Higher Adalimumab Concentration is Associated with Complete Fistula Healing in Patients with Perianal Fistulizing Crohn's Disease.

Perianal fistulas can develop in around 30% of patients with Crohn's disease (CD) and are associated with impaired quality of life and worse outcomes including increased rates of hospitalizations and surgeries.1 The cornerstone of pharmacologic treatment for perianal fistulizing CD is anti-tumor necrosis factor therapy, mainly infliximab and adalimumab (ADM).2 Therapeutic drug monitoring (TDM) can be used to identify potential pharmacokinetic and pharmacodynamic issues and avoid or manage unwanted outcomes, such as primary nonresponse and secondary loss of response.3 There are several exposure-response relationship data demonstrating a positive correlation between serum infliximab concentrations and favorable objective therapeutic outcomes in patients with perianal fistulizing CD.4 Nevertheless, there are only limited data, which is mostly from small retrospective studies regarding the association of ADM concentration and outcomes in patients with perianal fistulizing CD.4-8 Furthermore, the optimal ADM concentration for fistula healing still remains to be elucidated. This is clinically important because drug concentration cutoffs are used in reactive and proactive TDM algorithms to define therapeutic drug concentrations. This study investigates the association of maintenance ADM concentrations with complete fistula healing (CFH) and identifies an optimal ADM concentration threshold for CFH.

Risankizumab Concentration but not IL-22 Levels are Associated With Clinical and Biochemical Remission in Patients With Crohn's Disease.

Risankizumab (RZB) is a monoclonal antibody that targets the p19 subunit of interleukin (IL)-23.1 The ADVANCE and MOTIVATE randomized controlled trials (RCTs)2 demonstrated that intravenous (IV) RZB compared with placebo led to higher rates of clinical remission and endoscopic response at week 12 in patients with active Crohn's disease (CD).2 The phase III FORTIFY RCT showed that subcutaneous (SC) RZB was significantly more effective than placebo for achieving clinical remission and endoscopic response as maintenance therapy in patients with moderate-to-severe active CD.3.

Anti-infliximab antibodies and low infliximab levels correlate with drug discontinuation in pediatric inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) use is limited by loss of response often due to the development of anti-IFX antibodies and low drug levels. METHODS: We performed a single center prospective observational cohort study of pediatric and young adult subjects with inflammatory bowel disease (IBD) on IFX with over 3 years of follow-up. Infliximab levels (IFXL) and antibodies to infliximab (ATI) were measured throughout the study. Subjects were followed until IFX was discontinued. RESULTS: We enrolled 219 subjects with IBD (184: Crohn's disease; 33: Ulcerative colitis; and 2 Indeterminant colitis; 84 female, median age 14.4 years, 37% on concomitant immunomodulator). Nine hundred and nineteen serum samples (mean 4.2 ± 2.1 per patient) were tested for IFXL and ATI. During the study, 31 (14%) subjects discontinued IFX. Sixty patients had ATI. Twenty-two of those 60 patients with ATI discontinued IFX; 14 of 31 patients who discontinued IFX had detectable ATI at study onset. The combination of ATI and IFXL < 5 µg/mL at study entry was associated with the highest risk of drug discontinuation (hazard ratios [HR] ATI 4.27 [p < 0.001] and IFXL < 5 µg/mL [HR]: 3.2 p = 0.001). Patients with IFXL 5-10 µg/mL had the lowest rate of discontinuation (6%). IFX dose escalation eliminated ATI in 21 of 60 subjects. CONCLUSIONS: ATI is a strong predictor of needing to stop IFX use and inversely correlates with IFXL. Detection of ATI during therapeutic drug monitoring postinduction but also periodically during maintenance therapy identifies individuals who may benefit from IFX dose escalation and/or the addition of an immunomodulator, as these interventions may reduce or eliminate ATI.

Factors Associated with Delays in Initiating Biologic Therapy in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Expeditious initiation of biologic therapy is important in patients with inflammatory bowel disease (IBD). However, initiation of biologics in the outpatient setting may be delayed by various clinical, social, and financial variables. AIM: To evaluate the delay in initiation of an advanced therapy in IBD and to identify factors that contributed to this delay. METHODS: This was a multi-center retrospective study. Outpatients who were initiated on a biologic therapy from 3/1/2019 to 9/30/20 were eligible for the study. Univariate and multivariate linear regression analyses were performed to identify variables associated with a delay in biologic treatment initiation. Delay was defined as the days from decision date (prescription placement) to first infusion or delivery of medication. RESULTS: In total 411 patients (Crohn's disease, n = 276; ulcerative colitis, n = 129) were included in the analysis. The median [interquartile range-(IQR)] delay for all drugs was 20 [12-37] days (infliximab, 19 [13-33] days; adalimumab, 10 [5-26] days; vedolizumab, 21 [14-42] days; and ustekinumab, 21 [14-42] days). Multivariate linear regression analysis identified that the most important variables associated with delays in biologic treatment initiation was self-identification as Black, longer distance from treatment site, and lack of initial insurance coverage approval. CONCLUSION: There may be a significant delay in biologic treatment initiation in patients with IBD. The most important variables associated with this delay included self-identification as Black, longer distance from site, and lack of initial insurance coverage approval.

