES-CD ≤2 and SES-CD ≥6. Secondary outcomes were accuracy of TI BWT, MLS, and IUS scores to detect SES-CD ≥4 and correlation with the SES-CD. RESULTS: Eighty-two patients (median [interquartile range] age 16.5 [12.9-20.0] years) underwent IUS and ileocolonoscopy of 323 bowel segments. Segmental BWT ≤3.1 mm had a similar high accuracy to detect SES-CD ≤2 as IUS scores (area under the receiver operating curve [AUROC] 0.833 [95% confidence interval 0.76-0.91], 94% sensitivity, and 73% specificity). Segmental BWT ≥3.6 mm and ≥4.3 mm had similar high accuracy to detect SES-CD ≥6 (AUROC 0.950 [95% confidence interval 0.92-0.98], 89% sensitivity, 93% specificity) in the colon and an SES-CD ≥4 in the TI (AUROC 0.874 [0.79-0.96], 80% sensitivity, and 91% specificity) as IUS scores. Segmental IUS scores strongly correlated with the SES-CD. DISCUSSION: Segmental IUS BWT is highly accurate to detect moderate-to-severe endoscopic inflammation. IUS may be the ideal prescreening tool to reduce unnecessary trial screen failures.

Single-center Experience With Upadacitinib for Adolescents With Refractory Inflammatory Bowel Disease.

BACKGROUND: Upadacitinib (UPA) is a novel selective JAK inhibitor approved for adults with ulcerative colitis (UC) and with positive phase 3 data for Crohn's disease (CD). Pediatric off-label use is common due to delays in pediatric approvals; real-world data on UPA are needed to understand the safety and effectiveness in pediatric IBD. METHODS: This is a single-center retrospective case series study of adolescents (12-17 years) with inflammatory bowel disease IBD on UPA. The primary outcome was postinduction steroid-free clinical remission (SF-CR) defined as Pediatric UC Activity Index (PUCAI) or Pediatric CD Activity Index (PCDAI) ≤10. Secondary outcomes include postinduction clinical response (decrease ≥12.5 in PUCAI/PCDAI), postinduction C-reactive protein (CRP) normalization, 6-month SF-CR, and intestinal ultrasound response and remission. Adverse events were recorded through last follow-up. RESULTS: Twenty patients (9 CD, 10 UC, 1 IBD-U; 55% female; median age 15 years, 90% ≥2 biologics) were treated with UPA for ≥12 weeks (median 51 [43-63] weeks). Upadacitinib was used as monotherapy in 55% and as combination with ustekinumab and vedolizumab in 35% and 10%, respectively. Week 12 SF-CR was achieved in 75% (15/20) and 80% (16/20) with CRP normalization. About 3/4 (14/19) achieved SF-CR at 6 months. Adverse event occurred in 2 patients (10%): Cytomegalovirus colitis requiring hospitalization and hyperlipidemia requiring no treatment. In the 75% with ultrasound monitoring, response and remission were achieved in 77% and 60%, respectively. CONCLUSION: While awaiting pediatric registration trials, our data suggest that UPA is effective in inducing and maintaining SF-CR in adolescents with highly-refractory IBD with an acceptable safety profile.

This case series presents novel data on the effectiveness and safety of upadacitinib in adolescent patients with IBD.

The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn's Disease with Infliximab.

Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn's disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108). Concentrations were measured using homogeneous mobility shift assay. Clearance was estimated using the nonlinear mixed effects methods with Bayesian priors. C-reactive protein-based clinical remission (<3 mg/L in the absence of symptoms) was used for the disease control outcome measure. Longitudinal changes in disease control due to factors including time, IFX concentration, and Clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and Clearance. The results indicated that lower baseline Clearance and proactive dosing associated with enhanced disease control during induction (p < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance (p < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = -19.2; p < 0.001), and the combination of both further minimized OFV (p < 0.001) with markedly improved clinical yield in the presence of both PF of PK origin. We conclude that the combination of IFX concentration and Clearance are better predictors of therapeutic outcome compared with either one alone.

Choosing the Right Therapy at the Right Time for Pediatric Inflammatory Bowel Disease: Does Sequence Matter.

Despite the enlarging therapeutic armamentarium, IBD is still plagued by a therapeutic ceiling. Precision medicine, with the selection of the "rights," may present a solution, and this review will discuss the critical process of pairing the right patient with right therapy at the right time. Firstly, the review will discuss the shift to and evidence behind early effective therapy. Then, it delves into promising future strategies of patient profiling to identify a patients' biological pathway(s) and prognosis. Finally, the review lays out practical considerations that drive treatment selection, particularly the impact of the therapeutic sequence.

