Conventional treatment in inflammatory bowel disease--recent trends. Immunosuppressants and biologic agents: should they or need they be used together? How to use immunosuppressive therapy better (and safer) tomorrow?

Although the use of concomitant immunosuppressants (IS) with biologics has been demonstrated to reduce the immunogenicity of chimeric (infliximab), humanized (natalizumab), human (adalimumab) antibodies and antibody fragments (certolizumab pegol), to date concomitant IS with biologics has not impacted on the short or intermediate responses in the treatment of Crohn's disease in most induction and maintenance trials. The optimal strategy to reduce antibodies to infliximab is to use an induction and maintenance strategy rather than episodic therapy. Any potential benefit of concomitant IS use with biologic agents needs to be balanced against the risk of combination therapy including serious infections and the risk of neoplasia. The discovery of genetic polymorphism for production of thiopurine methyltransferase (TPMT), a key enzyme in the metabolism of thiopurine antimetabolites, has made it possible to rationalize therapy in terms of patient and dosage selection. TPMT screening prior to initiation of thiopurine antimetabolites is currently recommended to avoid treating patients with low or absent TPMT activity with potentially toxic doses of thiopurines. Routine monitoring of blood counts and liver enzymes is recommended even in individuals with normal TPMT activity. The ability to monitor thiopurine metabolites may make it possible to optimize therapeutic response by guiding clinicians on dose escalation.

Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study).

BACKGROUND: Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. AIMS: To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. DESIGN: In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x108 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. RESULTS: Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). CONCLUSIONS: Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.

Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis.

BACKGROUND: Adalimumab is used to treat moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) when conventional therapies fail. AIM: To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years (PYs). METHODS: Treatment-emergent adverse events (AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (MedDRA-v18.1). Rates were assessed as events/100 (E/100 PYs). RESULTS: The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs (CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs (CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies (CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent MedDRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population (CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon (CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). CONCLUSIONS: Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals.

Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy.

BACKGROUND: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported. METHODS: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding. RESULTS: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. CONCLUSIONS: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial.

BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease. PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline. RESULTS: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated. CONCLUSIONS: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day.

Review article: high-dose aminosalicylates to induce and maintain remissions in ulcerative colitis.

Sulfasalazine was the first aminosalicylate to be used for induction and maintenance therapy of ulcerative colitis (UC). Initial trials demonstrated a dose response that was compromised by dose-related intolerance. Recognition that the 5-aminosalicylic acid moiety (5-ASA, mesalazine) is the active ingredient of sulfasalazine has allowed the development of sulpha-free formulations of mesalazine and alternative azo-bond derivatives (olsalazine, balsalazide) that substantially reduce the dose-related (and allergic) consequences of the sulfapyridine moiety of sulfasalazine. Dose-ranging studies of mesalazine formulations for induction of remission have demonstrated increased efficacy of oral mesalazine up to 4-4.8 g/day, particularly in patients with more moderate disease activity. Combination therapy with oral and rectal mesalazine provide additional efficacy for patients with both distal and extensive colitis. The mesalazine formulations have dose-related benefits without dose-related side effects. In contrast, the azo-bond formulations are compromised by secretory diarrhoea at doses providing greater than 2-2.4 g/day of mesalazine. There are less data regarding dose-related benefits of aminosalicylates to maintain remissions in UC greater than 1.6 g/day of mesalazine, although the absence of dose-related side effects allows continuation of the same inductive dose through maintenance treatment without dose-related toxicity.

Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine.

