Henit Yanai

Assessing response and loss of response to biological therapies in IBD.

OBJECTIVES:The advent of biological therapies for inflammatory bowel disease (IBD) began in 1998 with the approval of infliximab for the treatment of refractory (to conventional agents) Crohn’s disease (CD). Since then, the indications for anti-tumor necrosis factor-α (anti-TNFα) therapy have increased to include induction and maintenance of clinical responses and remissions for luminal and fistulizing CD, the treatment of children with CD, and the treatment of adults with ulcerative colitis. Additional utilities of biological therapies have included demonstrable mucosal healing, improvement in quality of life, reduction in surgeries and hospitalizations, and the treatment of extraintestinal manifestations of IBD including central and peripheral arthritis and pyoderma gangrenosum. Natalizumab has also been approved for the treatment of refractory Crohn’s in patients who have failed conventional agents and anti-TNFα therapies. Unfortunately, despite the overall effectiveness of biological agents in a spectrum of indications for IBD, a significant proportion of patients do not respond or lose response over time. In this review, we intend to appraise the latest evolution in treatment strategies in IBD and to suggest an evidence-based approach and risk stratification while coping with cases of non-responders or loss of response to biological therapies.METHODS:We conducted a literature search of English publications listed in the electronic databases of MEDLINE (source PUBMED) and constructed an analytical review based on definitions of response and loss of response, considering potential responsible mechanisms, clinical assessment tools, and finally recommending a practical approach for its prevention and management.RESULTS:Favorable clinical outcome appears to be the consequence of sustained therapeutic drug levels, and the current literature supports a practice of dose adjustments. When immunogenicity develops to a single biological agent, response can be regained by introduction of an alternative biological agent of the same or different class. Efficacy is reduced with second-line agents either within or across classes compared with naive patients. In the absence of direct measurement of drug levels and anti-drug antibodies, clinical judgment is necessary to assess the mechanisms of loss of response, and more empiric decision making may be necessary to determine the choice of second-line biological agents. Optimal treatment strategies are still controversial.CONCLUSIONS:It is essential to recognize the spectrum of mechanisms affecting response and loss of response to form a logical and efficient management algorithm, and, perhaps, it is time to incorporate the measurement of trough levels and anti-drug antibodies in the strategy of such an assessment. Prospective controlled trials are direly needed to investigate the optimal tailored management in individual patients who lose response.

Levels of Drug and Antidrug Antibodies Are Associated With Outcome of Interventions After Loss of Response to Infliximab or Adalimumab

BACKGROUND & AIMSnThere is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab.nnnMETHODSnWe performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies).nnnRESULTSnAmong 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (Pxa0= .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (Pxa0=xa0.02). An analysis of definite inflammatory loss-of-response events (nxa0= 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (Pxa0= .002; log-rank test).nnnCONCLUSIONSnThe results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.

Patient Factors That Increase Infliximab Clearance and Shorten Half-life in Inflammatory Bowel Disease: A Population Pharmacokinetic Study

Background:Infliximab (IFX) is effective therapy for ulcerative colitis and Crohns disease, but it may be associated with side effects and loss of response. One loss of response mechanism is increased IFX clearance (IFX-CL), resulting in short half-life and decreased troughs. Methods:Patients were recruited, and relevant demographic, clinical, and laboratory data were recorded. IFX serum concentrations and antibodies against IFX (ATI) were measured for therapeutic drug monitoring and modeled using NONMEM. Results:There were 169 IFX concentrations (Crohns disease = 73, ulcerative colitis = 92, and diagnosis undetermined = 4). Patient factors significantly associated with high IFX-CL were low albumin, high body weight, and the presence of ATI (P ⩽ 0.001). Disease type did not affect IFX-CL. The typical IFX-CL was 0.381 L/d. ATI formation was associated with a 259% increase in IFX-CL. The estimated median IFX effective half-life was 5.6 ± 2.4 days. Patients with low weight are more likely to have low troughs because IFX CL is not linearly related to weight, but IFX dosing is weight-based (in mg/kg). Simulations investigating alternative dose strategies suggested that more reliably measurable concentrations over the dose interval were achieved when the dose interval was shortened than by increasing administered dose. Conclusions:IFX-CL is significantly influenced by patient factors, specifically, albumin, body weight, and ATI. There should be a decreasing IFX dose interval strategy, particularly for low albumin patients. Higher starting doses may benefit low body weight patients. Pharmacokinetic models and therapeutic drug monitoring may ensure that patients maintain measurable concentrations throughout dose intervals. Individualized dosing may improve outcomes for IFX-treated patients with Crohns disease and ulcerative colitis.

