Tag Archives: Ulcerative colitis

Tofacitinib –a JAK Inhibitor for UC

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There are definitely a lot of new therapies on the horizon for inflammatory bowel disease.  One of these agents is likely to be tofacitinib which has shown efficacy for active ulcerative colitis (NEJM 2012; 367: 616-24).

Background: Tofacitinib is a selective oral inhibitor of Janus kinase (JAK) which mediates activity for multiple cytokines, including interleukins 2, 4, 7, 9, 15, and 21.  Blockage of a common signaling molecule by these cytokines “should result in suppression of both T and B cells while maintaining regulatory T-cell function.  It has shown efficacy for organ allograft rejection, rheumatoid arthritis, and psoriasis.”  A previous small study by these investigators did not demonstrate efficacy in Crohn’s disease (Gastroenterology 2011; 140: Suppl: S124 Abstract).

Design: In this study which began as a double-blind, placebo-controlled, phase 2 trial, tofacitinib or placebo was given to 194 adult patients (from 51 centers in 17 countries) with moderate-to-severe active ulcerative colitis. Dosing for tofacitinib included groups receiving 0.5 mg, 3 mg, 10 mg, or 15 mg (all BID).  “The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system.”  Most of these patients had failed conventional therapy, including mesalamine, corticosteroids, immunosuppressants, and anti-TNF agents.

Results: At 8 weeks, the primary outcome with the highest doses (10 mg & 15 mg) of tofacitinib had clinical response rates of 61% (p=0.1) and 78% (p<0.001) respectively compared with a 42% placebo response.  Clinical remission (Mayo score ≤ 2) occurred in 48% and 41% respectively (both p<0.001) compared with 10% in placebo group.  Endoscopic remission was noted in 30% and 27% respectively (both p<0.001) compared with 2% of placebo group.

In addition, tofacitinib administration improved CRP values and fecal calprotectin concentrations (Figure 2 of article).

Potential adverse effects included the following

  • neutropenia (ANC 1000-1500) observed in three treated patients
  • two tofacitinib patients (10 mg group) developed abscesses
  • mild increases in LDL and HDL were noted and dose-related (these changes have been seen in rheumatoid arthritis patients as well)

Additional reference:

  • N Engl J Med 2012; 367:495-507 | August 9, 2012.  Tofacitinib for rheumatoid arthritis

Serology in IBD

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Serological antibodies against a number of antigens have shown some utility in differentiating inflammatory bowel disease (IBD) from non-IBD and in distinguishing Crohn’s disease (CD) from ulcerative colitis (UC).  A recent article evaluated 204 articles in a systematic review of these serological markers (Inflamm Bowel Dis 2012; 18: 1340-55).

The study has several useful tables and a long list of references.  In its Table 1, 10 serologies are listed with a range for prevalence in CD, UC, alternative GI conditions, and in healthy population.  Table 2 summarizes the data in terms of sensitivity, specificity, positive predictive value, negative predictive value for these antibodies in determining IBD from non-IBD.

With regard to specific antibodies, the review highlights 10 antibodies:

1. Anti-neutrophil cytoplasmic antibodies (ANCA).  Autoantibody directed against a constituent of neutrophil granules.  With IBD (especially UC), an atypical perinuclear (pANCA) staining pattern with indirect immunofluorescence and DNase-sensitive make this pattern different from ANCA due to vasculitis.

2-7. Anti-glycan antibodies –directed against cell wall microbes and reflect interaction between the immune system and glycosylated cell wall components of microbiota.

2. Anti-Saccharomyces cerevisiae (ASCA IgA and IgG) –antibodies directed against yeast cell wall.  While ASCA antibodies are commonly found in CD patients, 20-25% (or higher in some studies) of healthy relatives will test positive for these antibodies as well.  Approximately 6% of relatives of UC patients will be ASCA-positive.

3. Anti-laminaribioside carbohydrate IgG antibodies (ALCA) –antibodies directed against laminaribioside

4. Anti-chitobioside carbohydrate IgA antibodies (ACCA) –antibodies directed against chitobioside

5. Anti-mannobioside carbohydrate IgG antibodies (AMCA) –antibodies directed against mannobioside

6. Anti-L –antibodies directed against laminarin (large polysaccharide)

7. Anti-C –antibodies directed against chitin (large polysaccharide)

8. Anti-OmpC.  OmpC is a transport protein of E coli

9. Anti-I2.  I2 is a Pseudomonas-associated antigen

10. Anti-CBir1.  CBir1 is a bacterial flagellin antigen

Conclusions:

  • Serology has only limited value for the initial diagnosis of IBD.
  • Serology has ‘better value’ in differentiating CD from UC, though there is substantial variability in serologic responses in both diseases.  Probably, serology is most useful in unclassified IBD (IBD-U) in preoperative setting; serology may help predict risk of developing complications among patients undergoing pouch surgery.
  • Serology is useful in predicting a complicated disease course. The presence and magnitude of these antibodies are strong predictors of disease progression.

