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Biomedical subjects

Gary R Lichtenstein

Publications and source records attributed to Gary R Lichtenstein.

At least 19 recordsLinked to original sources
PubMed2006

Safety of biologics in inflammatory bowel disease.

Various biologic agents have been evaluated in patients with inflammatory bowel disease (eg, Crohn's disease ) and ulcerative colitis (UC). At present, only one, infliximab (humanized monoclonal anti-tumor necrosis factor-alpha antibody), is approved by the US Food and Drug Administration for induction and maintenance treatment in patients with active moderate to severe and/or fistulizing CD who are refractory to conventional therapy. Two recent trials, Active Ulcerative Colitis Trial (ACT) 1 and ACT 2, observed high efficacy of infliximab in inducting and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. A plethora of randomized, double-blind, controlled and open-label, uncontrolled studies on large and small numbers of patients has assessed efficacy and safety of various biologic agents of potential use in treatment of inflammatory bowel disease. With respect to safety of biologic agents used for treatment, the most accurate data are available only in the case of infliximab. This is due to the fact that infliximab was evaluated in many more trials than any other biologic agent. Moreover, postmarketing experience also provides very valuable information about any side effects occurring during treatment with this agent.

Journal Article↗
PubMed2006

The impact of increased body mass index on the clinical course of Crohn's disease.

BACKGROUND & AIMS: Tumor necrosis factor-alpha production in adipose tissue is well documented. Crohn's disease (CD) patients with increased adipose tissue may have more severe disease. This study evaluated overweight patients with CD to determine if their clinical course differs from those with a normal or low body mass index (BMI). METHODS: Patients at the Hospital of the University of Pennsylvania from 1997 to 2002 were included. Data were collected from outpatient records and standardized interviews. Overweight was defined as a BMI of 25 kg/m2 or higher. The primary outcome was time to first surgery. Secondary outcomes included age at diagnosis, number of surgeries, and escalation of therapy. Patients with a BMI of 25 kg/m2 or higher at diagnosis were compared with patients with a BMI of less than 25 kg/m2 using statistical analyses. Survival analysis compared time to first surgery. RESULTS: A total of 148 patients were included. Forty-eight (32.4%) had a BMI of 25 kg/m2 or higher at diagnosis. Patients with a BMI of 25 kg/m2 or higher were older at diagnosis; 35 years vs 22.5 years for patients with a BMI of less than 25 kg/m2 (P = .0001). The number of surgeries, escalation of therapy, and disease distribution did not differ between the 2 groups. A significant difference was found for time to first surgery, 252 months vs 24 months for patients with a BMI of less than 18.5 kg/m2 vs patients with a BMI of 25 kg/m2 or higher, respectively (P = .043). CONCLUSIONS: CD patients with a BMI of 25 kg/m2 or higher at diagnosis were older at diagnosis and had a shorter time to first surgery than those with a BMI of less than 18.5 kg/m2. This suggests that overweight CD patients require earlier surgical intervention and perhaps more aggressive medical therapy.

Adult↗
PubMed2006

Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry.

BACKGROUND & AIMS: Long-term safety data for infliximab and other therapies in Crohn's disease (CD) are needed. METHODS: We prospectively evaluated patients for prespecified safety-related outcomes. RESULTS: As of August 2004, 6290 patients were enrolled; 3179 received infliximab (5519 patient-years), 87% of whom received at least 2 infusions, and 3111 received other therapies (6123 patient-years). The mean length of follow-up evaluation was 1.9 years. More infliximab-treated patients had moderate-to-severe (30.8% vs 10.3%) or severe-fulminant (2.5% vs .6%) CD, and had surgical (17.5% vs 13.8%) or medical (14.4% vs 9.1%) hospitalizations in the previous year. More patients were taking prednisone (27.4% vs 16.1%), immunomodulators (49.4% vs 32.2%), or narcotic analgesics (9.8% vs 5.4%) when compared with those receiving other therapies (P<.001, all comparisons). The mortality rates were similar for infliximab- and non-infliximab-treated patients (.53 per 100 patient-years vs .43; relative risk, 1.24; 95% confidence interval [CI], .73-2.10). In multivariate logistic regression analysis, only prednisone was associated with an increased mortality risk (odds ratio [OR], 2.10; 95% CI, 1.15-3.83; P=.016). Although the unadjusted analysis showed an increased risk for infection with infliximab use, multivariate logistic regression analysis suggested that infliximab was not an independent predictor of serious infections (OR, .99; 95% CI, .64-1.54). Factors independently associated with serious infections included prednisone use (OR, 2.21; 95% CI, 1.46-3.34; P<.001), narcotic analgesic use (OR, 2.38; 95% CI, 1.56-3.63; P<.001), and moderate-to-severe disease activity (OR, 2.11; 95% CI, 1.10-4.05; P=.024). CONCLUSIONS: Mortality rates were similar between infliximab- and non-infliximab-treated patients. The increased risk for serious infection observed with infliximab likely was owing to disease severity and prednisone use.

