Presented data from our center showing upto 44% risk reduction for surgery with biologics in pts with enterography proven strictures…a stricture severity score can help identify pts that will benefit most from biologics

Here are links to social media sites for DDW

DDW BLOG http://www.ddwblog.org
Twitter hashtag #DDW12
Facebook http://www.facebook.com/ddwmeeting
Linkedin http://www.linkedin.com/groups?gid=4349272

Looking forward to interacting with you all..
Ashish

Colombel JF, Sandborn WJ, Reinisch W et al. SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010 Apr 15;362(15):1383-95.

Sonic study results published this month in NEJM- The abstract highlights details very well- so I have decided to include it’s link here: http://www.ncbi.nlm.nih.gov/pubmed/20393175

Briefly, RCT to evaluate the efficacy of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate-to-severe Crohn’s disease who had not undergone previous immunosuppressive or biologic therapy. Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P=0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone. Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group.

Our 2 cents: Landmark study suggesting benefit of combination treatment (anti- TNF + azathioprine) over monotherapy in maintaining corticosteroid-free clinical remission (and musosal healing) in patients who have NOT undergone previous immunosuppressive or biologic therapy. Interesting to note nearly double the rate of remission in combination therapy as compared to azathiprine monotherapy (56.8% versus 30%) without risk of serious infections during study period.

Lin MV, Blonski W, Lichtenstein GR.What is the optimal therapy for Crohn’s disease: step-up or top-down? Expert Rev Gastroenterol Hepatol. 2010 Apr;4(2):167-80.

Critical review of evidence for step-up or top-down therapy. Authors reported a recent preliminary study from D’Haens et al. that has provided evidence suggesting that reversing the treatment paradigm from a ‘step-up’ to a ‘top-down’ approach may positively alter the natural course of this illness. However, there is still need for better evidence especially for long term effects of biologics and to identify subset of patients most likely to benefit from top-down since approximately 30% of patients might have been overtreated.

Our 2 cents- studies with better design (such as comparative cohorts or nest case-control) need to be done as evidence still not conclusive that top down therapy alters natural course.http://www.ncbi.nlm.nih.gov/pubmed/20350264

McGovern DP, Gardet A, Törkvist L et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 2010 Apr;42(4):332-7. Epub 2010 Mar 14.

After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, data implicate approximately 30 loci in ulcerative colitis (and confirmed association with 14 previously identified ulcerative colitis susceptibility loci). An analysis of acknowledged Crohn’s disease loci showed that roughly half of the known Crohn’s disease associations are shared with ulcerative colitis.

Our 2 cents: The challenge is how to apply information from rapid evolving information from these prolific GWA studies for clinical practice or research.http://www.ncbi.nlm.nih.gov/pubmed/20228799

Siegel CA, Schwartz LM, Woloshin S, Cole EB, Rubin DT, Vay T, Baars J, Sands BE.When should ulcerative colitis patients undergo colectomy for dysplasia? Mismatch between patient preferences and physician recommendations.Inflamm Bowel Dis. 2010 Feb 23.

In nutshell, 60% of patients would refuse a physician’s recommendation for elective colectomy if dysplasia was detected, despite being told that they had a 20% risk of having cancer now. On average, these patients would only agree to colectomy if their risk of colon cancer “right now” were at least 73%.

Our 2 cents: Conversation with patients regarding colectomy as possible outcome if dysplasia found, need to happen BEFORE rather than AFTER surveillance instituted. http://www.ncbi.nlm.nih.gov/pubmed/20186940

Schreiber S, Colombel JF, Bloomfield R, Nikolaus S, Schölmerich J, Panés J, Sandborn WJ.Increased Response and Remission Rates in Short-Duration Crohn’s Disease With Subcutaneous Certolizumab Pegol: An Analysis of PRECiSE 2 Randomized Maintenance Trial Data.Am J Gastroenterol. 2010 Mar 16.

In this post-hoc analysis, authors found that maintenance of response with certolizumab pegol was achieved in 89.5% of patients with a diagnosis <1 year (P<0.01 vs. placebo), compared with 57.3% of patients with a diagnosis >/=5 years (P<0.001 vs. placebo). Corresponding remission rates were 68.4% (P<0.05 vs. placebo) and 44.3% (P<0.001 vs. placebo), respectively. These data suggest that patients treated with certolizumab pegol 400 mg earlier rather than later, with a confirmed Crohn's disease diagnosis, may achieve better treatment outcomes

Our 2 cents- Good post-hoc study adding to growing evidence that earlier use of TNF agents lead to better response. Wheher this response maintains long term (>5yrs) and leads to change in natural course of disease- remains to be proven (though hoped to be true by many)
http://www.ncbi.nlm.nih.gov/pubmed/20234346

