Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.

BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn's disease: real world experience from a multicentre cohort.

BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukins-12 and -23, with efficacy in Crohn's disease (CD) demonstrated in clinical trials. AIM: To assess the real-world clinical, endoscopic and radiographic response and remission outcomes achieved with ustekinumab in medically-refractory CD. METHODS: A retrospective multicentre cohort study was performed on CD patients receiving ustekinumab between 2011 and 2016. The primary outcome was achievement of clinical and objective steroid-free response and remission at 3, 6 and 12 months. Clinical response and remission were defined by reduction in Harvey Bradshaw Index (HBI) of ≥3 points and an HBI ≤4 points respectively. Objective response was defined by improvement in endoscopic or radiographic CD, as assessed by ileocolonoscopy, contrast-enhanced ultrasound or CT/MR enterography. Objective remission was defined by endoscopic mucosal healing or complete resolution of inflammatory parameters on radiographic assessment. RESULTS: A total of 167 CD patients were treated with ustekinumab. 95.2% (159/167) previously failed anti-TNF therapy. Median follow-up was 45.6 weeks (IQR: 24.4-88.9). At 3 months, clinical response was achieved in 38.9% (65/167) and remission in 15.0% (25/167) of patients. At 6 months, clinical response was achieved in 60.3% (91/151) and remission in 25.2% (38/151) of patients. At 12 months, clinical response was achieved in 59.5% (66/111) and remission in 27.9% (31/111) of patients. Endoscopic or radiographic response was demonstrated in 54.5% (67/123) at 6 months and 55.8% (48/86) of patients at 12 months. CONCLUSIONS: Ustekinumab is an effective therapeutic option for inducing and maintaining clinical, endoscopic and radiographic response in patients with Crohn's disease failing anti-TNF therapy.

Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs. placebo as induction therapy in active Crohn's disease.

BACKGROUND: Many patients with active Crohn's disease do not adequately respond to therapies, highlighting the need for new treatments. AIMS: To conduct a randomised, double-blind, placebo-controlled phase 3 study to assess the efficacy and safety of vercirnon, an oral inhibitor of CC chemokine receptor-9, for the treatment of patients with moderately-to-severely active Crohn's disease. METHODS: Patients with a Crohn's Disease Activity Index (CDAI) of 220-450, plus evidence of active disease (endoscopically confirmed or elevation of both C-reactive protein and faecal calprotectin), who had failed corticosteroid or immunosuppressant therapy were enrolled. Patients were equally randomised to receive placebo, vercirnon 500 mg once daily or vercirnon 500 mg twice daily. The primary endpoint was clinical response, defined as a 100-point decrease in CDAI from baseline to week 12. RESULTS: Six hundred and eight patients were randomised. Patient characteristics and baseline demographics were similar among the groups. The proportions of patients achieving a clinical response were 25.1%, 27.6% and 27.2% for placebo, once daily and twice daily respectively; treatment differences were not significant (2.5%; 95% confidence interval, CI -6.1% to 11.0%, P = 0.546 for once daily vs. placebo, and 2.1%; 95% CI -6.5% to 10.7%, P = 0.648 for twice daily vs. placebo). Adverse events were reported in 69.8%, 73.3% and 78.1% with serious adverse events in 8.9%, 5.9%, and 6.0% of patients in the placebo, once-daily and twice-daily groups, respectively. CONCLUSIONS: We did not demonstrate efficacy of vercirnon as an induction therapy in patients with moderately-to-severely active Crohn's disease; its effect in maintenance therapy was not addressed.

Adalimumab dose escalation is effective for managing secondary loss of response in Crohn's disease.

