• Crohn’s disease
• antibodies to infliximab
• clinical remission
• infliximab
• population pharmacokinetic model

• Crohn’s disease
• advanced therapies
• biologics
• surgery

• funding

• Humans
• Bayes Theorem
• Drug Monitoring
• Gastrointestinal Agents/therapeutic use
• Inflammatory Bowel Diseases/drug therapy
• Infliximab/therapeutic use
• Retrospective Studies

• Biologics
• Inflammatory bowel disease
• Precision medicine
• Small molecules
• Therapeutic ceiling

• Humans
• Biosimilar Pharmaceuticals/adverse effects
• Tumor Necrosis Factor Inhibitors/therapeutic use
• Precision Medicine
• Quality of Life
• Inflammatory Bowel Diseases/drug therapy
• Tumor Necrosis Factor-alpha

The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.

• Precision medicine
• Therapeutic ceiling
• Inflammatory bowel disease
• Biologics
• Small molecules

• CT-P13
• Crohn’s disease
• inflammatory bowel disease
• infliximab
• infliximab trough level
• subcutaneous
• switch
• ulcerative colitis

Tumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn’s disease (CD), but not all patients achieve fistula healing.

To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.

In this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test, t test or Mann-Whitney U test.

One hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083].

Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.

• Crohn’s disease
• Perianal disorders
• Biologics
• Inflammatory bowel disease

• Adalimumab/therapeutic use
• Crohn Disease/complications
• Crohn Disease/drug therapy
• Crohn Disease/pathology
• Gastrointestinal Agents/therapeutic use
• Humans
• Infliximab/therapeutic use
• Rectal Fistula/drug therapy
• Rectal Fistula/etiology
• Rectal Fistula/pathology
• Retrospective Studies
• Treatment Outcome
• Tumor Necrosis Factor-alpha

• Crohn’s disease
• anti-TNF
• biologic
• fistulizing
• internal fistula
• perianal fistula
• stem cells therapy

Perianal fistulas are a common complication of Crohn’s disease (CD) that has, historically, been challenging to manage. Despite the strong available evidence that anti-tumor necrosis factor (anti-TNF) agents are useful in the treatment of perianal fistulizing Crohn’s disease (PFCD), a significant number of these patients do not respond to therapy. The use of therapeutic drug monitoring (TDM) in patients with CD receiving biologic agents has evolved and is currently positioned as an important tool to optimize and guide biologic treatment. Considering the treatment of PFCD can represent a challenge; identifying novel tools to improve the efficacy of current treatments is an important unmet need. Given its emerging role in other phenotypes of Crohn’s disease, the use of TDM could also offer an opportunity to enhance the effectiveness of available therapies and improve outcomes in the subset of patients with PFCD receiving biologics. Overall, there is mounting evidence that higher anti-TNF drug levels are associated with better rates of “fistula healing”. However, studies have been limited by their use of subjective outcomes and observational designs. Ultimately, further interventional, randomized controlled trials looking into the relationship between drug exposure and fistula outcomes are needed.

Crohn’s disease (CD) is complicated by perianal fistulas in approximately 20% of patients. Achieving permanent fistula closure remains a challenge for physicians. An association between serum anti-tumor necrosis factor-α concentrations and clinical outcomes in patients with CD has been demonstrated; however, little information is available on serum adalimumab (ADA) concentrations and remission of perianal fistulas in such patients.

To study the relationship between serum ADA concentrations and clinical remission of CD-associated perianal fistulas.

This cross-sectional study of patients with CD-associated perianal fistulas treated with ADA was performed at four French hospitals between December 2013 and March 2018. At the time of each serum ADA concentration measurement, we collected information about the patients and their fistulas. The primary study endpoint was clinical remission of fistulas defined as the absence of drainage (in accordance with Present’s criteria), with a PDAI ≤ 4, absence of a seton and assessment of the overall evaluation as favorable by the proctologist at the relevant center. We also assessed fistula healing [defined as being in clinical and radiological (magnetic resonance imaging, MRI) remission] and adverse events.