Lowy I et al. Treatment with monoclonal antibodies against Clostridium difficile toxins.Engl J Med. 2010 Jan 21;362(3):197-205. http://www.ncbi.nlm.nih.gov/pubmed/20089970

This is a landmark study that has immediate practical utility for all gastroenterologists. The results are reported from a multicenter double blind RCT of novel neutralizing fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1) for the secondary prevention of C. difficile infection. 200 patients were given standard therapy for C. difficile infection and were randomly assigned to receive a single intravenous infusion of either CDA1+CDB1 or saline placebo. The trial results are impressive. In the intention-to-treat analysis, recurrent infection developed in 7 of 101 patients (7%) in the antibody group, as compared with 25 of 99 patients (25%) in the placebo group, a relative reduction of 72%. Patients with multiple recurrences were particularly likely to benefit, with a relative reduction of 82% in the recurrence rate, as compared with the placebo group. CDA1+CDB1 had no effect on the duration or severity of initial episodes of infection. The monoclonal antibodies were not immunogenic and had an adverse-event profile similar to that of placebo.

There is nice editorial accompannying in current issue of NEJM (http://content.nejm.org/cgi/content/full/362/3/264) According to the editorial, Parenteral administration of monoclonal antibodies will be useful for hospitalized patients who may be unable to take oral medications but may be less convenient for outpatients. The mean age of the patients in the study was 64 years (range, 20 to 101).3 This factor is relevant, since an age of more than 65 years is associated with an increased risk of recurrence by a factor of six, and older patients are likely to benefit most from secondary prevention. Studies are needed to determine whether monoclonal antibodies are useful as adjunctive therapy in patients with severe or fulminant C. difficile infection or whether there is a role for prophylactic passive immunization of patients at high risk for infections associated with health care settings. It is unlikely that monoclonal antibodies will be used for primary treatment, but they may allow a reduction in the number of days of standard antibiotic therapy for C. difficile infection. These novel approaches to breaking the cycle of C. difficile infection, along with continued attention to appropriate antibiotic use and infection prevention and control, offer hope in the battle against this increasingly prevalent and difficult-to-manage disease.

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Malireddy K et al. Recurrence and impact of postoperative prophylaxis in laparoscopically treated primary ileocolic Crohn disease. Arch Surg. 2010 Jan;145(1):42-7.http://www.ncbi.nlm.nih.gov/pubmed/20083753

In this retrospective cahrt review from Mayo Clinic, authors attemted to define risk factors for recurrence and to determine whether postoperative prophylaxis would influence time to recurrence after primary laparoscopic ileocolectomy for Crohn disease. DESIGN: Retrospective record review. SETTING: Tertiary academic medical center. 89 were followed up postoperatively at Mayo Clinic with a median follow-up of 3.5 years with 44 patients (49%) received postoperative immunosuppressive prophylaxis (37 [42%] received azathioprine, 8 [9%] received 6-mercaptopurine, and 3 [3%] received infliximab). In a multivariate model of various risk factors for recurrence, presence of granulomas (and not absence of postop prophylaxis) was the only significant predictor of recurrence (P = .01).

The results of the study are in contrast to many other studies showing value of postop prophylaxis. Some of this could be secondary to biasis in retrospective design and limited power since only 3% using infliximib- the drug which has been strongest association with preventing postop prophylaxis .
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Sandborn WJ et al. Once-Daily Dosing of Delayed-Release Oral Mesalamine (400-mg Tablet) for Maintenance of Remission of Ulcerative Colitis: The QD Dosing Investigation for Efficacy in UC Maintenance Trial.Gastroenterology. 2010 Jan 11. http://www.ncbi.nlm.nih.gov/pubmed/20064514

The aim of this multicentric RCT was to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Asacol 400-mg tablets, dose 1.6-2.4 g/day) compared with twice-daily dosing for maintaining remission in UC patients. The rationale was that the practice of dosing mesalamines in divided doses began with sulfasalazine and was driven by sulfapyridine toxicity. At month 12, 85.4% (379 of 444) of patients receiving once-daily dosing had maintained clinical remission, compared with 85.4% (380 of 445) of patients receiving twice-daily dosing. Authors concluded that once-daily dosing of delayed-release mesalamine at doses of 1.6-2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC.

Switching to once daily dose has a great potential to dramatically increase patient adherence-ashish.

