Remo Panaccione

Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.

BACKGROUND & AIMS We conducted a systematic review to determine changes in the worldwide incidence and prevalence of ulcerative colitis (UC) and Crohns disease (CD) in different regions and with time. METHODS We performed a systematic literature search of MEDLINE (1950-2010; 8103 citations) and EMBASE (1980-2010; 4975 citations) to identify studies that were population based, included data that could be used to calculate incidence and prevalence, and reported separate data on UC and/or CD in full manuscripts (n = 260). We evaluated data from 167 studies from Europe (1930-2008), 52 studies from Asia and the Middle East (1950-2008), and 27 studies from North America (1920-2004). Maps were used to present worldwide differences in the incidence and prevalence of inflammatory bowel diseases (IBDs); time trends were determined using joinpoint regression. RESULTS The highest annual incidence of UC was 24.3 per 100,000 person-years in Europe, 6.3 per 100,000 person-years in Asia and the Middle East, and 19.2 per 100,000 person-years in North America. The highest annual incidence of CD was 12.7 per 100,000 person-years in Europe, 5.0 person-years in Asia and the Middle East, and 20.2 per 100,000 person-years in North America. The highest reported prevalence values for IBD were in Europe (UC, 505 per 100,000 persons; CD, 322 per 100,000 persons) and North America (UC, 249 per 100,000 persons; CD, 319 per 100,000 persons). In time-trend analyses, 75% of CD studies and 60% of UC studies had an increasing incidence of statistical significance (P < .05). CONCLUSIONS Although there are few epidemiologic data from developing countries, the incidence and prevalence of IBD are increasing with time and in different regions around the world, indicating its emergence as a global disease.

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.

Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.