Adult↗
PubMed2006

Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease.

BACKGROUND: The endoscopic substudy of the ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) Crohn's disease trial examined the effects of infliximab on mucosal inflammation and mucosal healing, and assessed their impact on outcomes. DESIGN: ACCENT I was a randomized, double-blind, parallel group study. SETTING: This study took place at multiple centers in North America, Europe, and Israel. MAIN OUTCOME MEASUREMENTS: Ileocolonoscopic examinations were performed at weeks 0, 10, and 54. Complete mucosal healing was defined as the absence of all mucosal ulcerations. The end point of principal interest was the proportion of patients randomized as responders with mucosal healing at week 10. The proportion of responders who demonstrated mucosal healing at week 54 or at both weeks 10 and 54 is also summarized. Changes in Crohn's disease endoscopic index of severity (CDEIS) scores from baseline to week 10 and 54 were calculated for all patients in this substudy. RESULTS: Complete mucosal healing by week 10 occurred in significantly more week 2 responders who had received 3 doses of infliximab compared with a single dose (31% vs. 0%, p = 0.010). A significantly higher proportion of week 2 responders in the combined scheduled maintenance group had complete mucosal healing at week 54 compared with the episodic group (50% vs. 7%, p = 0.007). The results for all patients are consistent with those for week 2 responders only. Significantly greater improvement in the CDEIS occurred with scheduled maintenance compared with episodic treatment at week 10 (p </= 0.001) and week 54 (p = 0.026). Notably, no strong relationship between clinical remission and complete mucosal healing was found. Overall, mucosal healing appeared to correlate with fewer hospitalizations, although these results were not statistically significant. CONCLUSIONS: Scheduled infliximab maintenance therapy resulted in more improvement in mucosal ulceration and in higher rates of mucosal healing. There was a numerical trend for patients with better mucosal healing to have a lower rate of Crohn's disease-related hospitalizations.

Adult↗
PubMed2006

Chemoprevention: risk reduction with medical therapy of inflammatory bowel disease.

The ideal chemopreventative agent, in addition to being efficacious in the prevention of cancer, must be easily administered, affordable, safe, and well tolerated, with minimal side effects. In the past decade, a growing body of literature has emerged on the prevention of CRC in patients with long-standing CD and UC. The data are not definitive and consist almost exclusively of retrospective case-control and cohort studies rather than the more rigorous prospective RCTs. 5-ASA compounds have been most thoroughly studied, and most of the existing data support the use of 5-ASA in the prevention of CRC. Although the precise dose and duration are unclear, studies suggest that chronic systemic administration of 5-ASA at a dose of at least 1.2 g/d is most likely to be effective. A beneficial effect of folate, albeit not statistically significant, has been consistently shown in every study performed for this purpose. Folate supplementation, which is safe and affordable, should also be recommended for all patients with IBD, especially those taking sulfasalazine. UDCA has been shown to exert a protective effect in most studies on patients with UC and concomitant PSC. Because this patient population is at particularly high risk for CRC, it is advisable to consider UDCA in all patients with colitis complicated by PSC. For patients without PSC, sufficient data do not exist to recommend it for the purpose of cancer prevention. Five of the six corticosteroid studies have found a beneficial effect of systemic steroids, although most did not reach statistical significance. Regardless, given the frequent and serious adverse effects associated with chronic steroid use, systemic corticosteroids should not be prescribed for this indication. Budesonide, an oral corticosteroid with minimal systemic absorption, is a potential alternative, although it has not yet been studied as a chemopreventative agent. Similarly, until the long-term safety of chronic NSAID use can be demonstrated in patients with IBD, the role of NSAIDs in chemoprevention remains undefined. Although the data are conflicting, immune-modulating medications, such as AZA, do not seem to confer any reduction in the risk of dysplasia or CRC. The data on calcium supplementation and statin use are still too limited to endorse their use for the prevention of colitis-related CRC. Chemoprevention is an area that holds great promise in the reduction of morbidity and mortality associated with IBD. Further studies, including prospective trials when possible and cost-effectiveness analyses, need to be performed to develop an optimal strategy for the reduction of cancer risk in patients with IBD.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Infliximab in ulcerative colitis.