The impact of magnetic resonance enterography and capsule endoscopy on the re-classification of disease in patients with known Crohn’s disease: A PROSPECTIVE ISRAELI IBD RESEARCH NUCLEUS (IIRN) STUDY

BACKGROUND AND AIMSnThe classification of Crohns disease (CD) is usually determined at initial diagnosis and is frequently based on ileocolonoscopic and cross-sectional imaging data. Advanced endoscopic and imaging techniques such as small-bowel video capsule endoscopy (VCE) and magnetic resonance enterography (MRE) may provide additional data regarding disease extent and phenotype. Our aim was to examine whether VCE or MRE performed after the initial diagnosis may alter the original disease classification.nnnMETHODSnConsecutive patients with known small-bowel CD in clinical remission or mild disease were prospectively recruited and underwent MRE and VCE (if small-bowel patency was confirmed by a patency capsule (PC). Montreal classifications before and after evaluation were compared.nnnRESULTSnSeventy-nine patients underwent MRE and VCE was performed in 56. Previously unrecognized disease locations were detected with VCE and MRE in 51 and 25%, respectively (p < 0.01) and by both modalities combined in 44 patients (55%). Twenty-two patients (27%) were reclassified as having an advanced phenotype (B2/B3). MRE and VCE reclassified the phenotype in 26 and 11% of cases, respectively (p < 0.05). Overall, both modalities combined altered the original Montreal classification in 49/76 patients (64%).nnnCONCLUSIONnVCE and MRE may lead to reclassification of the original phenotype in a significant percentage of CD patients in remission. VCE was more sensitive for detection of previously unrecognized locations, while MRE was superior for detection of phenotype shift. The described changes in the disease classification may have an important impact on both clinical management and long-term prognosis in these patients.

Low-dose smoking resumption in ex-smokers with refractory ulcerative colitis

BACKGROUND AND AIMnUlcerative colitis (UC) is primarily a disease of non-smokers. Ex-smokers may have a more refractory disease course and anecdotal evidence in non-controlled clinical trials have suggested that smoking resumption, or the administration of nicotine, may ameliorate signs and symptoms of UC in ex-smokers. We report outcomes of ex-smokers with refractory UC who resumed low-dose cigarette smoking.nnnMETHODSn17 ex-smokers with refractory UC were identified. Clinical remission was defined as a disease activity index score of 0.nnnRESULTSnTwo out of 17 patients refused the recommendation to resume smoking. Of the 15 patients who resumed smoking, the mean daily number of cigarettes was 8.6. Fourteen out of those 15 patients who resumed smoking were able to maintain prolonged clinical remission off steroids. One out of the 15 patients failed to improve and required oral steroids. Another patient was compelled to quit smoking since he became addicted. His disease flared after maintaining a prolonged remission of 3 years and he eventually underwent surgery. Three out of these 15 patients switched from cigarettes smoking to nicotine compounds and continued to maintain remission.nnnCONCLUSIONnResumption of low dose smoking in a selected group of ex-smokers with refractory UC may ameliorate signs and symptoms. Quality of life, medication side effects, and smoking risk factors should all be considered and discussed with patients. Smokers should be meticulously followed for compliance with low-dose regimen and all associated smoking risks.

Practice of gastroenterologists in treating flaring inflammatory bowel disease patients with clostridium difficile: antibiotics alone or combined antibiotics/immunomodulators?

