Judith Collins

Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis

BACKGROUND & AIMS Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF-α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment. METHODS We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6-12; endoscopic subscore ≥ 2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change. RESULTS In phase 2, median changes from baseline in the Mayo score were -1.0, -3.0, -2.0, and -3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P ≤ .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess. CONCLUSIONS Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539.

Subcutaneous Golimumab Maintains Clinical Response in Patients With Moderate-to-Severe Ulcerative Colitis

BACKGROUND & AIMS Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy. METHODS We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. The primary end point was clinical response maintained through week 54; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54. RESULTS Clinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Percentages of serious adverse events were 7.7%, 8.4%, and 14.3% among patients given placebo, 50 mg, or 100 mg golimumab, respectively; percentages of serious infections were 1.9%, 3.2%, and 3.2%, respectively. Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis. CONCLUSIONS Golimumab (50 mg or 100 mg) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54. Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications. ClinicalTrials.gov number: NCT00488631.

Accuracy of Screening for Fecal Occult Blood on a Single Stool Sample Obtained by Digital Rectal Examination: A Comparison with Recommended Sampling Practice

Context Many physicians screen for advanced colonic neoplasia by testing the stool obtained from a digital rectal examination for occult blood. Contribution The authors performed fecal occult blood tests (FOBTs) on samples from digital rectal examination and did complete optical colonoscopy on 2665 average-risk asymptomatic adults. The sensitivity and specificity of digital FOBT for advanced colonic neoplasia were 4.9% and 97.1%, respectively. The positive and negative likelihood ratios were 1.68 and 0.98, respectively. Implications A negative result on a test for fecal occult blood in a digital rectal sample does not change the odds of advanced colonic neoplasia. Physicians should not rely on FOBT performed on a single sample of stool. The Editors Many organizations and expert panels recommend colorectal cancer screening in average-risk asymptomatic persons older than 50 years of age (1-3). Randomized, controlled trials show that screening with fecal occult blood tests (FOBTs) can reduce both death from colorectal cancer and subsequent incidence of new cancer (4-9). These studies performed FOBT by having patients submit 2 samples from 3 stools obtained on 3 consecutive days for analysis. The expert panels recommend 6-sample FOBT to reduce the likelihood of false-negative results due to sampling error (1-3). Recent studies have found that many primary care providers use FOBT as their primary screening test. However, the methods used to obtain stool samples vary greatly. In 24% to 64% of practices, a single digital rectal examination performed in the office is the primary method for obtaining stool for FOBT (10, 11). The presumed rationale for using an office-based test is to improve patient adherence. Previous studies have found that the positive predictive value of an office-based FOBT is similar to that of the standard 6-sample home test (12, 13). There are no data evaluating the sensitivity and specificity of office-based digital FOBT or its effect on mortality reduction in colorectal cancer (2). No previous studies performed colonoscopy in patients with negative results on office-based digital FOBT. Therefore, negative results on digital FOBT may falsely reassure both patients and physicians. If a single office-based digital FOBT is commonly used for colorectal cancer screening, it is important to understand the sensitivity and specificity of this strategy. Our group previously reported the results of screening with colonoscopy in 2885 asymptomatic patients 50 to 75 years of age (14). The prevalence of advanced neoplasia was 10.6% in a predominantly male cohort of veterans. Advanced colonic neoplasia was defined as an adenoma with a diameter of 10 mm or more, a villous adenoma (that is, 25% villous), an adenoma with high-grade dysplasia, or invasive cancer. Patients with intramucosal carcinoma or carcinoma in situ were classified as having high-grade dysplasia. Patients with more than 1 lesion were classified according to the most advanced disease stage. In that prospective study, the home-based 6-sample FOBT with rehydration yielded positive results in 24% of patients with advanced neoplasia (14). To our knowledge, no previous study has evaluated the sensitivity of digital FOBT. The primary aim of the current study was to compare the sensitivity and specificity of digital FOBT and recommended 6-sample FOBT in asymptomatic patients who had both types of FOBT and underwent complete screening colonoscopy regardless of FOBT results. We now report the test results in patients who had both types of FOBT, followed by a complete screening colonoscopy. Colonoscopy was performed regardless of positive or negative FOBT results. Methods Patient Entry Patients 50 to 75 years of age were randomly recruited from primary care clinics at 13 Veterans Affairs medical centers from February 1994 to January 1997. We also recruited patients referred for screening flexible sigmoidoscopy and those with a family history of colorectal cancer (14, 15). Patients were excluded if they reported symptoms of lower gastrointestinal tract disease, including rectal bleeding on more