Leonard Baidoo

Infliximab Prevents Crohn's Disease Recurrence After Ileal Resection

BACKGROUND & AIMS Crohns disease commonly recurs after intestinal resection. We evaluated whether the administration of infliximab after resective intestinal surgery for Crohns disease reduces postoperative recurrence. METHODS We randomly assigned 24 patients with Crohns disease who had undergone ileocolonic resection to receive intravenous infliximab (5 mg/kg), administered within 4 weeks of surgery and continued for 1 year, or placebo. The primary end point was the proportion of patients with endoscopic recurrence at 1 year. Secondary end points were clinical recurrence and remission and histologic recurrence. RESULTS The rate of endoscopic recurrence at 1 year was significantly lower in the infliximab group (1 of 11 patients; 9.1%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .0006). There was a nonsignificant higher proportion of patients in clinical remission in the infliximab group (8 of 10; 80.0%) compared with the placebo group (7 of 13; 53.8%) (P = .38). The histologic recurrence rate at 1 year was significantly lower in the infliximab group (3 of 11 patients; 27.3%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .01). The occurrence of adverse events was similar between the placebo and infliximab groups, and none occurred in the immediate postoperative period. CONCLUSIONS Administration of infliximab after intestinal resective surgery was effective at preventing endoscopic and histologic recurrence of Crohns disease.

Crohn's disease activity index does not correlate with endoscopic recurrence one year after ileocolonic resection

Background: Crohns disease clinical trials utilize the Crohns Disease Activity Index (CDAI) to measure primary endpoint assessments of clinical recurrence and remission. We evaluated the extent of agreement between clinical recurrence/remission as defined by the CDAI and endoscopic recurrence 1 year after intestinal resection for Crohns disease (CD). Methods: Twenty‐four CD patients who had been randomly assigned to a postoperative clinical trial had 1 year clinical, endoscopic, and histological assessment for disease recurrence. The primary endpoint was the extent of agreement between endoscopic recurrence and clinical recurrence 1 year after intestinal resection for CD. Secondary endpoints were extent of agreement between endoscopic recurrence and the surrogate markers of CD activity, i.e., histological activity, sedimentation rate, and C‐reactive protein (CRP). Results: Twelve of the 24 patients (50%) were in endoscopic remission (i0, i1) and 12 (50%) had endoscopic recurrence (i2, i3, or i4). There was good agreement between endoscopy and histological activity scores (intraclass correlation coefficient = 0.53, kappa coefficient = 0.58). In contrast, there was little to no relationship between endoscopy and CDAI scores; median CDAI scores for endoscopy scores of i0/i1, i2, i3, and i4 were 118, 76, 156, and 78, respectively (P for trend = 0.88). The kappa coefficient (of agreement) between endoscopy score ± 2 and CDAI score ± 150 was 0.12 (exact P = 0.68), indicating poor agreement. Similarly, there was no consistent association observed between endoscopy scores and mean CRP and ESR values at week 54. Conclusions: The CDAI shows poor agreement with endoscopic recurrence 1 year after intestinal resection. Endoscopic recurrence should be the primary endpoint of future postoperative studies and ileocolonoscopy the gold standard test to detect postoperative recurrence. (Inflamm Bowel Dis 2011;)

Effects of Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti–Tumor Necrosis Factor Therapy for Crohn’s Disease: A Meta-analysis of Placebo-controlled Trials

BACKGROUND & AIMS There is debate over whether patients with Crohns disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy. METHODS We performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohns disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4-14 and 24-30 and remission at weeks 24-30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents. RESULTS Overall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI, 0.79-1.48), maintaining a response (OR, 1.53; 95% CI, 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.) CONCLUSIONS On the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.

The Appropriateness of Concomitant Immunomodulators With Anti–Tumor Necrosis Factor Agents for Crohn's Disease: One Size Does Not Fit All

BACKGROUND & AIMS There is no consensus on the appropriateness of concomitant immunomodulators with anti-tumor necrosis factor (TNF) therapy for Crohns disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohns disease. METHODS A literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohns disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index. RESULTS Concomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios. CONCLUSIONS The appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohns disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.

Association Between Telephone Activity and Features of Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS Telephone communication is common between healthcare providers and patients with inflammatory bowel disease (IBD). We analyzed telephone activity at an IBD care center to identify disease and patient characteristics associated with high levels of telephone activity and determine if call volume could identify individuals at risk for future visits to the emergency department (ED) or hospitalization. METHODS We performed a prospective observational study in which we categorized telephone calls received by nursing staff over 2 years at a tertiary care IBD clinic (2475 patients in 2009 and 3118 in 2010). We analyzed data on 21,979 ingoing and outgoing calls in 2009 and 32,667 calls in 2010 and assessed associations between clinical factors and logged telephone encounters, and between patterns of telephone encounters and future visits to the ED or hospitalization. RESULTS Telephone encounters occurred twice as frequently as office visits; 15% of the patients generated >10 telephone encounters per year and were responsible for half of all telephone encounters. A higher percentage of these high telephone encounter (HTE) patients were female, had Crohns disease, received steroid treatment, had increased levels of C-reactive protein and rates of erythrocyte sedimentation, had psychiatric comorbidities, and had chronic abdominal pain than patients with lower telephone encounters. The HTE patients were also more frequently seen in the ED or hospitalized over the same time period and in subsequent years. Forty-two percent of patients with >8 telephone encounters within 30 days were seen in the ED or hospitalized within the subsequent 12 months. CONCLUSIONS Based on an analysis of telephone records at an IBD clinic, 15% of patients account for half of all calls. These HTE patients are a heterogeneous group with refractory disease who are likely to visit the ED or be hospitalized.