Background: The optimal management of Clostridium difficile infection (CDI) in flaring inflammatory bowel disease (IBD) patients has not been defined. Limited data suggest that coadministration of immunomodulators (IM) with antibiotics (AB) results in a worse outcome. We investigated the prevalent practice among North American gastroenterologists in this scenario. Methods: A structured questionnaire presented the clinical cases of two hospitalized patients with ulcerative colitis and concomitant CDI, either with or without prior IM treatment. The questionnaire was distributed to a sample of gastroenterologists at medical centers across North America. Respondents were requested to denote their therapeutic choices for these patients. Results: The survey included 169 gastroenterologists, 122 from the US and 47 from Canada, with an average of 12 ± 10 years of experience in gastroenterology. Forty‐two (25%) of the respondents were IBD experts. Seventy‐seven (46%) respondents elected to add an IM in combination with AB, whereas 82/169 (54%) treated the flare with AB alone (P = NS). The rate of administering combined AB+IM was similar for the IBD experts and the non‐IBD experts. Only 11% of respondents withdrew maintenance azathioprine upon the diagnosis of CDI. More IBD experts stopped azathioprine treatment compared to the non‐IBD experts (12/42 versus 6/127, P < 0.001). Overall, 65% of surveyed gastroenterologists stated they believe these patients are afflicted by two simultaneous but separate disease processes. Conclusions: There is significant disagreement among gastroenterologists on whether combination AB+IM or AB alone should be given to IBD patients with CDI‐associated flares. Controlled trials are needed to investigate the optimal management approach to this clinical dilemma. (Inflamm Bowel Dis 2010;)

Gene expression profiles of ileal inflammatory bowel disease correlate with disease phenotype and advance understanding of its immunopathogenesis.

Background:Pouchitis may develop in patients with ulcerative colitis undergoing pouch surgery. We aimed to evaluate the de novo inflammation developing in the ileal pouch, hypothesizing that it may be similar to ileitis in Crohns disease (CD). Methods:Patients with ulcerative colitis pouch were prospectively recruited, stratified according to disease behavior into normal pouch, chronic pouchitis, and Crohns-like disease of the pouch groups, and compared with controls. Gene expression analysis was performed using microarrays, validated by real-time polymerase chain reaction. Gene ontology and clustering were evaluated using bioinformatic tools. Results:Sixty-six subjects were recruited. Although in ulcerative colitis ileum there were no significant gene expression alterations, patients with normal pouch had 168 significant alterations (fold change ≥ 2, corrected P ⩽ 0.05). In chronic pouchitis and Crohns-like disease of the pouch, 490 and 1152 alterations were detected, respectively. High degree of overlap in gene expression alterations between the pouch subgroups was demonstrated. The magnitude of change correlated with pouch disease behavior. Gene expression profiles were more reflective of disease behavior compared with inflammatory indices. CD ileitis had 358 alterations, with a 90% overlap with pouchitis. Gene ontology analyses revealed multiple biological processes associated with pouch inflammation, including response to chemical stimulus, small molecule metabolic and immune system processes, and specific infection-related pathways such as Staphylococcus aureus, leishmaniasis, and tuberculosis. Conclusions:Gene alterations in pouch inflammation and CD overlap, suggesting that inflammatory bowel diseases is a spectrum, rather than distinct diseases. Pouchitis may serve as a model of CD. The novel pathways associated with inflammatory bowel diseases may decipher pathophysiology and suggest targets for intervention.

Magnetic resonance enterography versus capsule endoscopy activity indices for quantification of small bowel inflammation in Crohn's disease.

Background: Video capsule endoscopy (VCE) and magnetic resonance enterography (MRE) are the prime modalities for the evaluation of small bowel (SB) Crohn’s disease (CD). Mucosal inflammation on VCE is quantified using the Lewis score (LS). Diffusion-weighted (DW) magnetic resonance imaging (MRI) allows for accurate assessment of SB inflammation without administration of intravenous contrast material. The Magnetic Resonance Index of Activity (MaRiA) and the Clermont index are quantitative activity indices validated for contrast-enhanced MRE and DW-MRE, respectively. The aim of this study was to compare the quantification of distal SB inflammation by VCE and MR-related activity indices. Methods: Patients with known quiescent SB CD were prospectively recruited and underwent MRE and VCE. LS, MaRIA and Clermont scores were calculated for the distal SB. Results: Both MRI-based indices significantly correlated with the LS and the Clermont index (r = 0.50, p = 0.001 and r = 0.53, p = 0.001, respectively). Both MaRIA and Clermont scores were significantly lower in patients with mucosal healing (LS < 135). The area under the curve (AUC) with both MR scores was moderate for prediction of any mucosal inflammation (LS ⩾ 135) and excellent for prediction of moderate-to-severe inflammation (LS ⩾ 790) (0.71 and 0.74 versus 0.93 and 0.91 for MaRIA and Clermont score, respectively). Conclusions: Modest correlation between VCE- and MRE-based quantitative indices of inflammation in patients with quiescent SB CD was observed. Between-modality correlation was higher in patients with endoscopically severe disease. DW-MRE gauged by Clermont score was at least as accurate as contrast-enhanced MRE for quantification of SB inflammation.

