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.

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.

Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease.

BACKGROUND: Azathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD). AIM: To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations. METHODS: This multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT) or 2.5 mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8 × 10(8) red blood cells (RBC), or to a maximal dose of 4 mg/kg/day. RESULTS: After randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P = 0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P = 0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10(8) RBC respectively (P = 0.07). CONCLUSIONS: Despite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm. [Clinicaltrials.Gov Identifier Nct00113503].

Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease.

BACKGROUND: Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). AIM: To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. METHODS: This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. RESULTS: Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. CONCLUSIONS: A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461.

Adalimumab sustains steroid-free remission after 3 years of therapy for Crohn's disease.

BACKGROUND: Treatments that achieve sustainable steroid-free clinical remission in Crohn's disease are needed; however, long-term steroid-sparing efficacy data are limited. AIM: To evaluate steroid-sparing efficacy and the impact of steroid discontinuation on adverse events during treatment of Crohn's disease with adalimumab in the phase III randomised, double-blind 1-year CHARM trial and for an additional 2 years in its open-label extension ADHERE. METHODS: Steroid-free remission and response and steroid-sparing (≥50% steroid dose reduction) remission rates were evaluated over 3 years in patients who were taking corticosteroids at CHARM baseline. RESULTS: Of 778 patients randomised in CHARM (including those who did not achieve clinical response to open-label induction therapy), 313 patients (40%) were on corticosteroids at baseline. In the 206 patients randomised to adalimumab, rates of steroid-free remission at 1 year and 3 years were 26% and 23% respectively; corresponding rates were 29% and 25% for steroid-sparing remission and 32% and 28% for steroid-free response. Although the incidence of serious infections with adalimumab treatment during CHARM was higher in patients taking steroids at baseline than those who were not, the rates of overall adverse events, serious infections and opportunistic infections were lower in patients who were able to discontinue corticosteroids than those who remained on steroids. CONCLUSION: Adalimumab therapy resulted in modest but clinically meaningful rates of steroid-free remission, sustained over 3 years of treatment, in a heavily pretreated population of patients with Crohn's disease receiving steroids at the start of therapy (http://www.clinicaltrials.gov number: NCT00077779).

Evaluation of a daily practice composite score for the assessment of Crohn's disease: the treatment impact of certolizumab pegol.

BACKGROUND: Successful treatment of systemic inflammatory symptoms is essential for improving health-related quality of life in patients with active Crohn's disease. Patient-reported outcomes provide unique perspectives on the impact of chronic disease. It is unknown whether a combination of different instruments might improve sensitivity to clinically relevant changes in health status. AIM: To develop a composite score based upon Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ) items. METHODS: Patients from the PRECiSE 2 trial who responded at week 6 to certolizumab pegol (CZP) were randomised to receive treatment with CZP 400 mg or placebo for up to 26 weeks. IBDQ and CDAI scores were assessed at weeks 0, 6, 16 and 26. A 'daily practice' composite score (DP-6) containing two items from the CDAI and four items from IBDQ was constructed. RESULTS: Correlation coefficients between the CDAI score and IBDQ total score at baseline and at week 26 were -0.344 and -0.603, respectively (P<0.05). All IBDQ items were improved following CZP treatment. The DP-6 had the highest responsiveness at assessing response to treatment, relative to CDAI total score, when compared with other scores. CONCLUSIONS: The DP-6 composite score could be used to optimise the use of existing instruments by serving as an index of symptoms due to systemic inflammation. Additional studies are needed to determine if the DP-6 composite score differentiates the impact of different treatments on patient-reported outcomes, and to determine if the use of the DP-6 improves the care of patients in clinical practice.

Randomised clinical trial: certolizumab pegol for fistulas in Crohn's disease - subgroup results from a placebo-controlled study.

BACKGROUND: Treatment options for fistulizing Crohn's disease (CD) are limited. AIM: To examine whether fistula closure is maintained at week 26 following treatment with certolizumab pegol. METHODS: Patients with draining fistulas at baseline from PRECiSE 2 (n = 108) received open-label induction with certolizumab pegol 400 mg at weeks 0 (baseline), 2 and 4. Response was defined as ≥100-point decrease from baseline in the Crohn's Disease Activity Index. Nonresponders (50/108) were excluded. At week 6, responders with draining fistulas (N = 58) were randomised to certolizumab pegol 400 mg (n = 28) or placebo (n = 30) every 4 weeks across weeks 8-24. Fistula closure was evaluated throughout the study, with a final assessment at week 26. RESULTS: The majority of patients (55/58) had perianal fistula. At week 26, 36% of patients in the certolizumab pegol group had 100% fistula closure compared with 17% of patients receiving placebo (P = 0.038). Protocol-defined fistula closure (≥50% closure at two consecutive post-baseline visits ≥3 weeks apart) was not statistically significant (P = 0.069) with 54% and 43% of patients treated with certolizumab pegol and placebo achieving this end point, respectively. CONCLUSION: Continuous treatment with certolizumab pegol improves the likelihood of sustained perianal fistula closure compared with placebo.

