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Biomedical subjects

S B Hanauer

Publications and source records attributed to S B Hanauer.

At least 55 records · Page 3Linked to original sources
PubMed2000

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease.

OBJECTIVE: Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients. METHODS: Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of > or = 1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk's criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose. RESULTS: In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500-5410 mg), given for a mean of 131.7 wk (range, 66-281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk's grade I and II), and one patient had hepatic fibrosis (Roenigk's grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk's grade IIIB hepatotoxicity. CONCLUSIONS: Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients.

Adult↗
PubMed2000

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 Crohn's disease. METHODS: All Crohn's 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) Crohn's 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.

Adult↗
PubMed2000

Comparative tolerability of treatments for inflammatory bowel disease.

Despite limited understanding of therapeutic aetiopathogenesis of ulcerative colitis and Crohn's disease, there is a strong evidence base for the efficacy of pharmacological and biological therapies. It is equally important to recognise toxicity of the medical armamentarium for inflammatory bowel disease (IBD). Sulfasalazine consists of sulfapyridine linked to 5-aminosalicylic acid (5-ASA) via an azo bond. Common adverse effects related to sulfapyridine 'intolerance' include headache, nausea, anorexia, and malaise. Other allergic or toxic adverse effects include fever, rash, haemolytic anaemia, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible sperm abnormalities. The newer 5-ASA agents were developed to deliver the active ingredient of sulfasalazine while minimising adverse effects. Adverse effects are infrequent but may include nausea, dyspepsia and headache. Olsalazine may cause a secretory diarrhoea. Uncommon hypersensitivity reactions, including worsening of colitis, pancreatitis, pericarditis and nephritis, have also been reported. Corticosteroids are commonly prescribed for treatment of moderate to severe IBD. Despite short term efficacy, corticosteroids have numerous adverse effects that preclude their long term use. Adverse effects include acne, fluid retention, fat redistribution, hypertension, hyperglycaemia, psycho-neurological disturbances, cataracts, adrenal suppression, growth failure in children, and osteonecrosis. Newer corticosteroid preparations offer potential for targeted therapy and less corticosteroid-related adverse effects. Azathioprine and mercaptopurine are associated with pancreatitis in 3 to 15% of patients that resolves upon drug cessation. Bone marrow suppression is dose related and may be delayed. The adverse effects of methotrexate include nausea, leucopenia and, rarely, hypersensitivity pneumonia or hepatic fibrosis. Common adverse effects of cyclosporin include nephrotoxicity, hypertension, headache, gingival hyperplasia, hyperkalaemia, paresthesias, and tremors. These adverse effects usually abate with dose reduction or cessation of therapy. Seizures and opportunistic infections have also been reported. Antibacterials are commonly employed as primary therapy for Crohn's disease. Common adverse effects of metronidazole include nausea and a metallic taste. Peripheral neuropathy can occur with prolonged administration. Ciprofloxacin and other antibacterials may be beneficial in those intolerant to metronidazole. Newer immunosuppressive agents previously reserved for transplant recipients are under investigation for IBD. Tacrolimus has an adverse effect profile similar to cyclosporin, and may cause renal insufficiency. Mycophenolate mofetil, a purine synthesis inhibitor, has primarily gastrointestinal adverse effects. Biological agents targeting specific sites in the immunoinflammatory cascade are now available to treat IBD. Infliximab, a chimeric antibody targeting tumour necrosis factor-or has been well tolerated in clinical trials and early postmarketing experience. Additional trials are needed to assess long term adverse effects.

Adrenal Cortex Hormones↗
PubMed1999

Updating the approach to Crohn's disease.

Recognizing clinical and pathologic scenarios, rather than ordering definitive tests, is still the basis for diagnosis of Crohn's disease. Steroids, salicylates, immunomodulating agents, and surgery remain the focus of treatment. The advent of infliximab, however, offers a new therapeutic option for patients with refractory disease.

Adult↗
PubMed1999

Infliximab for the treatment of fistulas in patients with Crohn's disease.

BACKGROUND: Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. METHODS: The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas. RESULTS: Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue. CONCLUSIONS: Infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.

Adult↗
PubMed1999

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 Crohn's disease. METHODS: Twenty-two patients with refractory Crohn's disease (Crohn's 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 Crohn's disease.

Adult↗
PubMed1999

Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.

BACKGROUND & AIMS: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit. METHODS: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied. RESULTS: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation. CONCLUSIONS: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.

Adolescent↗
PubMed1999

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Administration, Oral↗
PubMed1999

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease.

BACKGROUND & AIMS: Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity. METHODS: A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. RESULTS: Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. CONCLUSIONS: Short-term treatment with rhIL-11 is well tolerated in patients with active Crohn's disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohn's disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Adult↗
PubMed1999

Medical therapy for inflammatory bowel disease.