Gene expression alterations in ulcerative colitis patients after restorative proctocolectomy extend to the small bowel proximal to the pouch

Objectives To evaluate molecular profiles in the small bowel (SB) mucosa proximal to the pouch in ulcerative colitis (UC) patients after pouch surgery. Design Patients were prospectively recruited and stratified according to disease behaviour: normal pouch (NP), chronic pouchitis (CP), and Crohns-like disease of the pouch (CLDP). Biopsies obtained from the pouch and the normal-appearing proximal SB (40u2005cm proximal to the anal verge) were compared to ileal biopsies from normal controls (NC). A histopathological score based on the degree of polymorphonuclear and mononuclear infiltrates was used to assess inflammation in the pouch and the proximal SB. Gene expression analysis was performed using microarrays, and validated by real-time PCR. Gene ontology and clustering were evaluated by bioinformatics. Results Thirty-six subjects were recruited (age 18–71u2005years, 16 males). Histopathology scores demonstrated minimal differences in the normal-appearing proximal SB of all groups. Nonetheless, significant (fold change ≥2, corrected p [FDR] ≤ 0.05) molecular alterations in the proximal SB were detected in all groups (NP n=9; CP n=80; and CLDP n=230) compared with NC. The magnitude of DUOX2 alteration in the proximal SB was highest. An increase of 6.0, 9.8 and 21.7 folds in DUOX2 expression in NP, CP, CLDP, respectively was observed. This was followed by alterations in MMP1, SLC6A14 and PGC. Gene alterations in the proximal SB overlapped with alterations within the pouch (76% and 97% overlap in CP and CLDP, respectively). Gene ontology analysis in the proximal SB and pouch were comparable. Conclusions Significant gene expression alterations exist in an apparently unaffected proximal SB. Alterations in the pouch and the proximal SB were comparable, suggesting that inflammation may not be limited to the pouch, but that it extends to the proximal SB.

The incidence and predictors of lupus-like reaction in patients with IBD treated with anti-TNF therapies.

Background:The incidence of lupus-like reactions (LLRs) in patients with inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (ATNF) has not been well defined. We aimed to characterize the features and predictors associated with LLR. Methods:We studied a cohort of adult patients with IBD treated with ATNF by a single specialist during 2009. Patients with LLR were characterized and compared with those without LLR for possible predictors. Results:Twenty of 289 patients (6.9%) had LLR (19.9 cases per 1000 patient-years). Female gender and IBD-unclassified were more prevalent in the LLR group (85% versus 54%, P = 0.009; and 15% versus 2.2%, P = 0.018, respectively), with a hazard ratio of 3.89 (95% confidence interval = 1.12–13.55; P = 0.033) and 7.38 (95% confidence interval = 1.93–28.23; P = 0.003), respectively. ATNF duration was shorter in the LLR group (median, 1 year [interquartile range, 0–3] versus 3 years [interquartile range, 1–6.5], P = 0.005). Arthropathy was universal, followed by fatigue and dermatitis (30% each). Antinuclear antibodies were universally positive, and 16 of 20 had anti–double-stranded DNA. ATNF was discontinued in all; 8 patients required corticosteroids and 1 required hydroxychloroquine followed by complete clinical resolution (mean 7.9 ± 5.9 months). Antinuclear antibodies reverted or normalized in 7 of 16 patients (44%). Fourteen patients (70%) were switched to a second ATNF, 2 with concomitant immunomodulators, and 12 as monotherapy. One patient on ATNF monotherapy developed a second LLR and was successfully switched to a third ATNF. Conclusion:LLRs secondary to ATNFs are more frequent than previously reported, more common in women and IBD-unclassified. It is reversible with cessation of the culprit agent and steroids. Switching to an alternative ATNF rarely results in recurrence.