Context Can adalimumab, an antitumor necrosis factor (anti-TNF) agent, induce remission in patients with Crohn disease who do not respond to or cannot tolerate another anti-TNF agent? Contribution This double-blind, placebo-controlled trial included 325 adults with Crohn disease who had symptoms despite treatment with infliximab or who could not tolerate infliximab because of adverse events. At 4 weeks, more patients randomly assigned to the adalimumab group achieved remission than did those in the placebo group (21% vs. 7%). Cautions The trial did not directly compare efficacy of different anti-TNF agents and did not assess maintenance of response or the long-term immunogenicity of adalimumab. The Editors Tumor necrosis factor (TNF) is an important proinflammatory cytokine in treating Crohn disease (1). Infliximab is a chimeric, anti-TNF monoclonal antibody effective in inducing and maintaining response and remission in patients with moderate to severe Crohn disease (2, 3). Some patients treated with infliximab experience a loss of efficacy over time or become intolerant of infliximab (47). Adalimumab, a human anti-TNF monoclonal antibody, is effective for inducing and maintaining remission in patients with Crohn disease who are naive to infliximab (810). Both adalimumab and certolizumab pegol (a pegylated humanized antibody fragment [Fab] to TNF) are effective for maintaining remission in a broad population of patients with Crohn disease who are naive to infliximab or who have responded to infliximab and then electively discontinued treatment despite continued response or because of lost response, intolerance, or both (10, 11). To our knowledge, no controlled trials have been conducted with these agents in a sample restricted to patients with lost response or intolerance to infliximab. We conducted a 4-week, placebo-controlled trial (GAIN [Gauging Adalimumab Efficacy in Infliximab Nonresponders]), in which adult patients with moderate to severe Crohn disease who had symptoms despite infliximab therapy or who could not take infliximab because of adverse events received adalimumab induction therapy. The Appendix shows the list of investigators for the GAIN trial group. Methods Design Overview This randomized, double-blind, placebo-controlled trial was conducted at 52 centers from November 2004 to December 2005 (last patient contact was on 26 June 2006). The protocol was approved by the institutional review board at each center. All patients provided written informed consent. Setting and Participants Fifty-two sites in the United States, Canada, Belgium, and France enrolled patients, with 1 to 29 patients at each site. We recruited patients from tertiary care centers, academic medical institutions, and independent research organizations. Eligible patients included men and women 18 to 75 years of age with Crohn disease for at least 4 months that was moderately to severely active at baseline, defined by a Crohns Disease Activity Index (CDAI) (12) score of 220 to 450 points (range, 0 to 600 points; greater scores indicate more severe disease activity). We required radiologic or endoscopic evidence to confirm the presence of Crohn disease. To be included, patients must have been intolerant of infliximab or must have previously responded to infliximab and then lost response. We excluded patients who had a primary nonresponse to infliximab as defined by the investigator, received infliximab or another TNF antagonist within the past 8 weeks, previously received adalimumab (Humira, Abbott Laboratories, Abbott Park, Illinois), or participated in an adalimumab clinical trial. Concurrent therapies, including stable dosages of 5-aminosalicylates, prednisone (40 mg/d), budesonide (9 mg/d), azathioprine, 6-mercaptopurine, methotrexate, and antibiotics, were permitted. We excluded patients who changed dosages or discontinued azathioprine, 6-mercaptopurine, or methotrexate treatment within 12 weeks of screening. Similarly, we excluded patients who changed dosages or discontinued 5-aminosalicylates, mesalamine, or sulfasalazine treatment within 4 weeks of screening. Prednisone (40 mg/d) and budesonide (9 mg/d) dosages must have been stable for 2 weeks or more before screening. Dosages of all these medications were required to remain stable during the study. We excluded patients with the short bowel syndrome, a symptomatic stricture, or bowel resection within the past 6 months; those who had undergone ostomy or ileoanal pouch; and those receiving total parenteral nutrition. We also excluded patients who had received antibiotic treatment for infections not related to Crohn disease within 3 weeks of the study and those with untreated tuberculosis or demyelinating disorders. We excluded female patients who were pregnant or were breast-feeding. We also excluded patients with a history of clinically significant drug or alcohol abuse in the past year; abnormal results on electrocardiography; or elevated concentrations of aspartate or alanine aminotransferase (>1.75 times the upper limit of the reference range), total bilirubin (51.3 mol/L [3 mg/dL]), or serum creatinine (>141.4 mol/L [>1.6 mg/dL]). Randomization and Intervention We randomly assigned eligible patients to receive subcutaneous injections of adalimumab, 160 mg at week 0 and 80 mg at week 2, or placebo at weeks 0 and 2 and followed patients through week 4. Patients, investigators, study site personnel, and Abbott Laboratories were unaware of treatment assignments. Randomization was completed through a central computer-generated scheme stratified by site, with block sizes of 4. Patient numbers were centrally assigned by an interactive voice-response system in consecutive order. The system provided access to blinded patient treatment information for medical emergencies only. Patients who successfully completed week 4 were eligible to enter an open-label extension study of the long-term safety of repeated administration of adalimumab. Outcomes and Measurements We classified patients as having a loss of response if they had a history of an initial response to infliximab, as defined by the investigator; had received at least 2 doses of infliximab of 5 mg/kg of body weight or more every 8 weeks; and had lacked improvement or had worsening in at least 1 of the following signs or symptoms related to Crohn disease at least 2 weeks after receiving the last dose of infliximab: stool frequency, daily abdominal pain, fever, recurring drainage from a previously nondraining fistula or development of a new draining fistula, rectal bleeding, or change in use of antidiarrheal medication. We classified patients as having intolerance of infliximab if they had a history of discontinuing infliximab treatment because of a clinically significant acute or delayed infusion reaction. We defined a clinically significant acute infusion reaction as an adverse reaction that occurred during or within 24 hours of an infliximab infusion, was considered to be related to the infusion by the physician, and manifested as at least 1 of the following symptoms: temperature greater than 100F; chills or rigors; itching; rash; flushing; urticaria or angioedema; breathing difficulties (dyspnea, chest paint or tightness, shortness of breath, wheezing, or stridor); and clinical hypotension (pallor, diaphoresis, faintness, or syncope), blood pressure less than 90/60 mm Hg, or orthostatic decrease in systolic blood pressure greater than 20 mm Hg. We defined a clinically significant delayed infusion reaction as an adverse reaction that occurred more than 24 hours and fewer than 15 days after an infliximab infusion; was considered to be related to the infusion by the physician; and was manifested through at least 1 of the following symptoms: myalgias, arthralgias, temperature greater than 100F, malaise, and rash. The primary efficacy end point was the proportion of patients with remission at week 4. Remission was defined as a CDAI score less than 150 points (12). Response was defined as a decrease from baseline in CDAI score of 70 points or more (70-point response) or of 100 points or more (100-point response) at week 4. Follow-up Procedures Patients were assessed 2 weeks before randomly assigned treatment began; on day 0; and at 1, 2, and 4 weeks. At each visit, the CDAI score was determined, adverse events and concomitant medications were recorded, and samples were collected for laboratory evaluations. The Inflammatory Bowel Disease Questionnaire (IBDQ) was administered to assess patient-reported outcomes at weeks 0 and 4 (total score range, 32 to 224; greater scores indicate better quality of life) (13). Safety evaluations included physical examinations. Laboratory evaluations included hematologic analysis; serum biochemical analysis; urinalysis; and determination of concentrations of C-reactive protein, adalimumab and antibodies to adalimumab, and infliximab and antibodies to infliximab. Adverse events were recorded through queries, observations by site personnel, and spontaneous patient reports. Investigators assessed and recorded any adverse event, including date of onset, description, severity, time course, duration, outcome, relationship of event to the study drug, alternate causes for events not considered to be probably related to the study drug, final diagnosis (if known), and any actions taken. Investigators rated the severity of each event (mild, moderate, or severe) and the relationship to study drug (probably related, possibly related, probably not related, or not related) on the basis of standard definitions. Serious adverse events were recorded through scheduled telephone contacts, study visits, and spontaneous patient reports from the time informed consent was signed until 70 days after withdrawal of study drug treatment. A data monitoring committee met every 4 to 6 months to discuss unblinded data and recommend either continuing or amending the study. A sponsor steering committee of senior executives w