Clinical trial: impact of prior infliximab therapy on the clinical response to certolizumab pegol maintenance therapy for Crohn's disease.

BACKGROUND: Certolizumab pegol (CZP) is an effective therapy for Crohn's disease refractory to aminosalicylates, corticosteroids and immunosuppressants. In PRECiSE 2, patients were also eligible for enrolment if prior infliximab therapy was terminated due to loss of response. AIM: To evaluate prior infliximab therapy on sustained response and remission to CZP for Crohn's disease. METHODS: PRECiSE 2 were was analysed for predictors of sustained response and remission. Covariates included prior infliximab therapy, and baseline Crohn's Disease Activity Index (CDAI). RESULTS: Week 26 response (> or =100-point decrease from baseline CDAI) and remission (CDAI < or = 150) were greater with CZP vs. placebo in patients previously receiving infliximab (response: 44.2% vs. 25.5%, P = 0.018; remission: 32.7% vs. 13.7, P = 0.008) and infliximab-naïve patients (response: 68.7% vs. 39.6%, P < 0.001; remission: 52.8% vs. 33.3%, P < 0.001). Prior infliximab use was the only independent predictor of week 26 response and remission in both groups [response OR(CZP vs. placebo) = 3.06 (95% CI: 1.21-7.77); remission OR(CZP vs. placebo) = 4.22 (95% CI: 1.45-12.28)]. Adverse events were similar for both groups. CONCLUSIONS: Certolizumab pegol is an effective maintenance therapy in Crohn's disease regardless of prior infliximab use. Efficacy is higher in patients receiving CZP therapy as a first-line biologic, but approximately 50% of infliximab-experienced patients benefited from second-line CZP therapy.

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.

Review article: evolving concepts in treatment and disease modification in ulcerative colitis.

BACKGROUND: More than two-thirds of ulcerative colitis patients experience at least one relapse over a period of 10 years. Treatments that reduce the likelihood of relapses also reduce the risk of long-term complications. AIM: To review three topics: the current standard of treatment for ulcerative colitis, evolving concepts in treatment, and disease modification as a treatment goal of the future. RESULTS: Currently, 5-aminosalicylates are the standard treatment for the induction and maintenance of remission in mild-to-moderate ulcerative colitis patients. Evidence suggests that patients who take oral 5-aminosalicylates regularly are nearly six times more likely to experience regression in disease severity than those who do not. Additional treatment options such as corticosteroids, immunomodulators, biological therapies and ciclosporin are available for moderate-to-severe ulcerative colitis patients, or those who do not respond to 5-aminosalicylate. Surgery becomes pertinent for more than one-third of ulcerative colitis patients during the course of their disease. With the availability of a variety of therapies, advances in surgery and improved management strategies, a better understanding of patient treatment expectations can help improve the quality of care for ulcerative colitis patients. CONCLUSIONS: Disease modification is increasingly becoming a treatment goal in the management of ulcerative colitis. However, long-term studies are needed to examine further the disease modifying role of 5-aminosalicylates.

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.

Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial.

BACKGROUND: Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial. OBJECTIVE: To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow-on randomised controlled trial (CLASSIC II). METHODS: In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56. RESULTS: Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients. CONCLUSIONS: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti-TNF treatment.

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.

New lessons: classic treatments, expanding options in ulcerative colitis.

Ulcerative colitis (UC) of moderate severity is a common presentation in gastroenterological practice and a number of treatment options exist to rapidly and effectively induce remission. This review highlights how novel formulations and dosing regimens can ensure treatment success at a greater convenience for the patient with no increased risk of adverse effects. 5-aminosalicyclic acid (5-ASA) is well tolerated with a low incidence of adverse effects, and has a significant role in the management of UC. Different formulations of oral 5-ASA are now available and allow targeted treatment to inflammatory areas of the small bowel and ascending colon. 5-ASA is often initiated at a low dose for patients with mild to moderately active UC and with increasing doses for those who fail or have a poor response. 5-ASA at high doses is increasingly being used as induction therapy for active UC, particularly in patients with recurrent and/or extensive disease. The recent ASCEND studies show that an induction dose of 5-ASA of 4.8 g daily in patients with moderate UC is significantly more effective and resolves symptoms faster compared with a daily dose of 2.4 g. The evidence provided by the ASCEND studies support the rationale for a 'top-down' dosing strategy for UC where more potent therapies are introduced at an earlier stage of moderately severe disease.

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.

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.