BACKGROUND: The efficacy of adalimumab in maintaining remission in Crohn's disease patients may wane over time, leading to secondary loss of response that is often managed with dose escalation. However, the response to adalimumab dose escalation and long-term outcomes after escalation have not been well evaluated. AIMS: To characterise the short- and long-term clinical responses to adalimumab dose escalation for secondary loss of response. METHODS: A retrospective cohort study evaluating Crohn's disease out-patients requiring adalimumab dose escalation for secondary loss of response from 2003 to 2013 was conducted. The primary outcome was the proportion of patients achieving symptomatic clinical response to dose escalation and subsequent development of tertiary loss of response. Duration of regained response was assessed by Kaplan-Meier analysis. RESULTS: Ninety-two CD patients met inclusion criteria with mean duration of follow-up of 170.2 weeks (±129.6 weeks). Disease distribution was predominantly ileal (37/92, 40.2%) or ileocolonic (43/92, 46.7%), with equal distribution of inflammatory (34.8%), stricturing (27.2%), and penetrating (38.0%) disease phenotypes. At 24 weeks post-dose escalation, 74/92 (80.4%) patients had symptomatic clinical response. Among responders, median duration of sustained response was 69.2 weeks (IQR 29.4-107.1) but 42/74 (56.8%) responders experienced subsequent tertiary loss of response at a median time of 47.9 weeks (IQR 24.7-80.3). C-reactive protein >10.0 mg/L at the time of dose escalation predicted tertiary loss of response in univariate analysis (OR 3.32, 95% CI: 1.18-9.37). CONCLUSIONS: In patients with Crohn's disease, adalimumab dose escalation is effective for recapturing symptomatic response after secondary loss of response, but more than half will eventually experience a tertiary loss of response.

The incidence rate of colectomy for medically refractory ulcerative colitis has declined in parallel with increasing anti-TNF use: a time-trend study.

BACKGROUND: Medical therapy is standard treatment for ulcerative colitis with colectomy reserved for medically refractory disease or malignancy. The introductions of ciclosporin in 1994 and anti-TNF therapy in 2005 have extended medical management options. AIM: To determine whether the colectomy incidence rate for medically refractory ulcerative colitis has changed since the introduction of anti-TNF therapy. METHODS: Adult patients with a diagnosis of ulcerative colitis and who subsequently underwent an urgent or elective colectomy for medically refractory disease in Edmonton, Canada between 1 January 1998 and 31 December 2011 were identified. Log-linear regression was used to estimate the annual percent change in the total colectomy incidence rate (urgent and elective combined) and the urgent and elective incidence rates individually, before and after 2005, the year infliximab was approved for use in ulcerative colitis. Temporal trends of drug utilisation in this study population were also described. RESULTS: During 1998-2011, 481 patients with ulcerative colitis underwent a colectomy for medically refractory disease. There was negligible change in the total colectomy incidence rate from 1998 to 2005, with an annual percent change of 4.4% (95% confidence interval (CI): -1.12% to 10.16%). From 2005-2011, following the approval and increasing use of anti-TNF therapy, the total colectomy incidence rate decreased by 16.1% (95% CI: -21.32% to -10.54%) every year to 0.9 per 100 ulcerative colitis patients in 2011. CONCLUSION: The total incidence rate of colectomy for medically refractory ulcerative colitis has declined substantially since 2005, paralleling the increased use of anti-TNF therapy in this patient population.

Prevalence of Epstein-Barr Virus in a population of patients with inflammatory bowel disease: a prospective cohort study.

BACKGROUND: The Epstein-Barr Virus (EBV) is truly prolific, with a prevalence of more than 90% in the adult human population. There are, however, little data available on the prevalence of EBV among patients with Inflammatory Bowel Disease (IBD), a population that is frequently immunosuppressed and thus at risk for severe, often fatal, primary infection. AIM: To identify the prevalence of EBV in a population of patients with IBD and to compare it with that of the general population. METHODS: A database of 2500 IBD patients previously followed at the University of Alberta IBD Centre was queried; 60 of these patients were randomly chosen to participate. A total of 220 patients attending the IBD Centre for clinical appointment were also prospectively asked to participate. Participants completed serological testing for VCA-IgM, VCA-IgG and EBNA-IgG, to determine prior EBV exposure. RESULTS: A total of 263 patients underwent testing. Results for EBV seroprevalence of specific age groups were as follows: 18-20 years (n = 17), 29% seronegative; 21-25 years (n = 31), 29% seronegative; 26-30 years (n = 35), 31-35 years (n = 18) and 36-40 years (n = 25), 100% seropositive. Finally, 3% of those older than 40 (n = 117) were seronegative. EBV seroprevalence was similar for Crohn's disease and ulcerative colitis. Azathioprine was associated with seropositivity (P = 0.048). CONCLUSION: The prevalence of EBV seronegativity in the IBD population aged 18-25 years was similar to that described in the general population, and above age 25 years, seropositivity approached 100%.