Infliximab is effective for treatment of moderate-to-severe UC and is recommended for patients who have had an inadequate response to medical therapy or who are intolerant of or do not desire to take the potential risk of using specific agents including immunomodulators (cyclosporine A, azathioprine, or 6-mercaptopurine), corticosteroids, and, potentially, mesalamine. Future trials are needed to assess the efficacy of infliximab with immunomodulators to see if additional benefit is achieved so that the risk-benefit ratio is positive. Based on the favorable efficacy of infliximab for UC therapy, the ground work has been established for evaluating infliximab and addressing some of the many unanswered questions and also for assessing other anti-TNF agents and streamlining the anti-TNG antibody to improve efficacy, reduce side effects, and ease administration.

Animals↗
PubMed2006

Infliximab in fistulizing Crohn's disease.

The treatment of fistulizing CD has evolved greatly in the last 15 years, largely caused by improvements in medical therapy. Tables 2 and 3 summarize all published controlled and uncontrolled trials of immunomodulator and biologic therapy for the treatment of Crohn's fistulae. The advent of immunomodulators and anti-TNF-alpha agents has transformed the treatment of Crohn's fistulae from almost exclusively surgical to placing a much larger emphasis on medical therapy, either as initial therapy alone, with surgery reserved for refractory cases, or in combination with surgery from the start. For this reason, surgeons and gastroenterologists must work in concert to provide the best care for each patient. Proper fistula management also relies heavily on accurate diagnosis, especially defining the anatomy of the fistula, ascertaining whether abscess formation is present, and determining the location and extent of intestinal inflammation.

Anti-Inflammatory Agents↗
PubMed2006

Drug insight: antagonists of tumor-necrosis factor-alpha in the treatment of inflammatory bowel disease.

In the past decade, advances in the understanding of the pathogenesis of inflammatory bowel disease have permitted the development of agents directed against rational therapeutic targets. In particular, various antagonists of tumor-necrosis factor-alpha have been developed. These include infliximab, adalimumab, certolizumab (CDP870), CDP571, etanercept, and onercept. Clinical trials of these agents have demonstrated varying degrees of clinical efficacy. The use of these agents can be limited by infection, immunogenicity, acute infusion reactions, delayed hypersensitivity reactions, and autoimmune phenomena. This review provides insights into the use of antagonists of tumor-necrosis factor-alpha for the treatment of inflammatory bowel disease.

Adalimumab↗
PubMed2006

Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis.

BACKGROUND & AIMS: 6-Thioguanine nucleotide (6-TGN) levels have been proposed to correlate with inflammatory bowel disease (IBD) activity among patients treated with azathioprine or 6-mercaptopurine (6-MP). Previous studies, most with small sample sizes, yielded conflicting conclusions. Our aim was to pool the available data to provide a more precise estimate of the association between 6-TGN levels and IBD activity. METHODS: We searched Medline and PubMed (from 1966 to November 2004) and reviewed the reference lists of selected articles. Fixed and random-effects models were used to test whether mean/median 6-TGN levels differed among patients with active disease vs remission and whether 6-TGN levels above a threshold of 230-260 pmol/8 x 10(8) red blood cells were associated with clinical remission. When studies reported multiple 6-TGN threshold values, we used the data for the lower value. RESULTS: We identified 55 articles, 12 of which contained data sufficient for inclusion. The mean/median 6-TGN levels were higher among patients in remission than in those with active IBD (pooled difference, 66 pmol/8 x 10(8) red blood cells; 95% confidence interval, 18-113; P = .006), but with significant heterogeneity. Excluding the 1 outlier study eliminated this heterogeneity. Patients with 6-TGN levels above the threshold value were more likely to be in remission (62%) than those below the threshold value (36%) (pooled odds ratio, 3.3; 95% confidence interval, 1.7-6.3; P < .001), but with significant heterogeneity. Again, excluding the 1 outlier study eliminated this heterogeneity. CONCLUSIONS: Although prior studies yielded inconsistent conclusions, this analysis strongly supports that higher 6-TGN levels are associated with clinical remission.

Guanine Nucleotides↗
PubMed2006

Quality of life after proctocolectomy with ileoanal anastomosis for patients with ulcerative colitis.