Higher Postinduction Infliximab Concentrations Are Associated With Favorable Clinical Outcomes in Pediatric Crohn's Disease: A Post Hoc Analysis of the REACH Trial.

INTRODUCTION: Exposure-outcome relationship data show that higher infliximab concentrations are associated with better outcomes in patients with Crohn's disease (CD). However, most of these data were derived from adult patients on maintenance therapy. We aimed to investigate the association of infliximab concentrations during and early after induction therapy of infliximab with short-term and long-term clinical outcomes in a pediatric CD population. METHODS: We conducted a post hoc analysis of the REACH trial which included pediatric patients with moderate-to-severe CD treated with infliximab (n = 103). The investigated outcomes were early clinical remission (CR) defined as a pediatric CD activity index score of ≤ 10, assessed at week 10, and long-term clinical response (LTCR) defined as a decrease from baseline in the pediatric CD activity index score of at least 15 points, with a total score of ≤ 30 and no need for drug discontinuation, assessed at weeks 30 and 54. RESULTS: Based on multivariable logistic regression analysis, higher week 10 infliximab concentrations were independently associated with CR at week 10 (odds ratio: 1.54; 95% confidence interval: 1.06-2.22; P = 0.022) and LTCR at week 30 (odds ratio: 1.62; 95% confidence interval: 1.12-2.36; P = 0.010). Receiver operating characteristic analysis identified week 10 infliximab concentration thresholds of ≥7.1 µg/mL and ≥6.5 µg/mL to be associated with CR at week 10 and LTCR at week 30, respectively. DISCUSSION: Higher postinduction infliximab concentrations are associated with both short-term and long-term favorable clinical outcomes in pediatric patients with CD. Tailoring dosing during induction to achieve higher infliximab exposure may lead to better outcomes in pediatric patients with CD.

Patients With Low Drug Levels or Antibodies to a Prior Anti-Tumor Necrosis Factor Are More Likely to Develop Antibodies to a Subsequent Anti-Tumor Necrosis Factor.

Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibodies (ADAb) is used widely to confirm therapeutic exposure, rule out immunogenicity, and optimize treatment of biologics in patients with inflammatory bowel diseases.1 A recent genome-wide association study found the variant HLA-DQA1∗05 to increase the risk of development of antibodies against infliximab (IFX) and adalimumab (ADM) 2-fold, regardless of concomitant immunomodulator use.2,3 However, there is currently limited evidence showing whether patients who develop antibodies to 1 anti-tumor necrosis factor (TNF) are prone to develop antibodies to the subsequent anti-TNF. Our aim was to investigate the risk of subsequent antibody development in cases (with ADAb to prior anti-TNF) versus control subjects (without ADAb to prior anti-TNF) using a large cohort of patients with inflammatory bowel diseases who underwent TDM with a drug-tolerant assay.

Lymphoma in Pediatric-Onset Inflammatory Bowel Disease Treated with Infliximab Monotherapy: A Case Series.

BACKGROUND: Inflammatory bowel diseases (IBD) are often treated with anti-tumor necrosis factor alpha (anti-TNFα) medications. Concomitant treatment of IBD with anti-TNFα agents and immunomodulators appears to be associated with an increased risk for lymphoma. METHODS: Patients who developed lymphoma while on monotherapy with an anti-TNFα agent were identified at three centers. Institutional Review Board approval was obtained. RESULTS: Five adolescents and young adult patients with pediatric-onset IBD who were treated with infliximab (IFX) without exposure to thiopurines were subsequently diagnosed with lymphoma. Three of the five patients had bone involvement at presentation. Epstein-Barr virus was positive in 2 cases. Median time from diagnosis of IBD and exposure to IFX prior to diagnosis of lymphoma was 5 and 4.3 years, respectively. CONCLUSIONS: This case series reports long-term follow-up for young patients with IBD who were treated with IFX monotherapy and developed lymphoma. Three of the five patients had bone involvement. In general, the risk of lymphoma following exposure to anti-TNFα medications alone remains low, but the incidence of primary bone lymphomas in IBD has not been reported. Studies examining longer exposure times may be needed to determine the true lymphoma risk in patients treated with IFX monotherapy.