BACKGROUND: Many non-responders to azathioprine or mercaptopurine (6-mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce 6-methylmercaptopurine instead of the active 6-tioguanine (6-tioguanine) metabolites. AIM: To describe the use of allopurinol in mercaptopurine/azathioprine non-responders to deliberately shunt metabolism of mercaptopurine towards 6-tioguanine. METHODS: Fifteen thiopurine non-responders whose metabolites demonstrated preferential metabolism towards 6-methylmercaptopurine are described. Subjects were commenced on allopurinol 100 mg po daily and mercaptopurine/azathioprine was reduced to 25-50% of the original dose. Patients were followed clinically and with serial 6-tioguanine and 6-methylmercaptopurine metabolite measurements. RESULTS: After initiating allopurinol, 6-tioguanine levels increased from a mean of 185.73 +/- 17.7 to 385.4 +/- 41.5 pmol/8 x 10(8) red blood cells (P < 0.001), while 6-methylmercaptopurine decreased from a mean of 10 380 +/- 1245 to 1732 +/- 502 pmol/8 x 10(8) RBCs (P < 0.001). Allopurinol led to a decrease in white blood cell from a mean of 8.28 +/- 0.95 to 6.1 +/- 0.82 x 10(8)/L (P = 0.01). CONCLUSIONS: The addition of allopurinol to thiopurine non-responders with preferential shunting to 6-methylmercaptopurine metabolites appears to be an effective means to shift metabolism towards 6-tioguanine.

A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease.

AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.

Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. The U.S. PENTASA Enema Study Group.

The safety and efficacy of mesalamine enemas were determined ina dose-ranging study enrolling 287 patients with ulcerative proctitis and proctosigmoiditis in a double-blind, placebo-controlled, multicenter trial. Patients were randomized to receive placebo, 1, 2, or 4 g in 100 ml mesalamine (PENTASA) enemas h.s. for 8 weeks. Efficacy was assessed by clinical, sigmoidoscopic, and histologic improvement, as well as by induction of remission. Sixty-seven percent, 65%, and 75% of patients receiving 1-, 2-, and 4-g enemas were markedly improved according to the physician's global assessment compared with 27% of patients treated with placebo. The mean improvement in sigmoidoscopic index was 5.8, 5.9, and 6.4 points (on a 15-point scale) for the 1-, 2-, and 4-g enema groups compared with a decrease of 1.8 points for the placebo group. Improvement in biopsy scores was observed in 47, 55, and 59% of 1-, 2-, and 4-g groups contrasted with 27% of the placebo-treated patients. All three doses were significantly more effective than placebo in reducing symptoms and trips to the toilet compared with placebo. No dose-response relation was demonstrated. The safety profile was similar to that of placebo. In conclusion, mesalamine enemas are effective as a single agent in the short-term treatment of distal ulcerative colitis without an apparent dose response between 1 and 4 g nightly.

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.

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.

Confirmation of a susceptibility locus for Crohn's disease on chromosome 16.

SUMMARY: : Crohn's disease and ulcerative colitis are related complex genetic disorders producing chronic intestinal inflammation. A susceptibility locus for Crohn's disease, IBDI (inflammatory bowel disease), has been implicated on chromosome 16. To evaluate IBDI in a different population using alternative methodology, we tested markers in the region of IBDI. Seventy-two relative pairs with Crohn's disease only, 23 mixed relative pairs (one relative having Crohn's disease, the other, ulcerative colitis), and 5 relative pairs with ulcerative colitis were genotyped in the region of IBDI. Our population consisted of white Americans, with 29% of families of Ashkenazi Jewish descent. Among the Crohn's disease pairs, we found evidence for linkage at IBDI using multipoint analysis, p = 0.0082. Negative linkage scores were obtained for mixed and ulcerative colitis-only relative pairs. For the entire data set, including mixed relative pairs and relative pairs with ulcerative colitis, there was no significant evidence of linkage. No difference was observed in the evidence of linkage between Jewish and non-Jewish families. Our studies confirm that IBDI represents a susceptibility locus for Crohn's disease, but not ulcerative colitis.

Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study.

We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998.