Ulcerative colitis, a chronic inflammatory disease of the rectal and colonic mucosa, affects approximately 250,000 to 500,000 people in the United States, with 30% to 40% of patients requiring some form of surgical intervention during the course of their disease. The predominant reason for total proctocolectomy is for symptoms refractory to currently available medical therapy. Less common reasons are dysplasia or cancer. The goal of colectomy is to prevent recurrence of systemic inflammatory disease. Consequently, surgery with total proctocolectomy and creation of an ileal J-pouch-anal anastomosis has become the procedure of choice for many patients without other therapeutic options. Health-related quality of life (QOL) in patients with severe ulcerative colitis is so poor that, after ileal J-pouch-anal anastomosis, QOL is considered to improve in most clinical studies (8 studies, improved QOL; 1 study, no change; 1 study, QOL worse than general population). However, QOL and bowel function after such surgery cannot be considered "normal" in all patients, because a substantial number still have problems with urgency, leakage, nocturnal soiling, sexual dysfunction, and pouchitis, and some require conversion to a permanent ileostomy after ileal J-pouch-anal anastomosis failure. Thus, despite the availability of ileal J-pouch-anal anastomosis, surgery does not always restore all aspects of QOL to normal.

Anal Canal↗
PubMed2006

Prevention and treatment of osteoporosis in inflammatory bowel disease.

The following are guidelines for evaluation and consideration for treatment of patients with inflammatory bone disease (IBD) after bone mineral density (BMD) measurements. The Crohn's & Colitis Foundation of America (CCFA) has indicated that its recommendations are intended to serve as reference points for clinical decision-making, not as rigid standards, limits, or rules. They should not be interpreted as quality standards.

Absorptiometry, Photon↗
PubMed2006

Complications of biological therapy for inflammatory bowel diseases.

PURPOSE OF REVIEW: The purpose of this review is to analyze the complications associated with treatment of inflammatory bowel disease with biologic agents. RECENT FINDINGS: There have been various biologic agents evaluated in patients with inflammatory bowel disease; that is, Crohn's disease and ulcerative colitis. Thus far only infliximab has been approved by the US Food and Drug Administration as induction and maintenance treatment in patients with active Crohn's disease (moderate-to-severe and/or fistulizing) who are refractory to conventional therapy. Recent data from two large multicenter, multicountry, randomized controlled clinical trials have demonstrated that infliximab is efficacious also for the treatment of ulcerative colitis. Other biologics considered potentially efficacious are still undergoing evaluation in various clinical trials. SUMMARY: The data concerning biologics' associated toxicity in patients with inflammatory bowel disease are the most robust in the case of infliximab. These data are derived from both prospective, randomized clinical trials and from post-marketing experience. In the case of the remaining agents the data concerning safety in inflammatory bowel disease are limited, as these agents were not evaluated in as many trials as infliximab; indeed, some of them included only several patients.

Biological Therapy↗
PubMed2006

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 Crohn's 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 Crohn's Therapy, Resource, Evaluation, and Assessment Tool) Registry and ACCENT I (A Crohn's 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.

Adolescent↗
PubMed2006

The effect of anti-TNF-alpha therapy on spinal bone mineral density in patients with Crohn's disease.

Proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) might be, at least partially, responsible for the development of osteopenia or osteoporosis in Crohn's disease. We investigated whether anti-TNF therapy for Crohn's disease could have any skeletal impact. Therefore, we studied the effects of infliximab, a monoclonal antibody against TNF-alpha with and without bisphosphonates, on spinal bone mineral density (BMD). The effect of corticosteroids was also analyzed. A retrospective cohort analysis was performed on 61 patients with Crohn's disease and low BMD by serial DXA scans. Twenty-three patients were on infliximab and 36 patients were on bisphosphonates. Mean duration between DXA scans was 2.2 +/- 0.99 years. After controlling for corticosteroid use, patients with concurrent infliximab and bisphosphonate treatment exhibited a greater increase in BMD compared to those on bisphosphonates alone (+6.7%/year vs. +4.46%/year, P= 0.045); corticosteroids inhibited this effect (P= 0.025). However, infliximab alone had no effects on BMD. Patients receiving bisphosphonates showed a significant increase in lumbar spine BMD compared to those not on bisphosphonates (+3.97% change in T score/year vs. -3.68%/year, P < 0.0001). Concurrent corticosteroid use significantly inhibited this effect (+2.15%/year vs. +4.97%/year, P= 0.0014). Concurrent infliximab use may confer an additional benefit to that already documented for bisphosphonate use alone; bisphosphonates are beneficial in the treatment of low BMD in patients with Crohn's disease, though corticosteroids may partially inhibit this effect.

Antibodies, Monoclonal↗
PubMed2005

Infliximab for induction and maintenance therapy for ulcerative colitis.

BACKGROUND: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. METHODS: Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. RESULTS: In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). CONCLUSIONS: Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.)

Adult↗