Additional references:

  • Pediatrics. 2010 Jun ;125 (6):1230-6.  Shortcomings of the inflammatory bowel disease Serology 7 panel. 
  • -Clin Gastro & Hep 2008; 6: 1105. Increased immune reactivity/markers associated with aggressive disease.
  • -IBD 2006; 12:1122. Expression of I2 antibodies (against a bacterial antigen of psedomonas fluorescens) was highly associated with clinical response to diversion. 15/16 with I2-pos had clinical response; 2/11 I2-neg had clinical response.
  • -IBD 2008; 14: S4 abstract 0010. Practical experience with IBD serology (n=90) much less accurate than reported by Prometheus: overall accuracy of 63% (vs 92%), 66% sensitivity (vs 93%), 59% specificity (vs 95%), 75% PPV (vs 96%), and 49% NPV (vs 90%). In this population, 34% of known IBD were incorrectly predicted. Of 32 who did not have any evidence of IBD after clinical investigation, 40% (13) were seropositive.
  • -Clin Gastro & Hep 2008; 6: 1105. Increased immune reactivity/markers associated with aggressive disease.
  • -IBD 2008; 14; 129. Serologic markers not very useful clinically.
  • -Pediatrics 2007; 119: e193. IBD serology performed poorly in comparison to combination of Hgb/ESR with regard to sensitivity (60% vs. 83%), specificity (92% vs. 96%), positive predictive value (60% vs. 79%) for IBD in children, n=227. Also one third of all positive serology in patients w/o IBD. The positive predictive value in patients w/o rectal bleeding was 35% vs 60% for routine tests.
  • -Gastroenterol 2006; 131: 366. antibodies against laminaribioside, chitobioside, and mannan have predictive value in detecting Crohn’s disease.
  • -Gastroenterol 2006; 130: 1078. Unaffected relatives positive for either OmpC or ASCA in 20% in large cohor (n=619 unaffected relatives. OmpC present in up to 44% of CD pts, up to 24% of UC pts, and 6% of controls.

Colonic disease and PSC

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While primary sclerosing cholangitis (PSC) has been associated with inflammatory bowel disease, and ulcerative colitis (UC) in particular, the pathogenesis of this relationship has not been established.  A fascinating observation on this relationship is that an inflamed colon is important in PSC development (Clin Gastroenterol Hepatol 2012; 10: 439-41).

In this study which reviewed 2754 Irish patients with IBD, 59 (2.2%) had PSC.  PSC incidence correlated with increasing colonic involvement.  Among the 13 patients with Crohn’s disease, none had isolated small bowel disease.  The second part of the study involved a review of 82 separate PSC patients attending the Irish National liver transplant unit.  The majority of ulcerative colitis patients had a pancolitis; all 10 PSC patients with Crohn’s disease had colonic involvement.

Since PSC occurs without IBD, colonic inflammation is not necessary for PSC development.  However, in patients with IBD, colonic inflammation is very important.  In fact, in a previous study of 53 PSC-IBD patients, no UC patient status post a colectomy had recurrent liver disease following liver transplantation whereas seven patients with intact colons had recurrent disease following liver transplantation.

The authors speculate that bacterial translocation along with subsequent portal bacteremia may be an important step in pathogenesis among these patients.

Additional references/previous posts:

Improve Care Now

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Several years ago, “ImproveCareNow” Network was established with a goal of improving the quality of care children with inflammatory bowel disease. https://improvecarenow.org/ (http://www.youtube.com/watch?v=beG2eMROWqg)

Documentation of some outcomes of this effort have now been published (Pediatrics 2012; 129: e1030-e1041).  In this study from six U.S. centers, data from 843 children with Crohn’s disease and Ulcerative Colitis were available.  Centers were eligible to participate if they did not have extensive quality improvement (QI) experience and if they were able to enroll >75% of their IBD patients.  During the course of the study (2007-2010), there were increases in the proportion of patients with measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, increased percentage of individuals receiving an appropriate thiopurine dosage, and an increased percentage of patients with inactive disease.  In Crohn’s disease, the number with inactive disease changed from 55% to 68%; in ulcerative colitis, the number increased from 61% to 72%.  