Barriers to optimizing inflammatory bowel disease care in the United States.

Significant progress in the management and modification of inflammatory bowel disease (IBD) has been made; however, significant barriers to the optimization of IBD care in the United States still exist. The majority of these barriers are constructed by insurance carriers and the integration of market pressures into healthcare decision-making. In this review, we highlight the barriers to IBD care optimization within the context of the US insurance system and review current and proposed solutions.

Coinfection with Strongyloides and SARS-CoV-2: A Systematic Review.

BACKGROUND: Treatments for COVID-19, including steroids, might exacerbate Strongyloides disease in patients with coinfection. We aimed to systematically review clinical and laboratory features of SARS-CoV-2 and Strongyloides coinfection, investigate possible interventions, assess outcomes, and identify research gaps requiring further attention. METHODS: We searched two electronic databases, LitCOVID and WHO, up to August 2022, including SARS-CoV-2 and Strongyloides coinfection studies. We adapted the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment to evaluate if using corticosteroids or other immunosuppressive drugs in COVID-19 patients determined acute manifestations of strongyloidiasis. RESULTS: We included 16 studies reporting 25 cases of Strongyloides and SARS-CoV-2 coinfection: 4 with hyperinfection syndrome; 2 with disseminated strongyloidiasis; 3 with cutaneous reactivation of strongyloidiasis; 3 with isolated digestive symptoms; and 2 with solely eosinophilia, without clinical manifestations. Eleven patients were asymptomatic regarding strongyloidiasis. Eosinopenia or normal eosinophil count was reported in 58.3% of patients with Strongyloides reactivation. Steroids were given to 18/21 (85.7%) cases. A total of 4 patients (19.1%) received tocilizumab and/or Anakirna in addition to steroids. Moreover, 2 patients (9.5%) did not receive any COVID-19 treatment. The causal relationship between Strongyloides reactivation and COVID-19 treatments was considered certain (4% of cases), probable (20% of patients), and possible (20% of patients). For 8% of cases, it was considered unlikely that COVID-19 treatment was associated with strongyloidiasis reactivations; the relationship between the Strongyloides infection and administration of COVID-19 treatment was unassessable/unclassifiable in 48% of cases. Of 13 assessable cases, 11 (84.6%) were considered to be causally associated with Strongyloides, ranging from certain to possible. CONCLUSIONS: Further research is needed to assess the frequency and risk of Strongyloides reactivation in SARS-CoV-2 infection. Our limited data using causality assessment supports recommendations that clinicians should screen and treat for Strongyloides infection in patients with coinfection who receive immunosuppressive COVID-19 therapies. In addition, the male gender and older age (over 50 years) may be predisposing factors for Strongyloides reactivation. Standardized guidelines should be developed for reporting future research.

A Single-Center Experience with Dupilumab for Atopic or Psoriasiform Dermatitis in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Dupilumab blocks IL4/IL13 and is used in atopic disease. There are concerns that blockade may lead to inflammatory bowel disease (IBD) inception or activity. Limited data exist on the use of this therapy in patients with IBD; we aimed to describe our experience using dupilumab in IBD to treat concomitant atopic dermatitis (AD) or anti-TNF-induced dermatitis. METHODS: We analyzed the electronic medical records (2018-2022) in a single, tertiary care center to identify patients with IBD on dupilumab. Clinical and demographic data were gathered, including disease location/behavior, personal/family history of atopy, indication for and response to dupilumab, IBD medication history, and adverse events. RESULTS: Seventeen patients (65% Crohn's) were identified with IBD on dupilumab for dermatitis; 9 for severe AD and 8 for a worsened dermatitis, either AD or psoriasiform dermatitis (PD), induced by anti-TNF. They were treated for a median 1.2 [IQR 0.6-2.3] years. All patients had a dermatologic response to dupilumab and remained on dupilumab at last follow-up. No adverse events were identified, including no increase in IBD activity. In those with dermatitis worsened or induced by anti-TNF, all started dupilumab in combination with another biologic: 3 with anti-TNF, 4 with ustekinumab, and 1 with vedolizumab. Seven of the eight had a response to the initial combination of biologics; however, one patient using dupilumab-anti-TNF ultimately changed to combination dupilumab-ustekinumab to achieve resolution of the dermatitis. CONCLUSION: Dupilumab is safe and effective for dermatitis in patients with IBD, both primary atopic dermatitis and dermatitis induced or worsened by anti-TNF.

Transmission of SARS-CoV-2 Associated with Cruise Ship Travel: A Systematic Review.