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study.

BACKGROUND: Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. AIM: To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. METHODS: This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. RESULTS: No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. CONCLUSIONS: Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

A one-hour infusion of infliximab during maintenance therapy is safe and well tolerated: a prospective cohort study.

BACKGROUND: Infliximab is a chimeric monoclonal antibody to tumour necrosis factor alpha (TNFα) with efficacy in inducing and maintaining remission of inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis and psoriasis. Infliximab is generally administered over 2h with a further 1-h postinfusion observation. This time interval has substantial impact on healthcare resources and is costly in terms of patient's time away from work. AIM: To examine the safety and tolerability of a 1-h, relative to a 2-h maintenance of infusion of infliximab, and to determine the effect of corticosteroid premedication and concurrent immunosuppressor use on infusion reaction rates. METHOD: A prospective cohort study with variable follow-up duration of 2165 consecutive infliximab infusions in 415 patients during 2009 was conducted. Diagnosis, infusion episode number, infusion rate, premedication, concurrent immunosuppressor therapy, the nature and the outcome of infusion reactions were examined. RESULTS: The majority of infusions (74%) were for management of inflammatory bowel disease. Infusion reactions clustered within the first eight infusions with subsequent sporadic reactions. The infusion reaction incidence rate per 1000 person days in 274 1-h infusions from 54 patients and 1356 2-h infusions from 256 patients were 0.08 and 0.28 respectively (P=0.07). Poisson regression model confirmed that the concurrent use of immunosuppressor therapy was associated with a lower infusion reaction rate, whereas corticosteroid premedication was not. CONCLUSIONS: During maintenance therapy, infliximab infusion can be safely administered over 1h in patients with no past history of significant infliximab infusion reaction. Corticosteroid premedication had no impact on the infusion reaction rates.

Maintenance of clinical benefit in Crohn's disease patients after discontinuation of infliximab: long-term follow-up of a single centre cohort.

BACKGROUND: Tumour necrosis factor-blockade with infliximab has advanced the treatment of Crohn's disease. While infliximab is efficacious, it remains to be determined whether patients who enter clinical remission with an anti-tumour necrosis factor therapy can have their treatment stopped and retain the state of remission. AIM: To assess in patients with Crohn's disease who obtained infliximab-induced remission, the proportion who relapsed after infliximab discontinuation. METHODS: This longitudinal cohort study examined patients from a University-based IBD referral centre. Forty eight patients with Crohn's disease in full clinical remission and who then discontinued infliximab were followed up for up to 7 years. Crohn's disease relapse was defined as an intervention with Crohn's disease medication or surgery. RESULTS: Kaplan-Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7-year follow-up. CONCLUSIONS: In patients with Crohn's disease with an infliximab-induced remission, stopping infliximab results in a predictable relapse in a majority of patients. Nevertheless, a small percentage of patients sustain a long-term remission.

Treatment of ulcerative colitis with adalimumab or infliximab: long-term follow-up of a single-centre cohort.