This study shows significant progress in these patients and the potential benefit of a more-structured approach.  However, some of the improvements in these outcomes may not be to process improvements. 

Study limitations:

  • The study does not document the rate of inactive disease in non-participating centers; thus there is not an adequate control population.  Given more widespread use of biologic therapies, this may account for much of the improvement in outcomes.   In fact, the study does not describe the percentage of patients receiving thiopurines or biologic agents.
  • The use of the physician global assessment (PGA) as indicative of disease activity.  The authors acknowledge that “PGA ….is a relatively subjective measure.”  A more reliable measure of disease activity like a stool calprotectin, endoscopy, or imaging study improvement would have been helpful.  
  • Better documentation or better outcomes? It is not clear whether some of the improvement reflects better documentation or improved care delivery.

Despite the limitations of this study, it is a good starting point.  The goal of improving the care of patients is shared by almost all physicians.  One way to start making a difference is measuring specific outcomes and targeting specific goals/checklists. Going forward with QI there are many QI hurdles: 

  • Defining optimal care is nearly impossible, there are few trials comparing efficacy & difficult to judge risk/benefit ratio of many therapies.
  • Difficulty selecting appropriate outcome measures -indications for hospitalization and surgery are not clear-cut in many cases.  Surgery may be an appropriate treatment rather than a negative outcome. 
  • Risk adjustment is an imperfect science.

Goals with Quality Improvement:

  • Plan-Do-Study-Act cycles.
  • Learning from high-performing centers -benchmarking

Warranted vs unwarranted variations:
Unwarranted: selecting inadequate dosing of medications, failure to check for TB before remicade/biologics, failure to consider drug interactions, failure to discuss options with families
Warranted: variation due to differences in disease (eg budesonide for ileitis but not pancolitis), variation driven by patient preferences (eg. using NG instead of corticosteroids)

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

“Not everything that counts can be counted, and not everything that can be counted counts.” –Albert Einstein

Additional references on quality improvement:

  • Free Self Management Handbook endorsed by ImproveCareNow:

https://improvecarenow.org/patients/self-management-handbook

  • -JPGN 2009; 49: 272.  Review of quality measures/history.
  • -Kohn LT, et al. To Err is Human: Building Safer Health System.  Nat’l Academy Press; 2000
  • -Crossing the quality chasm.  Wash DC: Nat’l Academy Press; 2001.
  • -Clin Gastro & Hep 2010; 8: 709.  Quality indicator sets in cirrhosis.
  • -J Pediatr 2005; 146: 744-50.  Bucuvalas JC et al.  Adjusting calcinerin inhibitor dosing
  • -IBD guidelines: www.cincinnatichildrens.org/svc/alpha/health-policy/ev-based/ibd.htm
  • -JPGN 2009; 49: 297.  Variation in care in pediatric Crohn disease. (Our center participated in this study)
  • -J Pediatr 2009; 154: 582.  Ventilator assoc pneumonia reduced w bundle of hand hygiene, elevated HOB, not changing ventilator circuits except when soiled & mouth care
  • -“The Learning Curve”(Atul Gawande) in The Best American Essays 2003 -some CF ctrs outperform, extending life expectancy ~14yrs.
  • -” A Surgeons Notes on Performance-Atul Gawande
    -NEJM 2007; 357: 2652.  Nice editorial.
  • www.icsi.org
  • www.qualityforum.org
  • www.ambulatoryqualityalliance.org
  • www.ncqa.org
  • www.cms.hhs.gov/hospitalqualityinit

Comments from lead author forwarded to blog:

Thanks for including our recent paper in your blog.  I agree with the study limitations as you mentioned, but wanted to put a couple of things in context.  We actually thought very hard about the issue of a control group, and specifically how to determine what the remission rate would be without the intervention.  We could not come up with a reasonable comparator (very few people/groups outside of ICN even know what the remission rate of their population is).  One very rough measure (which we did not feel was legitimate to include) is the rate of remission for new sites as they are joining the collaborative.  Established sites with complete participation have better outcomes than newer sites or sites that participate less fully, suggesting that at least a significant portion of the effect is due to the QI intervention rather than secular trend.  As far as the objective measures for outcomes, I know you realize that we are not able to mandate specific objective evaluations for a QI/observational research study, so we may never be able to use mucosal healing (for example) as our measure of remission.  However you probably noticed in the paper that we did demonstrate improvements in objective measures including sPCDAI, PUCAI and use of corticosteroids.  Certainly improvements in process measures may have been due in part to better documentation, but it is unlikely that objective outcome measures improved due to documentation. Thanks again for sharing our work with your audience.