CD and UC represent a spectrum of chronic IBD that present in protean ways and are accompanied by a variety of systemic sequelae. Sulfasalazine and the newer 5-aminosalicylates are important in the management of mild-to-moderate disease, whereas corticosteroids remain the primary therapy for most patients with moderate-to-severe disease (Tables 2-5). The toxicities associated with long-term steroid therapy, combined with their ineffectiveness as maintenance medications, have led to increased use of immunomodulators, such as azathioprine and 6-MP, for the treatment of steroid-dependent and steroid-resistant IBD. Infliximab is a novel therapeutic adjunct for chronically active and fistulizing CD that will herald a new era of biologic therapy for IBD. Meanwhile, CSA remains an alternative to urgent colectomy in severe UC unresponsive to corticosteroids and also for CD patients with severe disease or refractory fistulas. Finally, continued insights into the etiopathogenic pathways in IBD will provide evolving and innovative approaches until the eventual causes and cures are elucidated. In the meantime, clinicians should remain optimistic regarding current ability to reduce the morbidity and maintain the quality of life for patients suffering with these frustrating diseases.

Acute Disease↗
PubMed1999

Review article: safety of infliximab in clinical trials.

Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha, contains murine protein elements and targets the immune system, raising concerns about the potential for immune sensitization and immunosuppressive sequelae. However, long-standing inflammatory disease with high activity and chronic immunosuppressant therapy can also predispose patients to immunosuppressive sequelae. Patients with Crohn's disease, rheumatoid arthritis and other indications received single or multiple doses of infliximab and their condition was followed for up to 3 years. Adverse events, most frequently headache, nausea, and upper respiratory tract infection, were generally mild and occurred in 76% of infliximab-treated patients vs. 57% of placebo-treated recipients. Human antichimeric antibodies developed in 13% of patients, increasing the potential for subsequent infusion reactions. Antibodies to double-stranded DNA developed in a small percentage of patients. Other antinuclear antibodies characteristic of serum lupus erythematosus were not found; no patient developed a true lupus syndrome and no other autoimmune disorders were reported. Infliximab is not associated with typical immunosuppressive sequelae, such as infections and malignancy, or with autoimmune disorders. Infliximab therapy was well tolerated, serious adverse events were infrequent, successfully managed with medication and without sequelae, and overall mortality was within the expected incidence for this patient population.

Adult↗
PubMed1999

Medical therapy for Crohn's disease.

The past year's literature pertaining to the medical treatment of Crohn's disease was highlighted by the US Food and Drug Administration's approval of infliximab. Other developments of interest include more evolutionary (in contrast to revolutionary) clinical data regarding aminosalicylates, antibiotics, and steroids as inductive agents and use of immunomodulatory agents as maintenance therapies. Comparative trials continue to demonstrate that steroids, including budesonide, have a greater acute benefit than aminosalicylates, but this benefit does not translate into long-term efficacy. Azathioprine and 6-mercaptopurine are the standard maintenance therapies for steroid-dependent Crohn's disease, and long-term safety data continue to accumulate regarding these agents in adults and children. Several novel approaches have been reported in preliminary fashion that will require much more extensive clinical experience and controlled-trial evidence.

Journal Article↗
PubMed1999

A comparison of the quality of life in patients with severe ulcerative colitis after total colectomy versus medical treatment with intravenous cyclosporin.

Cyclosporin (CSA) has emerged as a medical alternative to colectomy in severe, steroid-refractory ulcerative colitis (UC) patients. This is the first formal quality-of-life study comparing such patients treated with intravenously administered cyclosporin with those treated surgically with colectomy. Quality-of-life analyses were conducted in all patients who underwent colectomy or received intravenous CSA for severe UC from 1991 to 1995 using the Inflammatory Bowel Disease Questionnaire, a visual-analog scale (VAS), and the Oresland scale, with additional questions regarding health care utilization and medication use. The 18 CSA-treated patients reported a better ability to sleep (p = 0.002; VAS), better stool consistency (p < 0.001; VAS), less abdominal or rectal pain (p = 0.009, VAS), and fewer daytime (p < 0.001; Oresland), nighttime (p = 0.006; Oresland), and daily trips to the toilet (p < 0.001; VAS) than the 46 surgical patients. The mean number and rate of hospitalizations within the first year was also lower in the CSA patients (p < 0.001 for both). The surgical patients reported fewer initial visits to their specialist (p < 0.001) and less medication use (p < 0.001; Oresland). Patients with severe steroid-refractory UC treated with intravenously administered CSA scored as well as or better than their surgical counterparts. The use of CSA in selected patients is substantiated both by clinical results and quality-of-life analysis.

Adult↗
PubMed1999

Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety.

Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFalpha activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient to justify recent U.S. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis (RA). Similarly, preliminary controlled trials have suggested efficacy for CDP571 in active CD and RA. Larger controlled trials have demonstrated efficacy for etanercept in RA patients who have failed disease modifying antirheumatic drug (DMARD) therapy leading to FDA approval for RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin's lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti-TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Intravenous cyclosporin in ulcerative colitis: a five-year experience.

OBJECTIVE: Cyclosporin (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 Chicago's 5-yr CSA experience in these patients. METHODS: All steroid-refractory severe ulcerative colitis (UC) patients treated with IV CSA from 1991 to 1995 were identified by using the university's IBD database, with additional information from patient charts and physician files. RESULTS: A 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. CONCLUSIONS: CSA 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.

Adolescent↗
PubMed1998

Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1.

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 x 10(-5)), and at chromosome 1p (MLod = 2.65, P = 2.4 x 10(-4)) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 x 10(-4)), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly among Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC.

Chromosome Mapping↗