Appropriateness of Medical and Surgical Treatments for Chronic Pouchitis Using RAND/UCLA Appropriateness Methodology.

BACKGROUND AND AIMS: The treatment of chronic pouchitis remains a challenge due to the paucity of high-quality studies. We aimed to provide guidance for clinicians on the appropriateness of medical and surgical treatments in chronic pouchitis. METHODS: Appropriateness of medical and surgical treatments in patients with chronic pouchitis was considered in 16 scenarios incorporating presence/absence of four variables: pouchitis symptoms, response to antibiotics, significant prepouch ileitis, and Crohn's disease (CD)-like complications (i.e., stricture or fistula). Appropriateness of permanent ileostomy in patients refractory to medical treatments was considered in eight additional scenarios. Using the RAND/UCLA appropriateness method, international IBD expert panelists rated appropriateness of treatments in each scenario on a 1-9 scale. RESULTS: Chronic antibiotic therapy was rated appropriate only in asymptomatic antibiotic-dependent patients with no CD-like complications and inappropriate in all other scenarios. Ileal-release budesonide was rated appropriate in 6/16 scenarios including patients with significant prepouch ileitis but no CD-like complications. Probiotics were considered either inappropriate (14/16) or uncertain (2/16). Biologic therapy was considered appropriate in most scenarios (14/16) and uncertain in situations where significant prepouch ileitis or CD-like complications were absent (2/16). In patients who are refractory to all medications, permanent ileostomy was considered appropriate in all scenarios (7/8) except in asymptomatic patients with no CD-like complications. CONCLUSIONS: In the presence of significant prepouch ileitis or CD-like complications, chronic antibiotics and probiotics are inappropriate. Biologics are appropriate in all patients except in asymptomatic patients with no evidence of complications. Permanent ileostomy is appropriate in most medically refractory patients.

Comparison of Assays for Therapeutic Monitoring of Infliximab and Adalimumab in Patients With Inflammatory Bowel Diseases.

Comparison data regarding anti-tumor necrosis factor drug concentrations in inflammatory bowel disease (IBD) between the enzyme-linked immunosorbent assay (ELISA) and the homogenous mobility shift assay (HMSA) are scarce.1-3 As decisions in clinical practice depend on the thresholds that define a therapeutic drug concentration, it is important to determine if this varies based on the type of assay used for therapeutic drug monitoring.4 We recently showed a discrepancy between a commercially available ELISA and the HMSA for both infliximab and adalimumab concentrations in patients with IBD.5 Based on the results of the study, Prometheus Laboratories (San Diego, CA) initiated a comprehensive review of their HMSA assays and found that there was an upward drift for both infliximab (from December 2017 to May 2019) and adalimumab (from August 2017 to May 2019), including when our study was performed. Prometheus Laboratories corrected the errant values and reported the revised drug concentrations to physicians (Supplementary Methods). We aimed to compare the corrected infliximab and adalimumab concentrations with the original ELISA values.

Higher Postinduction Infliximab Concentrations Are Associated With Improved Clinical Outcomes in Fistulizing Crohn's Disease: An ACCENT-II Post Hoc Analysis.

INTRODUCTION: There are only limited data regarding the role of therapeutic drug monitoring in fistulizing Crohn's disease (CD). We investigated the association between both induction and maintenance serum infliximab concentrations and favorable therapeutic outcomes in patients with fistulizing CD. METHODS: This was a post hoc analysis of the ACCENT-II trial evaluating patients with fistulizing CD receiving induction (n = 282) and maintenance infliximab therapy (n = 139). Investigated therapeutic outcomes at both week 14 and week 54 included fistula response, complete fistula response, C-reactive protein (CRP) normalization (≤5 mg/L) in patients with an elevated baseline CRP, and a more stringent outcome of composite remission, defined as combined complete fistula response and CRP normalization. Associations between serum infliximab concentrations and outcomes were assessed by multivariable logistic regression models. RESULTS: Higher week 14 infliximab concentrations were independently associated with week 14 fistula response (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.02-1.32; P = 0.019), and composite remission (OR: 2.32; 95% CI: 1.55-3.49; P < 0.001). Higher week 14 infliximab concentrations were also independently associated with week 54 composite remission (OR: 2.05; 95% CI: 1.10-3.82; P = 0.023). Based on receiver operating characteristic curve analysis, week 14 infliximab concentrations thresholds with combined maximal sensitivity and specificity of ≥20.2 µg/mL at week 2, ≥15 µg/mL at week 6, and ≥7.2 µg/mL at week 14 were associated with week 14 composite remission. DISCUSSION: Higher post-induction infliximab concentrations are associated with early and long-term favorable therapeutic outcomes in patients with fistulizing CD.

