David A. Schwartz

Adalimumab for the treatment of fistulas in patients with Crohn’s disease

Objective: To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn’s disease (CD). Design: A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites. Patients: A subgroup of adults with moderate to severely active CD (CD activity index 220–450) for ⩾4 months who had draining fistulas at baseline. Interventions: All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension. Main Outcome Measures: Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression. Results: Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis). Conclusions: In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial. ClinicalTrials.gov Identifier: NCT00077779 and NCT00195715.

Peer group victimization as a predictor of children's behavior problems at home and in school

This study reports a short-term prospective investigation of the role of peer group victimization in the development of childrens behavior problems, at home and in school. Sociometric interviews were utilized to assess aggression, victimization by peers, and peer rejection, for 330 children who were in either the third or fourth grade (approximate mean ages of 8-9 years old). Behavior problems were assessed using standardized behavior checklists completed by mothers and teachers. A follow-up assessment of behavior problems was completed 2 years later, when the children were in either the fifth or sixth grade (approximate mean ages of 10-11 years old). Victimization was both concurrently and prospectively associated with externalizing, attention dysregulation, and immature/dependent behavior. Victimization also predicted increases in these difficulties over time, and incremented the prediction in later behavior problems associated with peer rejection and aggression. The results of this investigation demonstrate that victimization in the peer group is an important predictor of later behavioral maladjustment.

Use of Endoscopic Ultrasound to Guide Combination Medical and Surgical Therapy for Patients with Crohn's Perianal Fistulas

Background: This study was performed to assess if using endoscopic ultrasound (EUS) to assess and guide combination medical and surgical therapy during fistula healing will lead to a high rate of durable fistula closure and a low or absent incidence of perianal abscess formation in patients with Crohns perianal fistulas. Methods: This is a retrospective analysis of 21 patients who presented with a symptomatic Crohns perianal fistula. Patients were enrolled in a clinical practice protocol of serial EUS exams. All patients underwent a baseline rectal EUS and were placed on maximal medical treatment with 6‐mercaptopurine (6‐MP) or azathioprine, Cipro, and infliximab (5 mg/kg at 0, 2, and 6 wk and then every 8 wk). Patients were also assessed at baseline by a colorectal surgeon who was aware of the EUS findings. Seton placement and incision and drainage were performed when appropriate. Serial EUS examinations were performed, and the findings were used to guide therapy (i.e., the presence of fistula healing on EUS was used to guide seton removal, discontinuation of infliximab, and Cipro). Results: In the 21 patients enrolled, the median duration of active perianal symptoms was 9 wks (1‐36). 10 patients (48%) had previous perianal surgery and 5 (24%) had received infliximab previously. The fistulas treated included 8 trans‐sphincteric, 2 superficial, 3 recto‐vaginal, and 7 with multiple and horseshoe fistulas. 13 patients (62%) had associated abscesses at presentation. Eighteen of 21 patients (86%) had complete cessation of drainage initially. Median time to cessation of drainage was 10.6 weeks (range, 4‐32 wk). Sixteen of 21 patients (76%) maintained long‐term cessation of drainage. The median length of follow‐up was 68 weeks (range, 35‐101 wk). No abscess developed during treatment in any patient. EUS evidence of persistent fistula activity was seen in 10 patients (48%). Of the 11 patients (52%) in whom EUS showed no persistent fistula activity, 7 (64%) have maintained fistula closure off of infliximab and Cipro. Median duration from last infliximab infusion was 47 weeks (range, 20‐80 wk). The remaining 4 patients continued infliximab to maintain remission of their luminal disease. Only 1 patient with a horseshoe fistula showed complete healing on EUS. Conclusion: In conclusion, using EUS to guide therapy for Crohns perianal fistulas with infliximab, an immunosuppressive, and an antibiotic is associated with a high short and long‐term fistula response rate. EUS may identify a subset of patients who can discontinue infliximab without recurrence of fistula drainage.

The Successful Use of Adalimumab to Treat Active Crohn's Disease of an Ileoanal Pouch During Pregnancy

The use of immunosuppressive medications during pregnancy in patients with Crohn’s disease is controversial. However, most clinicians would agree that both the unborn baby and the mother will do better if the mother’s inflammatory bowel disease (IBD) can be controlled. Studies have shown that patients with active Crohn’s disease are more likely to experience preterm labor and have babies that are small for gestational age [1]. Currently, the most potent agent approved for Crohn’s disease is infliximab. This is a chimeric anti– tumor necrosis factor-alpha (TNF-α) antibody. Recently, adalimumab (Humira), a fully humanized anti–TNF-α antibody, was approved for the treatment of rheumatoid arthritis (RA) [2–5]. Preliminary studies have demonstrated efficacy in patients with Crohn’s disease, including those who have had a reaction to or lost their response to infliximab because of the development of antibodies to the murine component of this agent [6, 7]. The safety of adalimumab in pregnancy is unknown. There has only been 1 previous report of the use of adalimumab during pregnancy [8]. Herein, we report the first use of adalimumab during pregnancy to treat severe Crohn’s disease of the ileoanal pouch.