Crohn's disease is a heterogeneous entity. Previous attempts of classification have been based primarily on anatomic location and behavior of disease. However, no uniform definition of patient subgroups has yet achieved broad acceptance. The aim of this international Working Party was to develop a simple classification of Crohn's disease based on objective variables. Eight outcome-related variables relevant to Crohn's disease were identified and stepwise evaluated in 413 consecutive cases, a database survey, and by clinical considerations. Allocation of variables was conducted with well-defined Crohn's disease populations from Europe and North America. Cross-table analyses were performed by chi-square testing. Three variables were finally elected: Age at Diagnosis [below 40 years (A1), equal to or above 40 years (A2)], Location [terminal ileum (L1), colon (L2), ileocolon (L3), upper gastrointestinal (L4)], and Behavior [nonstricturing nonpenetrating (B1), stricturing (B2), penetrating (B3)]. The allocation of patients to these 24 subgroups proved feasible and resulted in specific disease clusters. Cross-table analyses revealed associations between Age at Diagnosis and Location, and between Behavior and Location (all p < 0.001). The Vienna classification of Crohn's disease provides distinct definitions to categorize Crohn's patients into 24 subgroups. Operational guidelines should be used for the characterization of patients in clinical trials as well as for correlation of particular phenotypes with putative biologic markers or environmental factors.

Cigarette smoking and ulcerative colitis: a case-control study.

OBJECTIVE: To determine whether the previously reported decreased risk of ulcerative colitis in current smokers and increased risk in former smokers are explained by age, sex, race, ethnicity, or socioeconomic status. DESIGN: We conducted a case-control study at a university hospital gastroenterology clinic. MATERIAL AND METHODS: One hundred patients with ulcerative colitis and 100 age- and sex-matched community control subjects were randomly selected for a telephone interview to collect information on smoking habits, race, religion, income, education, and occupation. Smoking habits at the onset of symptoms were analyzed with use of conditional logistic regression for matched data to obtain adjusted odds ratios and 95% confidence intervals for current or former smokers. RESULTS: In comparison with those who had never smoked, current smokers were less likely to have ulcerative colitis: odds ratio = 0.13; 95% confidence interval = 0.05 to 0.38. Former smokers had no increased risk for ulcerative colitis: odds ratio = 1.24; 95% confidence interval = 0.52 to 2.95. No dose-response effect was noted on the basis of pack-years of cigarette smoking, and among former smokers, the interval since quitting smoking was not significantly associated with the relative risk of ulcerative colitis. No confounding effect was detected from race, religion, income, education, or occupation. CONCLUSION: An association seems to exist between ulcerative colitis and nonsmoking; perhaps patients with ulcerative colitis who smoke are less likely to experience symptoms than are nonsmokers because of the effects of nicotine.

Review article: aminosalicylates in inflammatory bowel disease.

Aminosalicylate therapy for ulcerative colitis remains a foundational strategy for the induction and maintenance of remission for mild to moderate disease. Although it seems clear that topical mesalazine (mesalamine) is the most efficacious approach to distal ulcerative colitis, recent trials with orally delivered azo conjugates suggest that there may be an advantage over pH-released mesalazine as a first-line approach to active disease. No such comparisons are available for azo products and the prolonged-release formulation, Pentasa. However, recent meta-analyses have demonstrated that, although there is little difference in systemic exposure between marketed products, luminal concentrations may vary. In maintenance therapy, aminosalicylates remain the standard approach after aminosalicylate-induced remission. A number of gaps remain in the evidence base with regard to the optimal dosing of oral mesalazine as a maintenance agent, whether oral mesalazine can maintain remissions after rectal mesalazine induction, and the dose-response and efficacy of aminosalicylates after steroid- or ciclosporin-induced remissions. Although aminosalicylates have been advocated for several decades in Crohn's disease, a number of controversies have evolved since the original trials with sulfasalazine in active Crohn's disease. The original trials demonstrated benefits for sulfasalazine in colonic involvement, but controlled trial evidence for the role of sulfasalazine as maintenance therapy has not been as firmly established. In addition, although oral mesalazine has been demonstrated in controlled trials to be superior to placebo in mild to moderate disease, it is less efficacious than corticosteroids at inducing remissions. The maintenance benefits of mesalazine appear to be limited to patients 'induced into remission' with mesalazine and in some post-operative settings.

Review article: the long-term management of ulcerative colitis.