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Pekow JR et al.Outcome after surveillance of low-grade and indefinite dysplasia in patients with ulcerative colitis. Inflamm Bowel Dis. 2009 Dec 21. http://www.ncbi.nlm.nih.gov/pubmed/20027656

In this retrspective chart review, authors tried to measure outcomes of UC patients with low-grade and indefinite dysplasia since its current management and f/u remain controversial. 35 patients were included in the analysis, of whom 2 patients with IND and 2 patients with LGD developed HGD or CRC over a mean duration of about 4 years.In total, the incident rate for advanced neoplasia for all patients was 2.7 cases of HGD or CRC per 100 person-years at risk. Flat lesions had higher incident rate of 4.3 cases per 100 person years while polypoid LGD had low rate of 1.5 cases per 100 person-years at risk, respectively. Patients with PSC had an incident rate of 10.5 cases per 100 years of patient follow-up-consistent with prior studies.

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Ippoliti A et al (Targan SR senior author). Combination of innate and adaptive immune alterations increased the likelihood of fibrostenosis in Crohn’s disease. Inflamm Bowel Dis. 2009 Dec 21. http://www.ncbi.nlm.nih.gov/pubmed/20027650

The aim of this study was to confirm these relationships between the presence of NOD2 variants (innate immunity) and antibodies to oligomannan, CBir, outer membrane porin-C (OmpC), and I2 (adaptive immunity) in CD patients with fibrostenosis. Sera and DNA from 731 unrelated CD patients were tested for NOD2 variants (SNP 8, 12, and 13) and the antibodies. The results were correlated with CD phenotypes, fibrostenosis, internal penetrating, perianal penetrating, and ulcerative colitis (UC)-like as well as other clinical features. Authors found that the presence of both NOD2 allelic variants and level of antibodies was primarily associated with fibrostenosis.In the 316 patients with fibrostenosis the prevalence of NOD2 variants was significantly correlated with the antibody titer by quartile sum score. Further, when these patients with fibrostenosis were clustered by quartile sum score, the odds ratio for fibrostenosis was significantly higher in the patients with NOD2 variant alleles within each cluster, indicating synergy. Authors concuded that the defects of innate (NOD2 variants) and adaptive (antibodies to microbial antigens) immunity act synergistically to increase the risk of the fibrostenosis phenotype.

Your comments are welcome

Afif W, Loftus EV Jr, Faubion WA et al.Clinical Utility of Measuring Infliximab and Human Anti-Chimeric Antibody Concentrations in Patients With Inflammatory Bowel Disease. Am J Gastroenterol. 2010 Feb 9. http://www.ncbi.nlm.nih.gov/pubmed/20145610

EXPERT COMMENTARY BY DR BRET A LASHNER, MD, MPH
This important study highlights the clinical usefulness of measuring infliximab antibodies and infliximab levels in Crohn’s disease patients who have lost their response to infliximab.

In 155 patients (78% CD) when Infliximab levels and HACA were ordered because of loss of response (49%),Partial response (22%)or Autoimmune / delayed hypersensitivity reaction (10%), HACAs were identifi ed in 35 patients (23 % ), therapeutic infl iximab concentrations were found in 51 patients (33 % ), and
subtherapeutic concentrations were found in 69 patients (44 % ).Only 6 (4 %) could not be assessed b/w of lack of proper timing.

Take Home points:
There appears to be a scientific way to choose among the biologic therapies in patients who have lost response to infliximab.

1) Patients with high antibody levels should be switched to another antii-TNF therapy – over 90% of patients would be expected to respond.

2) In patients with low infliximab levels, dose escalation was associated with more than an 80% response rate.

3) In patients with a high infliximab levels and no or partial response, further testing is essential to confirm inflammation because a majority of those patients will not have active disease. Those who do have inflammation probably should be considered for biologic agents with different mechanisms of action, such as natalizumab or ustikinumab.

4) It is essential that timing for measurement of infliximib concentrations should be right to make it interpretable (therapeutic levels at 4 weeks > 12 mcg/ ml or detectable levels ( > 1.4 mcg / ml) at dosing trough.

Till now, the clinical utility of HACA and infliximab levels in routine practice remained unclear. This study showed the value of these tests in patients who are not responding or inadequately responding to infliximab.

Should these tests become standard of care on every patient who is inadequately responding to infliximab? Please add your comments

ashish

Leaving for vacation so will not be able to blog for next 2 weeks. This way all of you also get much needed respite from trying to stay up to date with literature!!

Anyway, the winner article is by Marla Dubinsky et al-
Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease. Inflamm Bowel Dis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=20014019

The authors found that in 22 of non respondents to Anti TNF agents (out of 94 subjects), the most predictive model included 3 novel “pharmacogenetic” GWAS loci, the previously identified BRWD1, pANCA, and a UC diagnosis ( (R square = 0.82 and area under the curve [AUC] = 0.98%). The relative risk of nonresponse increased 15-fold when number of risk factors increased from 0-2 to >/=3.