The study cohort comprised 34 patients who underwent 56 evaluations (patients had between one and four evaluations). Fifteen patients had clinical remissions (44%), four of whom had healed fistulas on MRI. Serum ADA concentrations were significantly higher at evaluations in which clinical remission was identified than at evaluations in which it was not [14 (10-16) vs 10 (2-15) μg/mL, P = 0.01]. Serum ADA concentrations were comparable at the times of evaluation of patients with and without healed fistulas [11 (7-14) vs 10 (4-16) μg/mL, P = 0.69]. The adverse event rate did not differ between different serum ADA concentrations.

We found a significant association between high serum ADA concentrations and clinical remission of CD-associated perianal fistulas.

• Crohn’s disease
• Clinical pharmacology
• Peri-anal disorders
• Adalimumab

• Adalimumab/therapeutic use
• Crohn Disease/complications
• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Cross-Sectional Studies
• Cutaneous Fistula/drug therapy
• Cutaneous Fistula/etiology
• Humans
• Rectal Fistula/drug therapy
• Rectal Fistula/etiology

• Anti-drug-antibody
• Biological
• Inflammatory bowel disease
• Therapeutic drug monitoring
• Trough level

• Crohn’s disease
• anti-TNF therapy
• inflammatory bowel disease
• surgery
• therapeutic drug monitoring
• ulcerative colitis
• ustekinumab
• vedolizumab

• Crohn's disease
• biological medicines
• endoscopy
• thiopurines

• Biologic therapies
• Inflammatory bowel disease
• Loss of response
• Proactive
• Reactive
• Therapeutic drug monitoring

• Biological Products/therapeutic use
• Drug Monitoring
• Gastrointestinal Agents/adverse effects
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Quality of Life

Fistula relapse occurs in 20–30% of patients with perianal Crohn’s disease (PCD) despite optimal medico-surgical management. We aimed in this study to assess the rate of perianal and luminal relapse after surgically induced remission and to determine factors associated with fistula relapse.

Consecutive perianal CD patients who achieved clinical remission after surgery for fistulising PCD from January 2013 to January 2019 were included. The cumulative probabilities of relapse-free survival were estimated using the Kaplan–Meier method.

A total of 130 patients were included. Sixty-six of 130 patients received infliximab (IFX) therapy after perianal surgery. After a median follow-up of 62 months (interquartile range [IQR]: 28–117 months), perianal relapse occurred in 30 of 64 (46.9%) nonbiological medication-treated cases and in 14 of 66 (21.1%) cases in the IFX therapy group. The cumulative probabilities of perianal relapse-free survival in patients with nonbiological treatment were 77.1% at 1 year, 54.6% at 3 years, and 30% at 5 years. The rates of survival without perianal fistula relapse in the IFX-treated group were 91.6%, 69.2%, and 59.3% at 1, 3 and 5 years, respectively. In patients treated with IFX after perianal surgery, discontinuation of IFX therapy (odds ratio [OR]=2.43, p=0.036), a penetrating CD phenotype (OR=4.324, p=0.019), and a complex perianal fistula (OR=3.392, p=0.026) were independently associated with perianal relapse in multivariate analysis.

Infliximab therapy reduced the risk of perianal relapse after surgical remission in PCD patients compared with nonbiological treatment. However, approximately 40% of patients using infliximab experienced perianal relapse at 5 years, and patients who discontinued use of IFX or experienced a penetrating phenotype or a complex perianal fistula were associated with increased relapse rate.

• Crohn’s disease
• anti-TNF therapy
• infliximab
• perianal fistula
• perianal surgery

• Biologics
• Fistula
• Inflammatory bowel disease
• Infliximab
• Stem cells
• Surgery
• Ustekinumab

• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Humans
• Infliximab
• Quality of Life
• Rectal Fistula/drug therapy
• Rectal Fistula/etiology
• Treatment Outcome
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factor-alpha

• clinical trials
• inflammatory bowel disease
• protocols & guidelines

• Adult
• Australia
• Crohn Disease/complications
• Crohn Disease/drug therapy
• Gastrointestinal Agents/therapeutic use
• Humans
• Infliximab/therapeutic use
• Prospective Studies
• Randomized Controlled Trials as Topic
• Rectal Fistula/drug therapy
• Rectal Fistula/etiology
• Treatment Outcome

Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.

