Russell D. Cohen

Serious Infection and Mortality in Patients With Crohn ' s Disease: More Than 5 Years of Follow-Up in the TREAT ™ Registry

OBJECTIVES:The objective of this study was to contribute long-term safety data for infliximab and other therapies in Crohns disease (CD).METHODS:We prospectively evaluated CD patients enrolled in the large, observational Crohns Therapy, Resource, Evaluation, and Assessment Tool registry, established to compare infliximab safety with conventional nonbiological medications in CD.RESULTS:A total of 6,273 patients were enrolled and evaluated on or before 23 February 2010; 3,420 received infliximab (17,712 patient-years; 89.9% received ≥2 infusions) and 2,853 received other-treatments-only (13,251 patient-years). Mean length of patient follow-up was 5.2 years. More infliximab- than other-treatments-only-treated patients had moderate-to-severe (30.6% vs. 10.7%) or severe-to-fulminant (2.5% vs. 0.6%) disease severity (P<0.001). In the year before enrollment, more infliximab- than other-treatments-only-treated patients required surgical intervention (17.4% vs. 13.6%), medical hospitalization (14.2% vs. 8.8%), prednisone (47.8% vs. 31.4%), immunomodulators (52.0% vs. 32.1%), and narcotic analgesics (17.3% vs. 9.1%). Patient mortality was similar for infliximab- and other-treatments-only-treated patients (0.58 vs. 0.59/100 patient-years). In multivariate logistic regression analyses, treatment with prednisone (hazard ratio (HR)=2.14, 95% confidence interval (CI)=1.55, 2.95; P<0.001) or narcotic analgesics (HR=1.79, 95% CI=1.29, 2.48; P<0.001) and age (HR=1.08, 95% CI=1.07, 1.09; P<0.001) were associated with increased mortality risk. Neither infliximab nor immunomodulator treatment was associated with increased mortality risk. Factors independently associated with serious infections included moderate-to-severe disease activity (HR=2.24, 95% CI=1.57, 3.19; P<0.001), narcotic analgesic treatment (HR=1.98, 95% CI=1.44, 2.73; P<0.001), prednisone therapy (HR=1.57, 95% CI=1.17, 2.10; P=0.002), and infliximab treatment (HR=1.43, 95% CI=1.11, 1.84; P=0.006).CONCLUSIONS:Mortality was similar between infliximab- and other-treatments-only-treated CD patients. An increased risk of serious infection with infliximab was observed, although CD severity and use of prednisone or narcotic analgesics carried higher risks.

Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis

OBJECTIVE:There are scant data regarding outpatient adherence in quiescent ulcerative colitis aside from patients enrolled in controlled clinical trials. We conducted a prevalence study to determine the medication adherence rate of maintenance therapy and to identify possible risk factors for nonadherence.METHODS:Outpatients with clinically quiescent ulcerative colitis for >6 months on maintenance mesalamine (Asacol, Procter and Gamble, Cincinnati, OH) were eligible. Patients were interviewed regarding disease history, and demographics were obtained from medical records. Refill information for at least 6 months was obtained from computerized pharmacy records. Adherence was defined as at least 80% consumption of supply dispensed. Using nonadherence as the outcome of interest, stratified analysis and regression modeling were used to identify significant associations.RESULTS:Data were complete for the 94 patients recruited. The overall adherence rate was found to be 40%. The median amount of medication dispensed per patient was 71% (8–130%) of the prescribed regimen. Nonadherent patients were more likely to be male (67%vs 52%, p < 0.05), single (68%vs 53%, p = 0.04), and to have disease limited to the left side of the colon versus pancolitis (83%vs 51%, p < 0.01). Sixty-eight percent of patients who took more than four prescription medications were found to be nonadherent versus only 40% of those patients taking fewer medications (p = 0.05). Age, occupation, a family history of inflammatory bowel disease, length of remission, quality-of-life score, or method of recruitment (telephone interview vs clinical visit) were not associated with nonadherence. Logistic regression identified that a history of more than four prescriptions (odds ratio [OR] 2.5 [1.4–5.7]) and male gender (OR 2.06 [1.17–4.88]) increased the risk of nonadherence. Two statistically significant variables, which were protective against nonadherence, were endoscopy within the past 24 months (OR 0.96 [0.93–0.99]) and being married (OR 0.46 [0.39–0.57]).CONCLUSION:Nonadherence is associated with multiple concomitant medications, male gender, and single status. These patient characteristics may be helpful in targeting those patients at higher risk for nonadherence.