Association of Vitamin D Level With Clinical Status in Inflammatory Bowel Disease: A 5-Year Longitudinal Study.

OBJECTIVES:Emerging data suggest that vitamin D has a significant role in inflammatory bowel disease (IBD). Prospective data evaluating the association of vitamin D serum status and disease course are lacking. We sought to determine the relationship between vitamin D status and clinical course of IBD over a multiyear time period.METHODS:IBD patients with up to 5-year follow-up from a longitudinal IBD natural history registry were included. Patients were categorized according to their mean serum 25-OH vitamin D level. IBD clinical status was approximated with patterns of medication use, health-care utilization, biochemical markers of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), pain and clinical disease activity scores, and health-related quality of life.RESULTS:A total of 965 IBD patients (61.9% Crohn’s disease, 38.1% ulcerative colitis) formed the study population (mean age 44 years, 52.3% female). Among them, 29.9% had low mean vitamin D levels. Over the 5-year study period, subjects with low mean vitamin D required significantly more steroids, biologics, narcotics, computed tomography scans, emergency department visits, hospital admissions, and surgery compared with subjects with normal mean vitamin D levels (P<0.05). Moreover, subjects with low vitamin D levels had worse pain, disease activity scores, and quality of life (P<0.05). Finally, subjects who received vitamin D supplements had a significant reduction in their health-care utilization.CONCLUSIONS:Low vitamin D levels are common in IBD patients and are associated with higher morbidity and disease severity, signifying the potential importance of vitamin D monitoring and treatment.

Impact of Obesity on the Management and Clinical Course of Patients with Inflammatory Bowel Disease.

Background:Obesity has been linked with a proinflammatory state and the development of inflammatory diseases. Data on the clinical course and treatment of obese patients with inflammatory bowel disease (IBD) are limited. We used an institutional IBD registry to investigate the impact of obesity on IBD severity and treatment. Methods:This was a retrospective analysis of prospectively collected data for 3 years (2009–2011). Patients with IBD were categorized by body mass index (BMI). IBD-related quality of life, biochemical markers of inflammation, comorbidities, health care utilization, and treatment were characterized. Obesity was defined as a BMI ≥30 (type I: 30–34.9, type II: 35–39.9, and type III ≥40). Results:Among 1494 patients with IBD, 71.9% were above their ideal BMI and 31.5% were obese. Obesity was more common in ulcerative colitis compared with patients with Crohns disease (P = 0.04). Obese class II and class III patients were predominantly female. Obesity in IBD was associated with female gender (P < 0.0001), diabetes mellitus (P < 0.001), hypertension (P < 0.001), hyperlipidemia (P < 0.001), poor quality of life (P < 0.0001), and increased rates of C-reactive protein elevation (P = 0.008). In logistic regression analysis, quality of life and C-reactive protein elevation were not independently correlated with obesity. There was no association between increasing BMI and annual prednisone use, emergency department visits, hospitalization, and surgery. Obesity was associated with lower milligrams per kilogram doses of purine analogs and biologics. Conclusions:Obesity in IBD is not associated with increased health care utilization and IBD-related surgeries. Optimal regimens for drug dosing in obese patients with IBD have yet to be defined.

Physician assessment of ulcerative colitis activity correlates poorly with endoscopic disease activity

Background: Subjective physician assessment is the cornerstone of routine ulcerative colitis (UC) management. Endoscopic and histologic assessment of UC provides objective measures of inflammatory disease activity. The level of agreement between physician impression of UC activity and endoscopic disease activity has not been evaluated. The aim was to assess the level of agreement between physicians clinical impression of UC disease activity and endoscopic and histologic findings of inflammation. Methods: Using the Medical Archival Retrieval System at the University of Pittsburgh Medical Center, we reviewed clinical information on all UC patients between 1995 and 2008 who had clinic visits recorded prior to colonoscopy. Clinical UC disease activity was defined by the physicians clinical impression and the endoscopic and histologic activity by colonoscopy with biopsy. The level of agreement between colonoscopy assessment of UC with histologic and clinical assessment was determined by sensitivity, specificity, positive and negative predictive values, and the kappa coefficient. Results: There were 369 UC patients who had a clinic visit proximate to a colonoscopy. The mean age of patients was 46 ± 16 years (50% female). The performance of clinical impression in recognizing disease activity, as determined by endoscopy, was relatively poor: sensitivity = 56.0%, predictive value negative = 56.8%, kappa coefficient = 0.35. In contrast, the performance of histological evaluation in recognizing disease activity was markedly better: sensitivity = 93.5%, predictive value negative = 89.1%, kappa coefficient = 0.70. Conclusions: The physicians clinical impression of UC activity shows poor agreement with endoscopy and histology, with over one‐third of patients with chronic inflammation underrecognized by clinical impression. The consequences of underestimated UC activity by clinical assessment may include undertreatment of active disease and uncontrolled chronic inflammation. (Inflamm Bowel Dis 2011;)