• biological therapy
• biomarkers
• inflammatory bowel disease
• predictors

• Clinical remission
• Combination therapy
• Crohn’s disease
• Mucosal healing
• Perianal disease

• Adult
• Anal Canal/pathology
• Anus Diseases/complications
• Anus Diseases/drug therapy
• Anus Diseases/pathology
• Azathioprine/administration & dosage
• Crohn Disease/complications
• Crohn Disease/drug therapy
• Crohn Disease/pathology
• Drug Therapy, Combination
• Endoscopy, Gastrointestinal/statistics & numerical data
• Female
• Gastrointestinal Agents/administration & dosage
• Humans
• Induction Chemotherapy
• Infliximab/administration & dosage
• Kaplan-Meier Estimate
• Male
• Odds Ratio
• Recurrence
• Retrospective Studies
• Treatment Outcome

With the overspread use of measurement of serum levels of anti-tumor necrosis factor (TNF) agents (therapeutic drug monitoring, TDM), new therapeutic strategies have been used in the management of Crohn’s disease (CD). Different targets are correlated with increased levels of circulating drugs. Recent evidence demonstrated that higher serum levels of anti-TNF agents may be associated to better outcomes in perianal fistulizing CD (PFCD). Overall, patients with healed fistulas had higher serum levels of infliximab and adalimumab as compared to those with active drainage. This was demonstrated in some cohort studies, in induction and maintenance, in adults and children with PFCD. In this narrative review, authors summarize current evidence on the use of serum level measurement of anti-TNF agents and its correlation with perianal fistula healing in CD patients. Data on the use of TDM in PFCD is discussed in detail. The retrospective design of the studies and the lack of objective parameters to measure fistula healing are the main limitations of published data. Prospective studies, with central reading of objective radiological parameters, such as pelvic magnetic resonance imaging scores, can improve the level of evidence on the possible advantages of TDM in perianal fistula in CD and are warranted.

• Crohn disease
• Fistula
• Tumor necrosis factor-alpha

• Crohn's disease
• luminal disease
• medical therapy
• optimising therapy
• perianal
• surgery.

• crohn's disease
• gastrointestinal fistulae

The disease course of autoimmune diseases such as rheumatoid arthritis is altered during pregnancy, and a similar modulatory role of pregnancy on inflammatory bowel disease (IBD) has been proposed. Hormonal, immunological, and microbial changes occurring during normal pregnancy may interact with the pathophysiology of IBD. IBD consists of Crohn's disease and ulcerative colitis, and because of genetic, immunological, and microbial differences between these disease entities, they may react differently during pregnancy and should be described separately. This review will address the pregnancy-induced physiological changes and their potential effect on the disease course of ulcerative colitis and Crohn's disease, with emphasis on the modulation of epithelial barrier function and immune profiles by pregnancy hormones, microbial changes, and microchimerism.

• Crohn Disease/drug therapy
• Drug Monitoring
• Gastrointestinal Agents/therapeutic use
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Infliximab/therapeutic use
• Remission Induction
• Retrospective Studies
• Treatment Outcome

• Crohn’s disease
• Deep remission
• Infliximab
• Optimization
• Perianal fistula
• Trough level

• Crohn Disease/complications
• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Drug Administration Schedule
• Humans
• Infliximab/administration & dosage
• Magnetic Resonance Imaging
• Proctoscopy
• Rectal Fistula/diagnosis
• Rectal Fistula/drug therapy
• Rectal Fistula/etiology
• Recurrence
• Remission Induction/methods
• Secondary Prevention/methods
• Time Factors
• Treatment Outcome
• Wound Healing/drug effects

• Anorectal fistula
• Crohn’s disease
• anti-TNF
• mesenchymal stem cells
• perianal fistula
• seton

• Biologics
• adalimumab
• anti-TNF
• infliximab
• therapeutic drug monitoring

Data on the radiologic evaluation of perianal fistulizing Crohn’s disease (PFCD) naïve to anti-tumor necrosis factor therapy are scarce, especially in Asian populations. We assessed the effectiveness of infliximab (IFX) on PFCD and explored predictors of ‘deep remission’ based on clinical and radiologic assessments.