Background: Maritime and river travel may be associated with respiratory viral spread via infected passengers and/or crew and potentially through other transmission routes. The transmission models of SARS-CoV-2 associated with cruise ship travel are based on transmission dynamics of other respiratory viruses. We aimed to provide a summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps. Methods: We searched four electronic databases (up to 26 May 2022) and included studies on SARS-CoV-2 transmission aboard cruise ships. The quality of the studies was assessed based on five criteria, and relevant findings were reported. Results: We included 23 papers on onboard SARS-CoV-2 transmission (with 15 reports on different aspects of the outbreak on Diamond Princess and nine reports on other international cruises), 2 environmental studies, and 1 systematic review. Three articles presented data on both international cruises and the Diamond Princess. The quality of evidence from most studies was low to very low. Index case definitions were heterogeneous. The proportion of traced contacts ranged from 0.19 to 100%. Studies that followed up >80% of passengers and crew reported attack rates (AR) up to 59%. The presence of a distinct dose−response relationship was demonstrated by findings of increased ARs in multi-person cabins. Two studies performed viral cultures with eight positive results. Genomic sequencing and phylogenetic analyses were performed in individuals from three cruises. Two environmental studies reported PCR-positive samples (cycle threshold range 26.21−39.00). In one study, no infectious virus was isolated from any of the 76 environmental samples. Conclusion: Our review suggests that crowding and multiple persons per cabin were associated with an increased risk of transmission on cruise ships. Variations in design, methodology, and case ascertainment limit comparisons across studies and quantification of transmission risk. Standardized guidelines for conducting and reporting studies on cruise ships of acute respiratory infection transmission should be developed.

Prognostication in inflammatory bowel disease.

Personalized care in inflammatory bowel diseases (IBD) hinges on parsing the heterogeneity of IBD patients through prognostication of their disease course and therapeutic response to allow for tailor-made treatment and monitoring strategies to optimize care. Herein we review the currently available predictors of outcomes in IBD and those on the both near and far horizons. We additionally discuss the importance of worldwide collaborative efforts and tools to support clinical use of these prognostication tools.

Transmission of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from pre and asymptomatic infected individuals: a systematic review.

BACKGROUND: The role of SARS-Cov-2-infected persons who develop symptoms after testing (presymptomatics) or not at all (asymptomatics) in the pandemic spread is unknown. OBJECTIVES: To determine infectiousness and probable contribution of asymptomatic persons (at the time of testing) to pandemic SARS-CoV-2 spread. DATA SOURCES: LitCovid, medRxiv, Google Scholar, and WHO Covid-19 databases (to 31 March 2021) and references in included studies. STUDY ELIGIBILITY CRITERIA: Studies with a proven or hypothesized transmission chain based either on serial PCR cycle threshold readings and/or viral culture and/or gene sequencing, with adequate follow-up. PARTICIPANTS: People exposed to SARS-CoV-2 within 2-14 days to index asymptomatic (at time of observation) infected individuals. INTERVENTIONS: Reliability of symptom and signs was assessed within contemporary knowledge; transmission likelihood was assessed using adapted causality criteria. METHODS: Systematic review. We contacted all included studies' corresponding authors requesting further details. RESULTS: We included 18 studies from a diverse setting with substantial methodological variation (this field lacks standardized methodology). At initial testing, prevalence of asymptomatic cases was 12.5-100%. Of these, 6-100% were later determined to be presymptomatic, this proportion varying according to setting, methods of case ascertainment and population. Nursing/care home facilities reported high rates of presymptomatic: 50-100% (n = 3 studies). Fourteen studies were classified as high risk of, and four studies as at moderate risk of symptom ascertainment bias. High-risk studies may be less likely to distinguish between presymptomatic and asymptomatic cases. Six asymptomatic studies and four presymptomatic studies reported culturing infectious virus; data were too sparse to determine infectiousness duration. Three studies provided evidence of possible and three of probable/likely asymptomatic transmission; five studies provided possible and two probable/likely presymptomatic SARS-CoV-2 transmission. CONCLUSION: High-quality studies provide probable evidence of SARS-CoV-2 transmission from presymptomatic and asymptomatic individuals, with highly variable estimated transmission rates.