A Randomized Prospective Trial of Endoscopic Ultrasound to Guide Combination Medical and Surgical Treatment for Crohn's Perianal Fistulas

AIMS:To prospectively determine if rectal endoscopic ultrasound (EUS) can guide combination medical and surgical therapy and improve outcomes for patients with perianal fistulizing Crohns disease.METHODS:Ten patients with perianal Crohns disease were prospectively enrolled in a randomized prospective pilot study. The patients were randomized to either the EUS cohort or the control group. All patients underwent a rectal EUS to delineate fistula anatomy followed by an examination under anesthesia by a colorectal surgeon with seton placement and/or incision and drainage, as indicated. The surgeon was blinded to the initial EUS results of patients in the control group. Medical treatment was maximized with 6-mercaptopurine (1.0–1.5 mg/kg) or azathioprine (2.0–2.5 mg/kg), ciprofloxacin (1,000 mg a day) or metronidazole (1,500 mg a day), and infliximab (5 mg/kg at 0, 2, and 6 wk and then every 8 wk). For patients in the control group, additional interventions (seton removal and repeat surgery) were at the discretion of the surgeon (without EUS guidance). Patients in the EUS cohort had EUS performed at weeks 22 and 38, with additional surgical interventions based on EUS findings. The primary end point was complete cessation of drainage at week 54. All patients had a repeat EUS performed at week 54 to determine the fistula status on EUS (secondary end point). The need for additional surgery was defined as a treatment failure.RESULTS:Ten patients were enrolled in the study. One of 5 (20%) in the control group and 4 of 5 (80%) in the EUS group had complete cessation of drainage. From the control group, 3 patients failed due to repeat surgery (2 for persistent/recurrent fistula and 1 for abscess), and 1 had a persistent drainage at week 54. In the EUS cohort, 1 patient had a recurrent abscess after his seton fell out prematurely.In the EUS cohort, the median time to cessation of drainage was 99 days, and the time to EUS evidence of fistula inactivity was 229 days.CONCLUSION:This pilot study suggests that using EUS to guide combination medical and surgical therapy for perianal fistulizing Crohns disease improves the outcomes.

Carcinoid tumors are 15 times more common in patients with Crohn's disease.

Background: The coexistence of intestinal neoplasms with Crohns disease (CD) has been reported, but the evidence of an increased risk of carcinoid tumor with Crohns disease has been mixed. We present 4 patients with CD with associated carcinoid tumor. Methods: The charts of 111 patients with CD who had undergone resection between June 2001 and March 2005 were reviewed. The number of incidental carcinoid tumors in patients who underwent an appendectomy was used as a control. Results: Four cases of carcinoid tumor discovered in patients at resection for CD were identified. None had metastatic disease or carcinoid syndrome. These included 1 cecal (1 mm), 2 appendiceal (3 and 7mm), and 1 transverse colon (7 mm) carcinoid tumors. None of the carcinoid tumors were identified in regions of active Crohns disease. The incidence of carcinoid tumor in patients with Crohns disease was 4 of 111 (3.6%). In comparison, 3 of 1199 patients (0.25%) who had appendectomies were identified as having appendiceal carcinoid tumor. Crohns disease was associated with an increased incidence of carcinoid tumor; OR 14.9 (95% CI 2.5–102.5), P < 0.0001. Conclusions: There was a significantly increased incidence of carcinoid tumor in our Crohns patients compared to the control patients. None of the carcinoid tumors developed in areas of Crohns disease. This suggests that the development of carcinoid tumors may be secondary to distant proinflammatory mediators, rather than a local inflammatory effect from adjacent Crohns disease. Patients with CD may be at increased risk of developing a carcinoid tumor.

The medical treatment of Crohn's perianal fistulas

Perianal fistulas are a frequent manifestation of Crohns disease. The correct application of the newer diagnostic and therapeutic agents for treating perianal Crohns disease are beginning to be better defined. In general, a combined medical and surgical approach is preferred. The perianal disease process should first be fully delineated with endoscopy and either MRI or EUS before treatment is begun. Patients are then stratified into one of three groups: simple fistulas and no proctitis; simple fistulas and concomitant proctitis; and complex fistulas. Patients with simple fistulas and no proctitis can be treated medically with a combination of antibiotics and an immunosuppressive agent (azathioprine or mercaptopurine). Patients with simple fistulas and concomitant proctitis should have infliximab added to their treatment plan. Complex fistulas require surgical intervention first prior to medical treatment. A combination of antibiotics, immunosuppressive therapy and infliximab are then initiated to facilitate fistula healing.