Aliment Pharmacol Ther 2010; 32: 522-528 Summary Background Randomized, controlled trials have demonstrated that anti-TNF agents are efficacious in inducing remission in cases of Crohn's disease and ulcerative colitis. However, response rates for anti-TNF agents in 'real life' clinical practice are less well-defined. Aims To examine the response rates and long-term outcomes of infliximab and adalimumab treatment for out-patients with ulcerative colitis and to study the variables associated with response rates. Methods In a prospective study, a single-centre out-patient cohort was treated and followed up according to a structured protocol of clinical care. Response to treatment was assessed using a physician's global assessment that focused on normalization of bowel frequency, absence of blood with defecation and tapering of corticosteroids to zero. Results Fifty-three ulcerative colitis patients were included in the study. Responses to induction therapy were 96.4% (27/28) for infliximab and 80% (20/25) for adalimumab (P = 0.0889). Responses to maintenance therapy were similar: infliximab 77.8% (14/18) and adalimumab 70.0% (14/20) (P = 0.7190). Multivariate analyses of the induction and maintenance responses did not reveal confounding elements. No new safety signals were identified. Conclusions This long-term follow-up of a single-centre cohort of ulcerative colitis patients demonstrates that 'real-life' out-patient treatment with infliximab and adalimumab is effective in induction and maintenance of response.

An imbalance in mucosal cytokine profile causes transient intestinal inflammation following an animal's first exposure to faecal bacteria and antigens.

Intestinal microflora play a critical role in the initiation and perpetuation of chronic inflammatory bowel diseases. In genetically susceptible hosts, bacterial colonization results in rapid-onset chronic intestinal inflammation. Nevertheless, the intestinal and systemic immune response to faecal bacteria and antigen exposure into a sterile intestinal lumen of a post-weaned animal with a mature immune system are not understood clearly. This study examined the effects of faecal bacteria and antigen exposure on the intestinal mucosal and systemic immune system in healthy axenic mice. Axenic wild-type mice were inoculated orally with a crude faecal slurry solution derived from conventionally raised mice and were analysed prior to and then at days 3, 7, 14 and 28 post-treatment. Ingestion of faecal slurry resulted in a transient, early onset of proinflammatory interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-17 response that was maximal at day 3. In contrast, the transient release of the anti-inflammatory cytokines IL-10 and IL-4 occurred later and was maximal at day 7. Both responses subsided by day 14. This early cytokine imbalance was associated with a brief rise in colonic and caecal histopathological injury score at day 7. The bacterial antigen-specific systemic response was found to follow the intestinal immune response with a maximal release of both pro- and anti-inflammatory cytokines at day 7. Thus, first exposure of healthy axenic wild-type mice to normal faecal flora and antigens results in an early proinflammatory cytokine response and transient colonic inflammation that then resolves in conjunction with a subsequent anti-inflammatory cytokine profile.

Steroid-sparing properties of sargramostim in patients with corticosteroid-dependent Crohn's disease: a randomised, double-blind, placebo-controlled, phase 2 study.

OBJECTIVE: Although treatment with corticosteroids induces remission in Crohn's disease, prolonged exposure to corticosteroids is undesirable. This randomised clinical trial evaluated the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (sargramostim), an activator of innate immunity, in corticosteroid-dependent patients with Crohn's disease. DESIGN: Patients were randomised in a 2:1 ratio, to sargramostim 6 microg/kg subcutaneously once daily or placebo for up to 22 weeks. The study consisted of (1) an adjunctive phase (weeks 1-4) in which patients received study drug plus corticosteroid therapy; (2) a forced corticosteroid tapering phase (weeks 4-14); and (3) an observation phase (4 weeks) in which patients received study drug plus prednisone < or =7.5 mg. The primary endpoint was corticosteroid-free remission (Crohn's Disease Activity Index (CDAI) < or =150) 4 weeks after corticosteroid elimination. Secondary endpoints were corticosteroid-free response (CDAI decreased by > or =100) and induction of remission in patients who reduced the dose of corticosteroid to 2.5-7.5 mg. RESULTS: Eighty-seven patients were randomised to sargramostim and 42 to placebo. Significantly more sargramostim-treated patients than placebo patients achieved corticosteroid-free remission (18.6% vs 4.9%; p = 0.03). Similar differences were seen for corticosteroid-free response and in patients who tapered corticosteroids to 2.5-7.5 mg/day. Sargramostim treatment was also associated with significant improvements in health-related quality of life. Patients who received sargramostim were more likely to experience musculoskeletal pain, injection site reactions and dyspnoea. CONCLUSIONS: Sargramostim was more effective than placebo for inducing corticosteroid-free remission in patients with Crohn's disease with corticosteroid dependence. Sargramostim may provide significant benefit in this population if these findings are confirmed.

Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of tumour necrosis factor-alpha antagonist therapy in Crohn's disease.

BACKGROUND: Guidelines regarding the use of infliximab in Crohn's disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn's disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn's disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn's disease is substantial and strengthened by results from longterm clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.

VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation.

BACKGROUND: Alkaline sphingomyelinase, an enzyme found exclusively in bile and the intestinal brush border, hydrolyzes sphingomyelin into ceramide, sphingosine and sphingosine-1-phosphate, thereby inducing epithelial apoptosis. Reduced levels of alkaline sphingomyelinase have been found in premalignant and malignant intestinal epithelia and in ulcerative colitis tissue. Probiotic bacteria can be a source of sphingomyelinase. OBJECTIVE: To determine the effect of VSL#3 probiotic therapy on mucosal levels of alkaline sphingomyelinase, both in a mouse model of colitis and in patients with ulcerative colitis. METHODS: Interleukin-10 gene-deficient (IL10KO) and wild type control mice were treated with VSL#3 (10(9) colony-forming units per day) for three weeks, after which alkaline sphingomyelinase activity was measured in ileal and colonic tissue. As well, 15 patients with ulcerative colitis were treated with VSL#3 (900 billion bacteria two times per day for five weeks). Alkaline sphingomyelinase activity was measured through biopsies and comparison of ulcerative colitis disease activity index scores obtained before and after treatment. RESULTS: Lowered alkaline sphingomyelinase levels were seen in the colon (P=0.02) and ileum (P=0.04) of IL10KO mice, as compared with controls. Treatment of these mice with VSL#3 resulted in upregulation of mucosal alkaline sphingomyelinase activity in both the colon (P=0.04) and the ileum (P=0.01). VSL#3 treatment of human patients who had ulcerative colitis decreased mean (+/- SEM) ulcerative colitis disease activity index scores from 5.3+/-1.8946 to 0.70+/-0.34 (P=0.02) and increased mucosal alkaline sphingomyelinase activity. CONCLUSION: Mucosal alkaline sphingomyelinase activity is reduced in the intestine of IL10KO mice with colitis and in humans with ulcerative colitis. VSL#3 probiotic therapy upregulates mucosal alkaline sphingomyelinase activity.

Review and clinical perspectives for the use of infliximab in ulcerative colitis.

Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences.

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.

Infliximab for the treatment of Crohn's disease: efficacy, safety and pharmacoeconomics.

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. From the perspective of the patient, symptoms of the disease significantly impair quality of life and interfere with activities of daily living. Conventional medical treatment of Crohn's disease includes the use of nonspecific anti-inflammatory drugs, immunosuppressives and antibiotics. These therapies are characterized by a delayed onset of action, incomplete response rates and a substantial risk of adverse effects. Although surgery is frequently used to treat complications, postoperative recurrence is an important problem. Infliximab, a chimeric monoclonal antibody directed toward tumour necrosis factor alpha, is highly effective for the treatment of active Crohn's disease. In randomized, placebo-controlled clinical trials, 82% of patients who received 5 mg/kg of infliximab had a clinically significant response, compared with 17% of those given placebo (P<0.001). Moreover, infliximab is the only medical therapy that has been shown to be effective for the treatment of fistulizing Crohn's disease. Infusion reactions are the most common adverse effect. Whether treatment with infliximab is associated with an increased risk of neoplasia, infection or autoimmune disease is unknown. Therefore, further long term safety studies are required. Despite the relatively high cost of drug acquisition, preliminary pharmacoeconomic analysis indicates that infliximab is cost effective compared with existing treatments. Infliximab is recommended for the treatment of active Crohn's disease refractory to conventional drugs, and is the treatment of choice for fistulizing Crohn's disease.