A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease.

Therapeutic drug monitoring (TDM) of biologics is a rapidly evolving field. We aimed to provide a consensus statement regarding the clinical utility of TDM for biologics in inflammatory bowel disease (IBD). A modified Delphi method was applied to develop consensus statements. A comprehensive literature review was performed regarding TDM of biologic therapies in IBD, and 45 statements were subsequently formulated on the potential application of TDM in IBD. The statements, along with literature, were then presented to a panel of 10 gastroenterologists with expertise in IBD and TDM who anonymously rated them on a scale of 1-10 (1 = strongly disagree and 10 = strongly agree). An expert consensus development meeting was held virtually to review, discuss, refine, and reformulate statements that did not meet criteria for agreement or that were ambiguous. During the meeting, additional statements were proposed. Panelists then confidentially revoted, and statements rated ≥7 by 80% or more of the participants were accepted. During the virtual meeting, 8 statements were reworded, 7 new statements were proposed, and 19 statements were rerated. Consensus was finally reached in 48/49 statements. The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response. It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10-15 µg/mL was achieved. Consensus was also achieved regarding the utility of proactive TDM for anti-tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance. Consensus was achieved in most cases regarding the utility of TDM of biologics in IBD, specifically for reactive and proactive TDM of anti-tumor necrosis factors.

Therapeutic drug monitoring in patients on biologics: lessons from gastroenterology.

PURPOSE OF REVIEW: To give an overview on the role of therapeutic drug monitoring (TDM) of biologics in patients with inflammatory bowel disease (IBD). RECENT FINDINGS: Numerous prospective exposure-response relationship studies and post-hoc analyses of randomized controlled trials (RCTs) show a positive correlation between biologic drug concentrations and favorable clinical outcomes in IBD. These studies also demonstrate that higher drug concentrations appear to be needed to achieve more stringent objective therapeutic outcomes. Reactive TDM rationalizes the management of primary nonresponse and secondary loss of response to antitumor necrosis factor (anti-TNF) therapy and is more cost-effective when compared with empiric dose optimization. Furthermore, recent data suggest that proactive TDM, with the goal of targeting a threshold drug concentration, is associated with better therapeutic outcomes when compared with empiric dose escalation and/or reactive TDM of infliximab or adalimumab. Finally, proactive TDM can also efficiently guide infliximab de-escalation or discontinuation in patients with IBD in remission. SUMMARY: Reactive TDM is currently considered as standard of care, whereas proactive TDM is emerging as a new therapeutic strategy for better optimizing anti-TNF therapy in IBD. However, more data from prospective studies are needed before a wide implementation of TDM-based algorithms in real life clinical practice for newer biologics.

Biological therapies in inflammatory bowel disease: Beyond anti-TNF therapies.

The pharmacological management of inflammatory bowel disease (IBD) over the last two decades has transitioned from reliance on aminosalycilates, corticosteroids and immunomodulators to earlier treatment with anti-tumor necrosis factor (anti-TNF) therapy. Nevertheless, 20-30% of patients discontinue anti-TNF therapy for primary non-response and another 30-40% for losing response within one year of treatment. These undesirable therapeutic outcomes can be attributed to pharmacokinetic (anti-drug antibodies and/or low drug concentrations) or pharmacodynamic issues characterized by a non-TNF driven inflammation. The latter issues necessitate the use of medications with different mechanisms of action. Besides the biologics natalizumab, vedolizumab and ustekinumab that have already been approved for the treatment of IBD new non-anti-TNF therapies are currently under investigation including small molecule drugs against Janus kinase and sphingosine-1-phosphate receptors. This manuscript will review the medications that are in the later stages of development for the treatment of IBD and directed against immune targets other than TNF.

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

Therapeutic drug monitoring in inflammatory bowel disease: for every patient and every drug?

PURPOSE OF REVIEW: The current review provides an updated overview on the role of therapeutic drug monitoring (TDM) of biological therapies in inflammatory bowel disease (IBD). We examine the data behind TDM for the antitumor necrosis factor agents, vedolizumab and ustekinumab, in patients with IBD. In addition, we discuss reactive vs. proactive TDM. RECENT FINDINGS: There is a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IBD, although the majority of data refer to antitumor necrosis factor therapy. Reactive TDM has rationalized the management of patients with IBD with loss of response to biological therapy. Moreover, reactive TDM of infliximab has been proven to be more cost-effective when compared with empiric dose optimization. Preliminary data suggest that proactive TDM of infliximab and adalimumab applied in patients with clinical response/remission is associated with better therapeutic outcomes compared with standard of care (empiric treatment and/or reactive TDM). SUMMARY: For all biologics in IBD, there is a positive correlation between drug concentrations and favorable therapeutic outcomes. Reactive TDM is the new standard of care for optimizing biologic therapies in IBD, whereas recent data suggest an important role of proactive TDM for optimizing antitumor necrosis factor therapy in IBD.