Demographic and Clinical Predictors of High Healthcare Use in Patients with Inflammatory Bowel Disease.

Background:Inflammatory bowel disease (IBD) is a heterogeneous chronic inflammatory condition requiring significant healthcare expenditure. Subgroups of individuals contribute disproportionately to spending. We aimed to determine demographic and clinical factors predictive of high healthcare expenditures for IBD patients followed over a multiyear period. Methods:This was a registry analysis using a prospective observational, consented, natural history registry from a tertiary IBD center and associated medical charges, not including pharmacy expenses. The 100 patients with the highest medical charges (top 5%) were compared with the median 300 patients. Logistic regression determined demographic and clinical factors associated with high charge patients. Results:IBD patients in the high charge group had significantly more unemployment (P < 0.0001), were of black race (P = 0.013), comorbid psychiatric illness (P = 0.002), hypertension (P = 0.01), diabetes (P = 0.004), opiate use (P < 0.0001), perianal involvement (P = 0.002), penetrating disease (P < 0.0001), and extensive colitis (P = 0.01). In multivariate analysis, unemployment (Crohns disease [CD]: odds ratio [OR], 3.04; 95% confidence interval [CI], 1.32–7.02; ulcerative colitis [UC]: OR, 2.68; 95% CI, 1.20–5.99), psychiatric illness (UC: OR, 2.08; 95% CI, 1.03–4.19), opiates (CD: OR, 5.61; 95% CI, 2.67–11.82; UC: OR, 5.14; 95% CI, 2.52–10.48), prior surgery (CD: OR, 3.29; 95% CI, 1.59–6.82; UC: OR, 2.72; 95% CI, 1.39–5.32), penetrating CD (OR, 3.29; 95% CI, 1.02–10.62), and corticosteroid requirement (CD: OR, 3.78; 95% CI, 1.86–7.65; UC: OR, 2.98; 95% CI, 1.51–5.90) remained independently associated with high charges. Conclusions:High expenditure IBD patients were affected by more severe disease. The high prevalence of depression, anxiety, and chronic pain in these patients suggests the need for focused treatment of these comorbidities ultimately to reduce financial burden.

What next after infliximab

The use of infliximab (Remicade®) has revolutionized the care of Crohns disease (CD) patients who have proved refractory to standard treatment. The use of infliximab is very well tolerated in the majority of patients but in a small subset of patients may lead to the production of antibodies (termed “antibodies to infliximab”—ATI). The production of these antibodies has been associated with the development of both acute and delayed infusion reactions, although even in patients who develop ATIs, these reactions are relatively uncommon. Nonetheless, these reactions may occasionally be severe enough to lead to intolerance to infliximab. Another group of patients, after initially having excellent responses to infliximab, experience an attenuated response or loss of response over time. What is the cause of this loss of efficacy? ATIs may play a role in some patients but other potential reasons for this phenomenon have provoked much debate. The importance of other cytokines after TNF-α has been neutralized may be relevant as (this has been shown to be the case in rheumatoid arthritis (RA) is the idea of beneficial autoimmunity production to TNF-α. (Wildbaum G, Nahir MA, Karin N. Beneficial autoimmunity to proinflammatory mediators restrains the consequences of self-destructive immunity. Immunity 2003;19:679–88.) It has been shown that during the course of an autoimmune condition, the immune system mounts a beneficial autoantibody response to proinflammatory mediators. This response counteracts, to a certain degree, the autoimmune pathology. This natural counteraction has been illustrated in animal models of autoimmunity, and there has been evidence demonstrated that this occurs in human RA. Whether this occurs in Crohns is unknown; infliximab is a chimeric monoclonal antibody containing an approximately 25% murine region. It had been hoped that the development of humanized or fully human monoclonal antibodies would provide therapeutic antibodies that did not induce an immune response. While this has unfortunately not proven to be the case—these products still have significant immunogenicity—these products do present an alternative therapy when infliximab cannot be used. In light of this, adalimumab (Humira®) a human monoclonal antibody used for treating rheumatologic conditions has been investigated as an alternate treatment for patients with CD who after initially responding to infliximab experience intolerance or loss of efficacy. Is this a viable alternative?