After the induction of remission, the second priority of therapy for ulcerative colitis is sustained clinical remission, defined as the absence of inflammatory symptoms (diarrhoea, bleeding, rectal urgency) and the maintenance of an intact mucosa, with the absence of ulcers, friability or significant granularity at endoscopy. The 'optimal' maintenance strategy will depend on the therapy needed to induce remission. Thus, the transition from induction to maintenance therapy will be determined by the intensity of acute therapy necessary to induce remission and the duration of therapy required to complete the resolution of clinical symptoms. There are few controlled clinical trials pertaining to maintenance after each induction regimen. However, experience dictates that aminosalicylates are efficacious after aminosalicylate-induced remissions, that steroids should be tapered according to the time required to induce remission, that patients requiring ciclosporin will benefit from the addition of long-term immunomodulation with azathioprine or mercaptopurine, and that many patients with distal colitis who require topical mesalazine (mesalamine) will continue to need topical therapy to maintain remission, albeit at reduced frequency. The expectations for maintenance therapy require patient adherence to the prescribed treatment regimen. Patients require education with regard to the long-term goals of maintenance therapy (e.g. prevention of relapse, reduction of long-term complications of disease activity or risks of acute therapy with steroids), and should be warned against the use of nonsteroidal anti-inflammatory drugs and cautioned about the cessation of smoking, when applicable, due to potential risks of relapse or chronic activity.

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.

Review article: the medical management of Crohn's disease.

The choice of medical therapies for Crohn's disease continues to grow. Although our understanding of the mechanisms of the disease is incomplete, increasing knowledge of the pathogenesis of inflammation in general and Crohn's disease in particular allows targeting of therapies at various points in the immunoinflammatory cascade. In addition, the division of Crohn's disease into subtypes by location, aggressiveness, and the presence or absence of perianal and fistulizing disease allows the tailoring of medical therapy to the individual patient. For those patients with moderate to severe symptoms or frequent flares of disease activity, and those who have required surgical resection, maintenance therapy can substantially reduce the rate of recurrence. Despite these advances, available medical therapies for Crohn's disease remain imperfect, as evidenced by their sometimes substantial toxicities and the continued frequent need for surgery.

Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis.

AIM: : To quantify through systematic review the pharmacokinetic profiles of the oral delayed release and sustained release mesalazine (5-aminosalicylate, 5ASA) formulations (Asacol, Salofalk, Mesasal, Claversal, Pentasa) and pro-drugs (sulfasalazine, olsalazine, balsalazide) used in the management of ulcerative colitis. METHODS: : Selected articles had: (1) adult healthy volunteers or patients with ulcerative colitis and (2) quantification of pharmacokinetic data to include, at a minimum, urinary excretion of total 5ASA [5ASA plus N-Acetyl-5ASA (N-Ac-5ASA)]. DATA COLLECTION AND ANALYSIS: : Pharmacokinetic data (Tmax, Cmax, AUC, urinary excretion, faecal excretion) of 5ASA, its major metabolite N-Acetyl-5ASA, total 5ASA, and the parent pro-drug compounds was extracted. MAIN RESULTS: : The summary results for urinary excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 11-33% or median 22%; olsalazine mean 14-31% or median 16-27%; balsalazide mean 12-35% or median 20%; Asacol mean 10-35% or median 18-40%; Pentasa mean 15-53% or median 23-34%; Salofalk, Mesasal and Claversal mean 27-56% or median 31-44%. The summary results for faecal excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 23-75% or median 38%; olsalazine mean 47-50% or median 17-36%; balsalazide mean 46% or median 22%; Asacol mean 40-64% or median 20-56%; Pentasa mean 12-51% or median 39-59%; Salofalk, Mesasal and Claversal mean 37-44% or median 23-35%. CONCLUSIONS: : The systemic exposure to 5ASA, as measured by urinary excretion of total 5ASA, and the faecal excretion of total 5ASA is comparable for all oral mesalazine formulations and pro-drugs. Thus, selection of a mesalazine therapy for the treatment of ulcerative colitis should be based on other factors such as efficacy, dose-response, toxicity of the parent compound and its metabolites, compliance issues related to dose forms and dosing schedules, and costs.