Thalidomide therapy for patients with refractory Crohn's disease: An open-label trial

BACKGROUND & AIMS Inhibition of tumor necrosis factor is a proposed mechanism for the anti-inflammatory properties of thalidomide. We performed an open-label trial of thalidomide in refractory Crohns disease. METHODS Twenty-two patients with refractory Crohns disease (Crohns Disease Activity Index [CDAI] > 200 and/or draining perianal disease) initiated therapy with thalidomide, 200 mg at bedtime (18 patients), or 300 mg at bedtime (4 patients). CDAI and goal interval scores (GIS) were assessed at weeks 0, 4, and 12. Clinical response for patients with luminal disease was defined as reduction in CDAI score of >150 points and for fistula patients was 2 scores of >/=1+ in 3 parameters of the GIS. Clinical remission was defined as a total CDAI < 150 (luminal patients) or >/=2+ for all parameters of the GIS (fistula patients). RESULTS Nine patients with luminal disease and 13 with fistulas (16 male, 6 female) were enrolled. The median CDAI score at entry was 371 (95-468). Sixteen patients completed 4 weeks of treatment (12 clinical responses, 4 clinical remissions). All 14 patients completing 12 weeks met criteria for clinical response. Nine achieved clinical remission (3 luminal, 6 fistula patients). The median CDAI score was 175 (30-468; P < 0.001 vs. baseline). CONCLUSIONS Thalidomide is efficacious in some patients with refractory Crohns disease.

Intravenous cyclosporin in ulcerative colitis: a five-year experience

ObjectiveCyclosporin (CSA) is a promising alternative for patients with severe steroid-refractory ulcerative colitis (UC) previously facing only surgical options. Concerns over the long term efficacy and side effects resulted in this investigation of the University of Chicagos 5-yr CSA experience in these patients.MethodsAll steroid-refractory severe ulcerative colitis (UC) patients treated with IV CSA from 1991 to 1995 were identified by using the universitys IBD database, with additional information from patient charts and physician files.ResultsA total of 42 patients with severe UC unresponsive to IV steroids were treated with IV CSA (4 mg/kg/day). Of 42 patients, 36 (86%) responded; 31 were continued on oral CSA (8 mg/kg/day) for an overall mean of 20 wk. Ten initial CSA responders had colectomies after a mean of 6 months. Of the 36 initial responders, 25 (69%) also received 6-mercaptopurine (6-MP) or azathioprine (aza), and CSA and steroids were tapered. A total of 20% required colectomy, vs 45% of those not receiving 6MP/aza. In all, 62% of all patients, 72% of initial CSA responders, and 80% of initial CSA responders receiving 6MP/aza have avoided colectomy, with a life table analysis of “noncolectomy survival” of 58%, 70%, and 71%, respectively, at 5.5 yr. All colectomies occurred within 18 months of CSA initiation. Complications, resulting in CSA discontinuation in six patients, were all reversible, with complete recovery.ConclusionsCSA successfully allows most severe steroid resistant UC patients to retain their colons, and provides time for “elective” colectomy in others, especially if 6MP/aza are also given. Careful monitoring for side effects, including PCP prophylaxis, should be part of the treatment protocol.

An Open-Label Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects with Prior Loss of Response or Intolerance to Infliximab for Crohn's Disease

BACKGROUND:We assessed the tolerability and clinical benefit of adalimumab, a human antibody to tumor necrosis factor (TNF), in patients with Crohns disease who had previously received and responded to the chimeric anti-TNF antibody infliximab, but who no longer had a sustained response and/or tolerance to infliximab.METHODS:A total of 24 patients with Crohns disease who had lost responsiveness or developed intolerance (acute or delayed infusion reactions) to infliximab were enrolled in a 12-wk uncontrolled trial and treated with subcutaneous adalimumab 80 mg at week 0 and then 40 mg every other week starting at week 2. After week 4, the dose could be escalated to 40 mg weekly in patients who did not achieve clinical remission, complete fistula closure, and complete steroid withdrawal. Outcome measures included the ability to tolerate adalimumab and clinical remission (defined as a Crohns disease activity index (CDAI) score ≤150 points) and clinical response (defined as a decrease in the CDAI) ≥100 points) in patients who had a baseline CDAI score ≥220.RESULTS:None of the patients experienced acute or delayed hypersensitivity reactions during treatment with adalimumab (including 14 who previously experienced treatment-limiting acute hypersensitivity reactions and 6 who previously experienced delayed hypersensitivity reactions with infliximab). Of 17 patients with baseline CDAI scores ≥220: clinical remission occurred at weeks 4 and 12 in 2 (12%) and 5 (29%), respectively; and clinical response occurred in 7 (41%) and 10 (59%), respectively. Nineteen patients (79%) escalated their dose during weeks 4–6.CONCLUSIONS:Adalimumab is well tolerated and appears to be a clinically beneficial option for patients with Crohns disease who have previously lost their response to, or cannot tolerate infliximab.