than 1 occasion in the previous 6 months, a marked change in bowel habits, or lower abdominal pain that would normally require a medical evaluation. Other exclusion criteria included any previous disease of the colon, structural examinations of the colon within the previous 10 years, and serious comorbid conditions that would increase the risk for colonoscopy. The current study sample includes all patients who had complete colonoscopy to the cecum and results from both 6-sample at-home FOBT and adequate digital FOBT (n= 2665). A central human subjects committee and local committees at each participating center approved the study protocol. Procedures Eligible patients had a complete physical examination by the study physician that included a digital rectal examination to identify rectal masses and obtain stool for FOBT. If adequate stool was present, FOBT was performed on a single sample by using guaiac-impregnated cards (Hemoccult II, SmithKline Beckman, Palo Alto, California). Since the digital FOBT sample was immediately developed by the study nurse, rehydration was not performed. In addition, patients were given Hemoccult II cards to collect 3 spontaneously passed stool samples before bowel preparation and colonoscopy. They also received a sheet of written dietary instructions advising them to restrict consumption of red meat, vitamin C, and aspirin before obtaining the samples, but adherence to these measures was not monitored. Each card contained 2 guaiac-impregnated windows, and fecal material from each stool sample was applied to 2 sites on the card, for a total of 6 samples per patient. The cards were returned on the day of the colonoscopy. After a drop of water was added (rehydration), the developer solution was applied. Trained study nurses interpreted the developed cards. In most cases, the endoscopist was not aware of the results of either FOBT. Patients who did not have a completed digital FOBT or who did not submit test cards were excluded from this analysis. All patients had complete colonoscopy to the cecum. Histologic Evaluation At colonoscopy, all visible polypoid lesions were removed or biopsied and sent to local pathology laboratories for processing. Results were interpreted by the local pathologist, a central pathologist, and, when there was disagreement, a third reviewing pathologist. None of the pathologists were aware of the other test results or interpretations. Patients were classified on the basis of the most advanced lesion detected during colonoscopy. Statistical Analysis The Veterans Affairs Cooperative Studies Program Coordinating Center at Perry Point, Maryland, served as the central statistical and data management coordinating center. The statistical analysis detailed here is based primarily on descriptive statistics, including means and SDs for continuous variables as well as the calculation of rates and proportions for categorical data. The performance characteristics of the diagnostic screening strategies were evaluated by calculating sensitivity and specificity according to the standard definition; these results are presented separately by histologic category, along with corresponding 95% CIs. We also included positive and negative predictive values and likelihood ratios with corresponding 95% CIs for both positive and negative FOBT results; patients who had no advanced neoplasia were compared with those who had advanced neoplasia. All data management and statistical analysis were performed with SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source This study was funded by the Department of Veterans Affairs Cooperative Studies Program (VACSP) and was conducted according to VACSP guidelines. In the VACSP, investigators propose, design, and conduct studies. The VACSP approved the design and conduct of this study and reviewed and approved the manuscript before submission. Results Of 17732 persons who were screened for study inclusion, 3196 met the criteria for enrollment. A complete examination of the colon was performed in 3121 eligible persons. Of these, 2885 had 6-sample at-home FOBT results (14). A total of 2665 (92.4%) had both digital FOBT and 6-sample FOBT completed before colonoscopy and are included in this analysis (Figure). The mean age (SE) of the study group was 63.1 0.14 years; 96.8% were men, and 14% reported having a first-degree relative with colorectal cancer. The demographic and pathologic characteristics of the 220 patients who were excluded on the basis of inadequate FOBT data are shown in Table 1. Reasons for incomplete FOBTs were failure to return the home-based cards or inadequate fecal material in the rectum at the time of digital examination. Included and excluded patients were similar except for a younger mean age (mean of 1.4 years younger) in the excluded group. Figure. Patient selection. Table 1. Characteristics of Included and Excluded Patients Of the 2665 patients, 1218 (45.7%) had no polypoid lesions found at colonoscopy. In 438 patients, the most advanced lesion found was a hyperplastic polyp, a nonadenomatous polyp, or a polyp with normal characteristics on biopsy. The FOBT results are shown in Table 2. Among the 1656 patients without adenomas, digital FOBT yielded positive results in 41 (specificity, 97.5% [95% CI, 96.8% to 98.3%]) and at least 1 window of the 6-sample FOBT yielded positive results in 101 (specificity, 93.9% [CI, 92.7% to 95.1%]). In 725 patients, the most advanced lesion was 1 or more tubular adenomas less than 10 mm in diameter. In this group, digital FOBT yielded positive results in 4.0% and the 6-sample test yielded positive results in 6.3%. Table 2. Results of Digital and 6-Sample Fecal Occult Blood Tests The sensitivity, specificity, and likelihood of predicting significant colorectal neoplasia with FOBT are shown in Table 3.