Meta-analysis of dye-based chromoendoscopy compared with standard- and high-definition white-light endoscopy in patients with inflammatory bowel disease at increased risk of colon cancer.

BACKGROUND: Patients with ulcerative colitis have an increased risk of colorectal cancer. We sought to assess the comparative efficacy of standard white-light endoscopy (SDWLE) or high-definition white-light endoscopy (HDWLE) versus dye-based chromoendoscopy through a meta-analysis and rate the quality of evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. METHODS: A systematic review of the literature in PubMed, EMBASE, and Web of Science was performed in April 2018. The primary outcome was the number of patients in whom dysplasia was identified using a per patient analysis in randomized controlled trials (RCT) and analyzed separately for non-RCTs. Analysis was performed using RevMan 5.3 reporting random-effects risk ratios. RESULTS: Of the 27,904 studies identified, 10 studies were included 6 of which were RCTs (3 SDWLE and 3 HDWLE). Seventeen percent (84/494) of patients were noted to have dysplasia using chromoendoscopy compared with 11% (55/496) with white-light endoscopy (relative risk [RR] 1.50; 95% confidence interval [CI], 1.08-2.10). When analyzed separately, chromoendoscopy (n = 249) was more effective at identifying dysplasia than SDWLE (n = 248) (RR, 2.12; 95% CI, 1.15-3.91), but chromoendoscopy (n = 245) was not more effective compared with HDWLE (n = 248) (RR, 1.36; 95% CI, 0.84-2.18). The quality of evidence was moderate. In non-RCTs, dysplasia was identified in 16% (114/698) of patients with chromoendoscopy compared with 6% (62/1069) with white-light endoscopy (RR, 3.41; 95% CI, 2.13-5.47). Chromoendoscopy (n = 58) was more effective than SDWLE (n = 141) for identification of dysplasia (RR, 3.52; 95% CI, 1.38-8.99), and chromoendoscopy (n = 113) was also more effective than HDWLE (n = 257) (RR, 3.15; 95% CI, 1.62-6.13). The quality of the evidence was very low. CONCLUSION: Based on this meta-analysis, non-RCTs demonstrate a benefit of chromoendoscopy over SDWLE and HDWLE, whereas RCTs only show a small benefit of chromoendoscopy over SDWLE, but not over HDWLE.

Bone of Contention: Helicobacter pylori and Osteoporosis-Is There an Association?

Helicobacter pylori (H. pylori) infection is a common disease that can cause chronic gastritis, peptic ulcers, and gastric cancer. Nevertheless, due to its ability to elicit a systemic inflammatory response, it has also been related to several extra-gastric manifestations including endocrine disorders, such as autoimmune thyroid diseases, diabetes mellitus, dyslipidemia, and obesity. H. pylori infection has also been linked to osteoporosis, although currently available data are equivocal. This brief review will focus on the possible association between H. pylori infection and osteoporosis, a silent disease characterized by decreased bone mass that can increase the occurrence of fractures, disability, and mortality.

Patients with core antibody positive and surface antigen negative Hepatitis B (anti-HBc+, HBsAg-) on anti-TNF therapy have a low rate of reactivation.

Anti-TNF agents are widely used to treat immune-mediated disorders. Reactivation of Hepatitis B virus (HBV) is associated with immunosuppressive agents and biologics such as anti-TNF. There are limited data and differing guidelines for patients with negative hepatitis B surface antigen (HBsAg-) but positive antibody to hepatitis B core antigen (anti-HBc+) on anti-TNF with regards to outcomes and need for anti-viral prophylaxis. We examined the prevalence of HBV reactivation in a single-center retrospective cohort study of 120 HBsAg-, anti-HBc+ patients on anti-TNF, totaling 346.6 patient years. One patient (0.8%) who had a detectable VL (<20 IU) prior to starting anti-TNF had reactivation of HBV with sero-conversion to positive HBsAg. Three patients (2.5%) had undetectable HBV VL prior to anti-TNF and developed detectable VL while on anti-TNF. In conclusion, there was a low rate of HBV reactivation or development of detectable HBV DNA in HBsAg-, anti-HBc+ patients on anti-TNF.