Infliximab for children with Ulcerative Colitis

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A large multicenter study of patients 6-17 years of age has shown that infliximab (IFX) can be effective for ulcerative colitis (UC) (Clin Gastroenterol Hepatol 2012; 10: 391-99). Our pediatric GI group was part of this multicenter study which enrolled 60 patients. Stanley Cohen was lead CCDHC investigator and is one of the authors.

At week 8, 44 patients (73.3%) had a clinical response to IFX.  This group of ‘responders’ were eligible for the maintenance phase of the study and were divided into a q8 week treatment group (Q8) and a q12 week treatment group (Q12).  During the maintenance phase, patients who had lost response were eligible to have a dose escalation from 5 mg/kg/dose to 10 mg/kg/dose. At week 54,  patients receiving every Q8 had a remission rate of 38% (8 of 21) whereas among the Q12 responder group only 18% (4 of 22) were in remission.  Overall, the authors projected that if the entire cohort had been placed on every 8 week treatment, the response would have been 28% at week 54; in addition, analysis with ‘real-world’ dose adjustments could achieve a 42.8% remission rate.

The main serious adverse events reported during the study was worsening of UC.  Two patients were receiving immunomodulators during the study. Five of 60 patients required a colectomy within the 54-week study period.

The risk/benefit ratio of TNF antagonists for UC has been discussed in related posts (see below).

Previous related posts:

TNF antagonists and UC

Only one chance to make first impression

Additional references:

  • -Am J Gastroenterol (Oussalah A et al) 2010; 105: 2617-25. Multicenter study of IFX for UC.
  • -Gastroenterology 2010; 138: 2282. Severe pediatric UC. 25/33 responded to IFX. colectomy rate 19% at 1 year.

VTE with IBD

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In our children’s hospital, work is underway to systematically screen children for risk factors for venous thromboembolism (VTE) and to establish an algorithm to lower the risk of a VTE with either mechanical or pharmacologic treatments. One of the risk factors has been the presence of inflammatory bowel disease (IBD).  The absolute risk of IBD for VTE is not clear.  However, a recent study relates the risk among a large Danish population of adults and children (Gut 2011; 60: 937-43).

The study included 49,799 patients with IBD (14,211 Crohn’s, 35,229 UC) and compared with 477,504 members of the general population.  VTE risk for IBD was increased with HR of 2.0.  The incidence of VTE increased with age; however, the RR was higher in younger patients.  Among those less than 20 years, HR was 6.6 for VTE; HR 6.0 for DVT and 6.4 for PE.  In this age group, “unprovoked” VTE had HR of 4.5.  Unprovoked VTE was defined as event occurring without malignancy, recent surgery, pregnancy or fracture.

Although the relative risk is increased, the authors caution that the absolute risk in younger patients is low.  In those IBD patients less than 20 years, the incidence rate was 8.9 per 10,000 person years.  In contrast, in those IBD patients older than 60, the incidence rate was 54.6 per 10,000 person years.  There did not seem to be a significant difference between Crohn’s disease and ulcerative colitis in absolute or relative risk. The authors conclude that in those IBD patients younger than 20 years without ‘other VTE risk factors or limited mobility, the benefits of prophylaxis may no longer outweigh the risks.”  In older patients (>60 years), even outpatients experiencing flares might benefit from VTE prophylaxis.

Additional references:

  • -NEJM 2012; 366: 860 (letter to editor). Authors emphasize importance of VTE with UC, especially during flares.
  • -Lancet 2010; 375: 657-63. VTE with active IBD and in remission.
  • -Clin Gastroenterol Hepatol 2008; 6: 41-5. Thrombosis with IBD.
  • -Gut 2004; 53: 542-8. IBD -risk factor for VTE?
  • -Gut 2004; 53 (suppl 5): v1-16. IBD guidelines for management.

TNF antagonists and UC

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In my fellowship (15 years ago), the use of thiopurines (eg. azathioprine, 6-mercaptopurine) for ulcerative colitis was debated.  Many physicians urged colectomy rather than using these drugs which could have long-term consequences.  At the time, the risk of thiopurines was less well-understood.  Over time, the use of these agents has become common when mesalamine products were ineffective.  The same issue comes up with TNF antagonists versus colectomy.