Preliminary report on isolation of mycobacteria from patients with Crohn's disease

Several investigators have recently described the isolation of slow growing mycobacteria from the tissues of patients with Crohns disease (CD). The primary purpose of this study was to culture and identify mycobacteria from the intestines of patients with CD and other intestinal diseases (control tissues). The culture methods were designed to eliminate most rapidgrowing mycobacteria and to enhance the isolation of slow growing mycobacteria. Eighty-two surgically resected intestinal tissue samples were cultured over a four-year period: 27 tissues were from CD patients and 55 from patients with other intestinal diseases. After 4–12 months of culture, five mycobacteria were isolated, but only two have been identified thus far. Both of these organisms appeared to have initially grown as spheroplasts, but revertant bacteria were cultivated after transfer into fresh media. Four of the mycobacteria were from CD tissues, and one isolate was from a control tissue. Two of the isolates have been identified as M. cheloneisubsp. abscessus,strain 390, and M. paratuberculosisstrain 410. This M. paratuberculpsisis similar to the previously identified M. paratuberculosisstrains isolated from other human intestinal tissues from patients with CD. Both strains 390 and 410 were inoculated into neonatal goats, but they failed to reproduce a CD-like disease. The isolation of four mycobacteria from 27 CD tissues and only one from 55 control tissues strengthens the findings of previous investigators and supports the hypothesis that mycobacteria may be etiologically associated with some cases of Crohns disease.

Predictors of Pouchitis after Ileal Pouch-Anal Anastomosis: A Retrospective Review