Precision Medicine in Pediatric Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) describes a heterogenous group of diseases characterized by chronic inflammation of the intestinal tract. The IBD subtypes, Crohn's disease, ulcerative colitis, and IBD-Unspecified, each have characteristic features, but heterogeneity remains even among the subtypes. There has been an explosion of new knowledge on the possible pathogenesis of IBD over the last 2 decades mirroring innovation and refinement in technology, particularly the generation of large scale - "-omic" data. This knowledge has fostered a veritable renaissance of novel diagnostics, prognostics, and therapeutics, with patients with IBD seeing hope bloom in the increasingly large armamentarium of IBD therapies. However, while there are increased numbers of therapies and more pathways being targeted, the number of medications for IBD is still finite and the efficacy has reached a plateau. Precision medicine (PM) is much needed to rationally select and optimize IBD therapies in the new reality of wider but still limited choice with a concurrent, increasingly fine resolution on the significance and utility of clinical, genetic, microbial, and proteomic characteristics that define individual patients. PM is a rapidly changing art, but this review will strive to detail the current state and future directions of PM in pediatric IBD.

Transmission of SARS-CoV-2 associated with aircraft travel: a systematic review.

RATIONALE FOR THE REVIEW: Air travel may be associated with viruses spread via infected passengers and potentially through in-flight transmission. Given the novelty of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, transmission associated with air travel is based on transmission dynamics of other respiratory viruses. Our objective was to provide a rapid summary and evaluation of relevant data on SARS-CoV-2 transmission aboard aircraft, report policy implications and to highlight research gaps requiring urgent attention. METHODS: We searched four electronic databases (1 February 2020-27 January 2021) and included studies on SARS-CoV-2 transmission aboard aircraft. We assessed study quality based on five criteria and reported important findings. KEY FINDINGS: We included 18 studies on in-flight SARS-CoV-2 transmission (130 unique flights) and 2 studies on wastewater from aircraft. The quality of evidence from most published studies was low. Two wastewater studies reported PCR-positive samples with high cycle threshold values (33-39). Index case definition was heterogeneous across studies. The proportion of contacts traced ranged from 0.68 to 100%. Authors traced 2800/19 729 passengers, 140/180 crew members and 8/8 medical staff. Altogether, 273 index cases were reported, with 64 secondary cases. Three studies, each investigating one flight, reported no secondary cases. Secondary attack rate among studies following up >80% of passengers and crew (including data on 10 flights) varied between 0 and 8.2%. The studies reported on the possibility of SARS-CoV-2 transmission from asymptomatic, pre-symptomatic and symptomatic individuals. Two studies performed viral cultures with 10 positive results. Genomic sequencing and phylogenetic analysis were performed in individuals from four flights. CONCLUSION: Current evidence suggests SARS-CoV-2 can be transmitted during aircraft travel, but published data do not permit any conclusive assessment of likelihood and extent. The variation in design and methodology restricts the comparison of findings across studies. Standardized guidelines for conducting and reporting future studies of transmission on aircraft should be developed.

Outcomes of Primary Ileocolic Resection for Pediatric Crohn Disease in the Biologic Era.

OBJECTIVES: Current clinical algorithms position surgery as the last option in pediatric Crohn disease (CD). Studies suggest improved outcomes with earlier surgery, but pediatric postoperative outcomes data in the biologic era are limited. We aimed to describe the preoperative management and postoperative outcomes in a pediatric CD cohort who underwent ileocolic resection (ICR) at a tertiary care inflammatory bowel disease center over the last decade. METHODS: Single-center, retrospective study of pediatric (<18 years) CD patients who underwent ICR between 2008 and 2019 with primary outcome of rate of endoscopic recurrence (Rutgeerts' >i2) at 2 years post-ICR. Key secondary outcomes included endoscopic remission (Rutgeerts' i0), frequency of 30-day postoperative complications, anthropometric changes, and histologic recurrence. Uni- and multivariable analyses examined associations of clinical/laboratory characteristics with endoscopic recurrence. Factors predictive of 30-day complications were also analyzed. RESULTS: Seventy-eight children underwent ICR a median of 17.8 months (interquartile range [IQR] 2.6-53.9) from diagnosis. Median age at diagnosis and surgery was 13.8 (11.1-16.7) and 16.8 years (15.1-17.8), respectively. In the 41 patients with >1 post-operative endoscopy, the rate of endoscopic recurrence was 46% at 2 years (median time to recurrence: 10 [7-20] months). Histologic recurrence was present in 44% in endoscopic remission (κ = 0.11, P = 0.53). Endoscopic recurrence was associated with younger age at diagnosis and longer disease duration. 30-day complications occurred at a rate of 18%; only 1% experienced severe complications. All anthropometric measures significantly improved after surgery. CONCLUSIONS: Given the inherent risk of postoperative recurrence associated with age and disease duration, children would benefit from postoperative surveillance and effective prophylaxis.