Proteomic profiling of mucosal and submucosal colonic tissues yields protein signatures that differentiate the inflammatory colitides

Background: Differentiating ulcerative colitis (UC) from Crohns colitis (CC) can be difficult and may lead to inaccurate diagnoses in up to 30% of inflammatory bowel disease (IBD) patients. Much of the diagnostic uncertainty arises from the overlap of clinical and histologic features. Matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) permits a histology‐directed cellular protein analysis of tissues. As a pilot study, we evaluated the ability of histology‐directed MALDI‐MS to determine the proteomic patterns for potential differences between CC and UC specimens. Methods: Mucosal and submucosal layers of CC and UC colon resection samples were analyzed after histologic assessment. To determine whether MALDI‐MS would distinguish inflammation, the uninflamed (n = 21) versus inflamed submucosa (n = 22) were compared in UC and the uninflamed (n = 17) versus inflamed submucosa (n = 20) in CC. To determine whether there were proteomic differences between the colitides, the uninflamed UC submucosa (n = 21) was compared versus the uninflamed CC submucosa (n = 17), the inflamed UC submucosa (n = 22) was compared versus the inflamed CC submucosa (n = 20), and inflamed UC mucosa versus inflamed CC mucosa. Pairwise statistics comparisons of the subsets were performed. Results: Pairwise comparative analyses of the clinical groups allowed identifying subsets of features important for classification. Comparison of inflamed versus uninflamed CC submucosa showed two significant peaks: m/z 6445 (P = 0.0003) and 12692 (P = 0.003). In the case of inflamed versus uninflamed UC submucosa, several significant differentiating peaks were found, but classification was worse. Comparisons of the proteomic spectra of inflamed submucosa between UC and CC identified two discrete significant peaks: m/z 8773 (P = 0.006) and 9245 (P = 0.0009). Comparisons of the proteomic spectra of uninflamed submucosa between UC and CC identified three discrete significant peaks: m/z 2778 (P = 0.005), 9232 (P = 0.005), and 9519 (P = 0.005). No significantly different features were found between UC and CC inflamed mucosa. Conclusions: MALDI‐MS was able to distinguish CC and UC specimens while profiling the colonic submucosa. Further analyses and protein identification of the differential protein peaks may aid in accurately diagnosing IBD and developing appropriate personalized therapies. (Inflamm Bowel Dis 2011;)

Long‐term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7‐year results from the PRECiSE 3 study

The efficacy and safety of certolizumab pegol (CZP) in moderate‐to‐severe Crohns disease were demonstrated in two 26‐week double‐blind studies (PRECiSE 1 & 2).

Prospective evaluation of biopsy number for the diagnosis of viral esophagitis in patients with HIV infection and esophageal ulcer

BACKGROUND Establishing a diagnosis of viral esophagitis in patients with human immunodeficiency virus (HIV) infection has important clinical relevance. However, the number of biopsies required to diagnose viral esophagitis is currently unknown. METHODS Over a 34-month period, all HIV-infected patients with esophageal ulcer underwent 10 biopsies of the largest and/or most accessible lesion, primarily from the ulcer base. The first 3 specimens were placed in one formalin container, the second 3 in another, and 4 additional specimens in the third. Standard histopathologic methods were employed, as well as in situ hybridization or immunohistochemical studies in most patients, and viral cytopathic effect was defined using previously proposed criteria. Patients were then treated on the basis of the results of the initial biopsy specimens with both clinical and endoscopic follow-up. RESULTS One hundred HIV-infected patients with esophageal ulcer were studied. Cytomegalovirus (CMV) was considered etiologic in 50 patients. Of these 50 patients, the first three biopsy specimens were sufficient to diagnosis CMV in 40 (80%). In 5 patients (10%), the first two sets were negative with only the third set of biopsies positive. Similarly, of the 4 patients with simultaneous CMV and herpes simplex virus (HSV) esophagitis, three sets of biopsy specimens were required for diagnosis of both agents in 3 patients. HSV esophagitis alone was found in 2 patients; diagnostic viral inclusions were present in the first 3 biopsies in each patient. Thirty-five patients had HIV-associated idiopathic esophageal ulcer; only one of these patients was misdiagnosed. CONCLUSIONS At least 10 biopsies may be required to exclude viral esophagitis in HIV-infected patients. If biopsy specimens are adequate and no evidence of viral cytopathic effect has been found, the patient may be treated on the basis of the results of the initial clinical, endoscopic, and pathologic findings with close clinical follow-up rather than repeat endoscopy.