PurposeThe primary end point of this study was to determine the risk factors that predict chronic pouchitis in those patients having ileal pouch-anal anastomosis.MethodsA total of 237 patients with ulcerative colitis and undergoing ileal pouch-anal anastomosis by one surgeon at Oregon Health & Science University from 1993 to 2003 were evaluated. Data were gathered via retrospective chart reviews and by a questionnaire administered by telephone in 2004. Patients were excluded if there was less than one-year follow-up documented in the chart or they could not be contacted by telephone (n = 62), postoperative diagnosis of Crohn’s disease (n = 3), failed ileoanal procedure (n = 1), and one-stage ileal pouch-anal anastomosis (n = 3), leaving 167 patients for evaluation. Patients were defined as having chronic pouchitis (>3 episodes of pouchitis) or no pouchitis (≤ 3 episodes of pouchitis). Potential risk factors included number of operations used to perform ileal pouch-anal anastomosis, fulminant ulcerative colitis with two-stage operation, duration of diverting ileostomy after pouch formation, primary sclerosing cholangitis, other extraintestinal manifestations of ulcerative colitis, preoperative liver function tests, duration of ulcerative colitis, and the occurrence of postoperative complications. Initial univariate analysis was performed on all risk factors. Multivariate analysis was performed on all univariate risk factors with P values < 0.2.ResultsThe prevalence of chronic pouchitis in our population was 46 percent. The following variables were identified during univariate analysis and entered into a multivariate model: preoperative serum albumin (P = 0.07), PSC (P = 0.126), duration of diverting ileostomy (P = 0.111), fulminant ulcerative colitis with two-stage operation, (P = 0.051), the presence of postoperative complications (P = 0.031), and the type of postoperative complications (anastomotic complications, P = 0.013). Patients who did not undergo diverting ileostomy at the time of their ileal pouch-anal anastomosis trended toward a lower likelihood of developing chronic pouchitis (P = 0.06). Multivariate analysis showed that patients with postoperative complications (53 percent, P = 0.042), specifically anastomotic complications, were more likely to develop chronic pouchitis (P = 0.005). Eight percent of patients had primary sclerosing cholangitis and 11 percent of patients had at least one extraintestinal manifestation of ulcerative colitis. Patients with primary sclerosing cholangitis were not more likely to develop chronic pouchitis (P = 0.168). Patients with extraintestinal manifestations also were not more likely to develop chronic pouchitis (P = 0.273).ConclusionsChronic pouchitis is a frequent complication after ileal pouch-anal anastomosis. In this study patients with primary sclerosing cholangitis or other extraintestinal manifestations of ulcerative colitis were not more likely to develop chronic pouchitis. Patients with postoperative complications, specifically anastomotic complications after ileal pouch-anal anastomosis, were more likely to develop chronic pouchitis and may benefit from early strategies to prevent pouchitis.

c-myc antisense oligonucleotides inhibit the colony-forming capacity of Colo 320 colonic carcinoma cells.

Colo 320 cells are colonic carcinoma cells known to express abundant c-myc mRNA. Based on the response of several hematopoietic cell lines to chemical inducers of differentiation, we reasoned that such agents might have similar inductive activity in Colo 320 cells. Accordingly, we exposed Colo 320 cells to 5 mM sodium butyrate (NaBT) for 7 d. C-myc expression decreased threefold and self-replicative potential decreased (defined as a greater than 60% decrease in colony-forming capacity in soft agar that did not contain inducer). In an effort to demonstrate a direct cause and effect between myc expression and the colony-forming capacity of Colo 320 cells, we exposed these cells to a 15-base antisense c-myc oligonucleotide (complementary to the translation initiation region of exon II). Cells were also exposed to equimolar (20 microM) amounts of sense and missense oligonucleotides. Subsequently, cells were incubated at 10, 20, 30, and 40 microM antisense DNA for 16 h, then washed and plated in oligonucleotide-free agar medium. We demonstrated that: (a) the oligomers were stable in the extracellular medium and in the cell cytoplasm; (b) the uptake of the oligonucleotides was 0.7%; (c) sense and missense oligonucleotides had no effect on colony-forming capacity; and (d) the antisense c-myc oligonucleotide resulted in a 40-75% concentration-dependent decrease in colony-forming capacity. The specific inhibition of colony-forming capacity by antisense DNA suggests that the role of myc expression in Colo 320 cells is similar to its role in hematopoiesis, and that the failure to inhibit myc expression maintains colony-forming capacity. This system provides a new strategy for inducing differentiation and may provide further insight into the genetic factors that govern the process of colonic carcinogenesis.