Infliximab in Crohn’s disease: first anniversary clinical experience

OBJECTIVE The aim of this study is to report on the first year experience with infliximab for Crohns disease. METHODS All Crohns patients receiving infliximab at our institution in the first year of release were prospectively registered. Disease activity was scored at initial infusion, and at 1, 3, 7, and 12 wk. Results were tabulated separately for patients with luminal (L) or fistulous (F) Crohns disease. Steroid withdrawal and adverse events were tabulated. RESULTS One hundred twenty-nine patients were treated (81 L, 48 F). Mean number of infusions/patient were 2.38 L, 3.23 F. Median time to response and remission was 8 and 9 days L; 9 and 10 days F, respectively. Initial infusion course response and remission rates at 3 wk were 65% and 31% L; 78% and 24% F, respectively. Rates were higher if concurrently treated with 6-mercaptopurine or azathioprine and improved with subsequent infusions. Relapse occurred in 78% at a mean 8.5 wk L and in 71% at a mean of 12.2 wk F. Steroid tapering was seen in >90%, with 54% completely off steroids after a second infusion. Infusion-related reactions were seen in up to 24% of patients. The incidence of side effects did not differ if on concurrent immunomodulatory therapy. CONCLUSIONS Clinical experience with infliximab closely parallels the results of the controlled clinical trials, and includes steroid-sparing effects.

A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis

OBJECTIVES:Therapeutic trials in left-sided ulcerative colitis (L-UC) and ulcerative proctitis (UP) have lacked control for medication type, dose, delivery, and duration of therapy.METHODS:All published therapeutic articles and abstracts in L-UC or UP from1958–1997 were reviewed. Improvement, remission rates, and adverse events were recorded for all (ALL), placebo-controlled (PC) studies, and for PC studies passing quality assessment (QA) scoring. Meta-analysis was used where appropriate.RESULTS:Left-sided UC: For active disease, 67 studies (17 PC; 10 QA) were identified. Mesalamine enemas achieved remission in a duration but not a dose response (QA), with higher remission rates than steroid enemas (ALL) and clinical improvement rates superior to oral therapies (QA, ALL). Remission maintenance: 17 (six PC, six QA) studies were identified. Mesalamine therapies had comparable remission rates at 6 months, with a possible dose but not delivery effect. Mesalamine enema dosing intervals between QHS to Q3 days maintained efficacy. Reported adverse events were most common with oral sulfasalazine and dose-independent for mesalamine. Withdrawals from therapy were less than placebo, or ≤3%. Ulcerative proctitis: For active disease, 18 (nine PC, three QA) studies were identified. Mesalamine suppositories achieved clinical improvement and remission in a duration but not dose response, with higher rates of remission than topical steroids (ALL). Remission maintenance: three (three PC, two QA) studies were identified. Remission ranged from 75% to 90% (6 months) and 61–90% (12 months) for mesalamine agents. Reported adverse events were most common for mesalamine foam (8%). Withdrawals from therapy were <2%.CONCLUSIONS:In L-UC and UP, the efficacy and side-effect profile of topical mesalamine are dose independent and superior to oral therapies and topical steroids. Economic analysis suggests that use of these agents will also result in an overall decrease in patient costs.

Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease

OBJECTIVE:Theoretical concern exists that rapid luminal healing in Crohns disease (CD) with therapies like infliximab increases the risk of intestinal stenosis, stricture, or obstruction (SSOs).METHODS:Data were analyzed from the ongoing observational TREAT (the Crohns Therapy, Resource, Evaluation, and Assessment Tool) Registry and ACCENT I (A Crohns Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) study. Investigators reported SSOs as adverse events or serious adverse events.RESULTS:In TREAT, SSOs occurred at a significantly higher rate in patients treated with infliximab compared with patients who received other treatments only (1.95 events/100 patient-years vs 0.99 events/100 patient-years; p < 0.001). Using multivariable analyses, however, infliximab therapy was not associated with SSO development. CD severity at the time of event onset (hazard ratio (HR) = 2.35, 95% confidence internal (CI) 1.35–4.09); CD duration (HR = 1.02, 95% CI 1.00–1.04); ileal disease (HR = 1.56, 95% CI 1.04–2.36); and new corticosteroid use (HR = 2.85, 95% CI 1.23–6.57) were associated with SSOs. In ACCENT I, no increase in SSOs was reported in patients who received infliximab maintenance therapy compared with those who received episodic therapy, despite higher median cumulative infliximab exposure. Additionally, there was no increase in SSO development with rapid mucosal healing (healing at week 10).CONCLUSIONS:Although unadjusted analyses suggested that patients who received infliximab were twice as likely to develop SSOs, multivariable analysis adjusting for other factors demonstrated that only disease duration, disease severity, ileal disease, and new corticosteroid use were significantly associated with SSO development.

The cost of hospitalization in Crohn's disease.

OBJECTIVE:The aim of this study was to evaluate the demographics, resource use, and costs associated with hospitalization of Crohns disease patients.METHODS:All patients hospitalized at our institution from 7/1/96 to 6/30/97 with a primary diagnosis of “Crohns Disease” were analyzed using a computerized database. Data are presented “per hospitalization.”RESULTS:A total of 175 hospitalizations (147 patients) were identified. Mean patient age was 36.5 yr; 61% were female; 82% Caucasian. Payer mix was most commonly contracted (57%), commercial (21%), or Medicare (13%). 57% of hospitalizations had a primary surgical procedure; the remainder were medical. Average length of stay was 8.7 days (surgical, 9.6 days; medical, 7.5 days). The average cost of hospitalization, excluding physician fees, was

Infliximab decreases resource use among patients with Crohn's disease

12,528 (surgical,