Ustekinumab Induction and Maintenance Therapy in Refractory Crohn's Disease

BACKGROUND In patients with Crohns disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. METHODS We evaluated ustekinumab in adults with moderate-to-severe Crohns disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. RESULTS The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. CONCLUSIONS Patients with moderate-to-severe Crohns disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).

Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial

Objective The aim of this study was to assess the efficacy and safety of adalimumab (ADA), a recombinant human monoclonal antibody against tumour necrosis factor α (TNF), for the induction of clinical remission in anti-TNF naïve patients with moderately to severely active ulcerative colitis. Methods This 8-week, multicentre, randomised, double-blind, placebo-controlled study (NCT00385736), conducted at 94 centres in North America and Europe, enrolled ambulatory adult patients with Mayo score of ≥6 points and endoscopic subscore of ≥2 points despite treatment with corticosteroids and/or immunosuppressants. Under the original study protocol, 186 patients were randomised (1:1) to subcutaneous treatment with ADA160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6) or placebo. Subsequently, at the request of European regulatory authorities, the protocol was amended to include a second induction group (ADA80/40: 80 mg at week 0, 40 mg at weeks 2, 4 and 6). The primary efficacy endpoint was clinical remission (Mayo score ≤2 with no individual subscore >1) at week 8, assessed in 390 patients randomised (1:1:1) to ADA160/80, ADA80/40, or placebo. Safety was assessed in all enrolled patients. Patients, study site personnel, investigators, and the sponsor were blinded to treatment assignment. Results At week 8, 18.5% of patients in the ADA160/80 group (p=0.031 vs placebo) and 10.0% in the ADA80/40 group (p=0.833 vs placebo) were in remission, compared with 9.2% in the placebo group. Serious adverse events occurred in 7.6%, 3.8% and 4.0% of patients in the placebo, ADA80/40, and ADA160/80 groups, respectively. There were two malignancies in the placebo group, none in the ADA groups. There were no cases of tuberculosis and no deaths. Conclusions ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants. Clinical trial NCT00385736.

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organization: When to Start, When to Stop, Which Drug to Choose, and How to Predict Response?

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohns disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES:The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a “treat-to-target” clinical management strategy using an evidence-based expert consensus process.METHODS:A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7–10 on a 10-point rating scale (where 10=agree completely).RESULTS:The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn’s disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0–1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.CONCLUSIONS:Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients’ quality of life.

Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease

Background As long-term treatment with antitumour necrosis factor (TNF) drugs becomes accepted practice, the risk assessment requires an understanding of anti-TNF long-term safety. Registry safety data in rheumatoid arthritis (RA) are available, but these patients may not be monitored as closely as patients in a clinical trial. Cross-indication safety reviews of available anti-TNF agents are limited. Objective To analyse the long-term safety of adalimumab treatment. Methods This analysis included 23 458 patients exposed to adalimumab in 71 global clinical trials in RA, juvenile idiopathic arthritis, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis (Ps) and Crohns disease (CD). Events per 100 patient-years were calculated using events reported after the first dose through 70 days after the last dose. Standardised incidence rates for malignancies were calculated using a National Cancer Institute database. Standardised death rates were calculated using WHO data. Results The most frequently reported serious adverse events across indications were infections with greatest incidence in RA and CD trials. Overall malignancy rates for adalimumab-treated patients were as expected for the general population; the incidence of lymphoma was increased in patients with RA, but within the range expected in RA without anti-TNF therapy; non-melanoma skin cancer incidence was raised in RA, Ps and CD. In all indications, death rates were lower than, or equivalent to, those expected in the general population. Conclusions Analysis of adverse events of interest through nearly 12 years of adalimumab exposure in clinical trials across indications demonstrated individual differences in rates by disease populations, no new safety signals and a safety profile consistent with known information about the anti-TNF class.

Effects of Adalimumab Therapy on Incidence of Hospitalization and Surgery in Crohn's Disease: Results From the CHARM Study

BACKGROUND & AIMS We determined the effects of adalimumab maintenance treatment on the risks of hospitalization and surgery in Crohns disease (CD). METHODS A total of 778 patients with CD were randomized to placebo, adalimumab 40 mg every other week or adalimumab 40 mg weekly, all after an 80-mg/40-mg adalimumab induction regimen. All-cause and CD-related hospitalizations and major CD-related surgeries were compared between the placebo and adalimumab groups (every other week, weekly, and both combined) using Kaplan-Meier analysis and Cox proportional hazard models. RESULTS Both 3- and 12-month hospitalization risks were significantly lower for patients who received adalimumab. Hazard ratios for all-cause hospitalization were 0.45, 0.36, and 0.40 for the adalimumab every other week, weekly, and combined groups, respectively (all P < .01 vs placebo). Hazard ratios for CD-related hospitalization were 0.50, 0.34, and 0.42, respectively (all P < .05). Cox model estimates demonstrated adalimumab every other week and weekly maintenance therapies were associated with 52% and 60% relative reductions in 12-month, all-cause hospitalization risk, and 48% and 64% reductions in 12-month risk of CD-related hospitalization. The combined adalimumab group was associated with 56% reductions in both all-cause and CD-related hospitalization risks. Fewer CD-related surgeries occurred in the adalimumab every other week, weekly, and combined groups compared with placebo (0.4, 0.8, and 0.6 vs 3.8 per 100 patients; all P < .05). CONCLUSIONS Patients with moderate-to-severe CD treated with adalimumab had lower 1-year risks of hospitalization and surgery than placebo patients.

Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic: the first 100 patients

OBJECTIVE:The aim of this study was to report the clinical outcome and adverse events in the first 100 patients with refractory inflammatory and/or fistulizing Crohns disease treated with infliximab at the Mayo Clinic.METHODS:Patient data was abstracted from medical records. Clinical response was classified as complete response, partial response, and nonresponse.RESULTS:Indications for infliximab therapy were: inflammatory disease (61 patients), fistulizing disease (26 patients), or both (13 patients). Patients received one to seven infusions of infliximab (5 mg/kg) for a total of 242 infusions. In all, 50 patients had complete response, 22 had partial response, and 28 had nonresponse. Median time to response was 7 days (range 1–21 days). Median duration of response was 10.3 weeks (range 3–25 wk). A total of 95 patients received concomitant treatment with immune modifiers. Steroid withdrawal was possible in 29/40 patients (73%). Median time of follow-up was 34 wk (range 14–48 wk). Clinically significant adverse events after infliximab included: abscess formation in two patients (perianal, peristomal), pneumonia in two patients, varicella zoster in three patients, candida esophagitis in one patient, and infusion-related reactions in 19 patients. A total of 23 patients were continued on infliximab as maintenance treatment.CONCLUSIONS:This study provides additional evidence that infliximab is safe and beneficial in clinical practice for refractory Crohns disease.