Assessment and management of low bone density in inflammatory bowel disease and performance of professional society guidelines

Background: Inflammatory bowel disease (IBD) patients have increased prevalence of osteoporosis, leading to guideline recommendations for bone mineral density (BMD) testing. The study aim was to identify predictors of BMD testing and treatment and assess guideline effectiveness to identify IBD patients with osteoporosis. Methods: Records of all IBD patients at seven medical facilities were reviewed for clinical data and BMD testing from January 1996 through October 2006. Results: A total of 2035 patients had 317 bone density tests performed. Osteopenia was found in 48% of patients, osteoporosis in 26%. Among patients meeting guideline criteria for BMD testing and ≥1 year of follow‐up, 23.3% underwent testing. The strongest predictors of testing were menopause (adjusted hazard ratio [AHR] 3.02) and receiving care at a tertiary center (AHR 2.56). Testing rates were low in patients with age ≥60 years, ulcerative colitis, and a history of inpatient IBD treatment. Osteoporotic patients received calcium/vitamin D and bisphosphonates in 59% and 75% of cases, respectively. Osteoporotic males had a 37% rate of hypogonadism. Guideline criteria do not distinguish patients with osteoporosis. The criteria had a sensitivity, specificity, positive predictive value, and negative predictive value of 84%, 23%, 27%, and 81% for osteoporosis in the tested population, respectively. Conclusions: Osteoporosis is highly prevalent in the IBD population, but BMD testing and osteoporosis treatments are underutilized. Male hypogonadism is common in osteoporotic IBD patients. Guidelines do not identify IBD patients with osteoporosis. Inflamm Bowel Dis 2011

Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy

Topical 20% benzocaine (Hurricaine, Beutlich, Inc., Niles, Ill.) spray is frequently used for oral anesthesia before upper endoscopy. Side effects attributed to this agent are exceedingly rare. The author reports one of these rare complications, drug-induced methemoglobinemia, in a patient with methemoglobin reductase deficiency. The mechanisms for the development of methemoglobinemia and its treatment are reviewed.

Maintenance of Efficacy and Continuing Safety of Golimumab for Active Ulcerative Colitis: PURSUIT-SC Maintenance Study Extension Through 1 Year

Objectives:The safety and efficacy of subcutaneous golimumab through 2 years of maintenance therapy was evaluated in patients with moderate-to-severe ulcerative colitis (UC).Methods:Patients completing treatment through week 52 (placebo, golimumab 50, 100, every-4-weeks (q4w)) and evaluations at week 54 were eligible for this long-term extension (LTE) trial. Patients receiving placebo or golimumab 50 mg with worsening disease during the LTE could receive golimumab 100 mg. Efficacy assessments included the Mayo physician’s global assessment (PGA) subscore, inflammatory bowel disease questionnaire (IBDQ), and corticosteroid use. Patients who were randomized to golimumab at PURSUIT-Maintenance baseline and continued receiving golimumab during the LTE were analyzed for efficacy (using intention-to-treat and “as observed” analyses; N=195) and safety (N=200). Patients treated with golimumab at any time from induction baseline through week 104 (N=1240) constituted the overall safety population.Results:Baseline demographics and disease characteristics of patients entering the LTE receiving golimumab were similar to those of all patients randomized to golimumab maintenance at baseline. At week 104, 80.5% (157/195) of patients had a PGA=0/1 (range weeks 56–104: 80.5–91.8%) and 56.4% (110/195) had a PGA=0 (weeks 56–104: range: 53.8–58.5%). Through week 104, 86% of patients maintained inactive or mild disease activity. Among 174 corticosteroid-free patients at week 54, 88.5% remained corticosteroid-free at week 104. At week 104, 62.2% (120/193) had an IBDQ score ≥170. Tuberculosis, opportunistic infection, and malignancy rates were low, and the overall safety profile was similar to that reported through week 54. Two non-melanoma skin cancers, one metastatic colon cancer, and two deaths (biventricular heart dysfunction, sepsis) occurred between weeks 54 and 104.Conclusion:Subcutaneous golimumab q4w through 2 years maintained clinical benefit and reduced corticosteroid use among patients who did well in the maintenance study. No new safety signals were observed.

Ulcerative colitis presenting as purpura fulminans

A 60-year-old man presented with purpura fulminans involving his chest and flank. He was subsequently found to have active ulcerative colitis (UC) and protein S deficiency. He was treated with heparin and plasma, but because of persistent colitis and progressively worsening purpura, a total colectomy was performed on hospital day 17. This report describes an interesting case of purpura fulminans associated with the hypercoagulable state of active UC that responded dramatically to colectomy.