I am impressed by the magnitude of r square and AUC in predicting non response to anti-TNFalpha agents- This is more than what we normal see from GWA studies alone and shows the benefit of combining phenotype and genotype information in prediction models.

Yang Z et al. Meta-analysis: preoperative infliximab treatment and short-term postoperative complications in patients with ulcerative colitis.Aliment Pharmacol Ther. 2009 Nov 19. PMID 19925496

From a total of 5 observational studies, authors reported that preoperative infliximab use increased short-term total postoperative complications (OR 1.80, 95% CI 1.12-2.87), with subgroup analysis showing a trend towards increased postoperative infection(OR 2.24, 95% confidence interval [CI] 0.63-7.95) but not that of non-infectious (OR 0.85, 95% CI 0.50-1.45) postoperative complications.

The key question is the quality of included observational studies and whether infliximib associated risk is independent of steroid use or not. ANY THOUGHTS?

1. Nielsen OH et al. Diagnosis and management of fistulizing Crohn’s disease. Nat Clin Pract Gastroenterol Hepatol. 2009 PMID 19153563

A nice review of pathology and current therapeutic options for management of fistulizing CD. Internal fistulas, such as ileoileal or ileocecal fistulas, are mostly asymptomatic and do not require intervention. By contrast, perianal fistulas can be painful and abscesses may develop that require surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy.

2. Wu H, Shen B. Pouchitis and pouch dysfunction. Med Clin North Am. 2010 Jan PMID 19913207
Review of various pouch disorders

3. Zuo L et al.Targeting delivery of anti-TNF-{alpha} oligonucleotide into activated colonic macrophages protects against experimental colitis.
Gut. 2009 Dec 1. PMID 19951904

In 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and CD4+CD45RB(hi) T cells transfer colitis mouse model, Intracolonic administration of antisense oligonucleotide (ASO) complex resulted in the successful delivery of ASO into activated colonic macrophages and a significant reduction of colonic TNF-alpha in colitis mice. The single injection in TNBS colitis or repeated treatment in CD45RBhi transfer colitis both significantly ameliorated the clinical and histopathologic severity of the wasting disease, reduced tissue levels of inflammatory cytokines, and abrogated body weight loss, diarrhea and intestinal protein loss.

4. Van Dieren JM et al.Local Immune Regulation of Mucosal Inflammation by Tacrolimus. Dig Dis Sci. 2009 Dec. PMID 19949865

After rectal administration in mice, tacrolimus blood levels were comparable to those obtained by oral intake. However, rectally treated mice exhibited a 14-fold higher concentration of tacrolimus within their colonic tissue than orally treated mice and resulted in a local but not a systemic immune suppression in mice. This may result in less systemic immunosuppression related toxicity.

5. Vargo JJ et al. Position statement: Nonanesthesiologist administration of propofol for GI endoscopy. Hepatology. 2009 Dec;50(6):1683-9. PMID 19937691

Doherty G, et al. Interventions for prevention of post-operative recurrence of Crohn’s disease. The Cochrane Database of Systematic Reviews 2009 Issue 4, 2009
http://www.cochrane.org/reviews/en/ab006873.html

In metanalysis of 23 RCTs, author reported that the use of nitroimidazole antibiotics reduces the risk of clinical (RR 0.23; NNT=4) and endoscopic (RR 0.44; NNT = 4) recurrence relative to placebo. However, there was about double the incidence of serious adverse events (RR 2.39). Mesalamine therapy was also associated with a significantly reduced risk of clinical recurrence (RR 0.76, NNT = 12), and severe endoscopic recurrence (RR 0.50; NNT = 8 ) when compared to placebo. Azathioprine/6MP was also associated with a significantly reduced risk of clinical recurrence (RR 0.59; NNT = 7), and severe endoscopic recurrence (RR 0.64; NNT = 4), when compared to placebo. Neither agent had a higher risk than placebo of serious adverse events. When compared to azathioprine/6MP, mesalamine was associated with a higher risk of any endoscopic recurrence (RR 1.45, 95% CI 1.03 to 2.06), but a lower risk of serious adverse events (RR 0.51; 95% CI 0.30 to 0.89).

It is a bit surprising to see the beneficial effect of mesalamine therapy reported in this meta-analysis.It would be interesting to analyze individual trials of mesalamine to see if beneficial effect was predominantly seen in colitis patients or not.