Patients with Crohn’s disease and active anal fistulas attending our care center for IFX therapy were prospectively enrolled. Each patient underwent clinical examination according to the Fistula Drainage Assessment Index, endoscopy for assessment of Crohn’s Disease Activity Index (CDAI) and Perianal Crohn’s Disease Activity Index (PCDAI), magnetic resonance imaging (MRI) to determine Van Assche score and Ng score, and laboratory tests up to 2 weeks prior to the start of and up to 2 weeks after the sixth IFX therapy (Week 32).

Among 38 patients treated with IFX, 52.6% achieved clinical remission based on the Fistula Drainage Assessment Index and 42.1% achieved deep remission based on Ng score. Van Assche score (from 14.5 ± 4.26 to 7.36 ± 7.53), CDAI (from 170 ± 92 to 71 ± 69) and PCDAI (from 7.45 ± 2.65 to 2.44 ± 3.20) decreased significantly after six IFX treatments. The only predictor of deep remission was simple fistula (P = 0.004, odds ratio = 3.802, 95% confidence interval: 1.541–9.383).

IFX has been shown to have appreciable effectiveness in Chinese patients with PFCD. MRI is the gold standard for evaluating PFCD, but Van Assche score has some limitations.

• Crohn’s disease
• infliximab
• magnetic resonance imaging
• perianal fistula

• IBD
• IFX
• Monitoring
• POC
• Pharmacokinetic

• antibiotic
• antitumor necrosis factor
• endoscopic ultrasound
• magnetic resonance imaging
• recommendations

• Azathioprine
• Biologics
• Inflammatory bowel disease
• Pediatrics
• Therapeutic drug monitoring
• Treatment

• Antibodies, Monoclonal, Humanized/administration & dosage
• Antibodies, Monoclonal, Humanized/blood
• Antibodies, Monoclonal, Humanized/therapeutic use
• Azathioprine/administration & dosage
• Azathioprine/blood
• Azathioprine/therapeutic use
• Biological Products/administration & dosage
• Biological Products/blood
• Biological Products/therapeutic use
• Child
• Drug Monitoring/methods
• Gastrointestinal Agents/administration & dosage
• Gastrointestinal Agents/blood
• Gastrointestinal Agents/therapeutic use
• Humans
• Inflammatory Bowel Diseases/blood
• Inflammatory Bowel Diseases/drug therapy
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Ustekinumab/administration & dosage
• Ustekinumab/blood
• Ustekinumab/therapeutic use

• Anti-Bacterial Agents/immunology
• Anti-Bacterial Agents/therapeutic use
• Anti-Inflammatory Agents/therapeutic use
• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/therapeutic use
• Anus Diseases/complications
• Anus Diseases/therapy
• Combined Modality Therapy
• Crohn Disease/complications
• Crohn Disease/therapy
• Female
• Humans
• Immunologic Factors/therapeutic use
• Mesenchymal Stem Cell Transplantation
• Tumor Necrosis Factor-alpha/immunology

• Adalimumab
• Drug monitoring
• Fistula healing
• Inflammatory bowel disease
• Infliximab
• Magnetic resonance imaging

• Adalimumab/therapeutic use
• Colonoscopy
• Crohn Disease/complications
• Crohn Disease/diagnostic imaging
• Crohn Disease/drug therapy
• Dose-Response Relationship, Drug
• Drug Monitoring
• Gastrointestinal Agents/therapeutic use
• Humans
• Infliximab/therapeutic use
• Magnetic Resonance Imaging
• Radiography
• Rectal Fistula/diagnostic imaging
• Rectal Fistula/drug therapy
• Rectal Fistula/etiology
• Standard of Care
• Treatment Failure
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

• T32 DK007760 NIDDK NIH HHS

• INFLAMMATORY BOWEL DISEASE

• Antibodies, Monoclonal
• Crohn Disease
• Drug Monitoring
• Gastrointestinal Agents
• Humans
• Infliximab
• Rectal Fistula
• Treatment Outcome