A recent study provides more information on the effectiveness of adalimumab for patients with moderate-to-severe UC but does not settle this debate (Gastroenterology 2012; 142: 257-65).  In this study, termed ‘ULTRA-2’ (Ulcerative colitis long-term remission and maintenance with adalimumab 2), the  efficacy of adalimumab for induction & maintenance of remission was studied in 494 patients.  This was a randomized, double-blind, placebo-controlled study; average age was 40 years.

Clinical remission in the adalimumab group were 16.5% at 8 weeks (9.3% placebo).  At 52 weeks, 17.3% in the adalimumab group were in remission (8.5% placebo).  Among patients naive to anti-TNF agents, the response rate was 21.3% at week 8 & 22% at week 52.  Safety overall was similar in both groups; however, in the adalimumab group one patient developed gastric cancer and one developed squamous cell carcinoma.

The authors conclude that adalimumab is safe and more effective than placebo in inducing and maintaining remission among patients with moderate-to-severe UC.

A second study, also published this past month, looks at the use of infliximab for maintenance therapy for UC (Inflamm Bowel Dis 2012; 18: 201-11).  Patients who had achieved benefit from ACT-1 and ACT-2 studies were followed for three years.  Dosage of infliximab could be adjusted.  A total of 229 patients entered the study.  During the study, 70 patients (30.6%) discontinued infliximab due to adverse effects (10.5%), lack of efficacy (4.8%) or other reasons (15.2%); the majority were able to continue infliximab.  The authors indicate that no new safety issues were identified. Yet, there were two deaths among the infliximab group including a 19 year-old nonsmoker who developed lung cancer and a lethal case of histoplasmosis.

Because the improvement compared to placebo is modest with both of these agents, the question about whether to use these medications or proceed to surgery in UC patients is unanswered.

Additional references:

  • -Aliment Pharmacol Ther. 2008 Oct 15;28(8):966-72. Epub 2008 Jul 24.  Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience.
  • -Am J Gastroenterol (Oussalah A et al) 2010; 105: 2617-25. Multicenter study of IFX for UC
  • -Gastroenterology 2010; 138: 2282. Severe pediatric UC. 25/33 responded to IFX. colectomy rate 19% at 1 year.
  • -Gastroenterology 2009; 137: 1204 (ed), 1250. lower colectomy rates at 54wks in IFX vs placebo (+concomitant meds): 10% vs. 17%.
  • -Clin Gastro & Hep 2008; 6: 1112. Do NOT use CYA post infliximab and vice versa. n=19. 1 death due to sepsis. Remission rates occur in ~1/3rd but are of short duration.
  • -NEJM 2005; 2462. 69% clinical response @ 8 weeks (vs. 37% placebo) & 45% at week 54 (vs. 20% placebo).
  • -JPGN 2004; 38: 298. 82% short-term response, 63% sustained response; n=16.

Why are we seeing so many more cases

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In this month’s Gastroenterology, two articles offer some insight into this question for two separate problems.

With regard to inflammatory bowel disease, (IBD) –both Crohn’s disease and UC –there is an increasing prevalence and incidence worldwide (Gastroenterology 2012; 142: 46-54). This article identified 8444 previous citations and then identified 262 studies with relevant data.  Overall, the highest incidence and prevalence of these disorders occurs in Europe and North America.  In North America, Canada has the highest prevalence with 0.6% of the population having IBD.

After going through the statistics, the authors offer some discussion on why IBD is increasing.  In the developing parts of the world, some of the increase is due to the ability to detect and differentiate these disorders due to improving access to medical care/colonoscopy.  In the areas of the world with the highest incidence/prevalence, environmental risk factors are playing an important role.  Potential factors include microbial exposures, sanitation, lifestyle behaviors, medications, and pollution.  These factors are supported by other epidemiological studies which show that individuals who move from low prevalence areas to higher ones are at increased risk for IBD, especially among first generation children (Gut 2008; 57: 1185-91).  Furthermore, in low prevalence regions, IBD is increasing with more industrialization (Chin J Dig Dis 2005; 6: 175-81, Indian J Gastroenterol 2005; 24: 23-24.)  Exact mechanisms are poorly understood; however, even in the U.S. it is recognized that rural/farm exposure at a young age reduces the likelihood of developing IBD at a later age (Pediatrics 2007; 120: 354).

Celiac disease, likewise, has seen an increase in prevalence.  With celiac disease, the proliferation of widely available and more accurate serology has been crucial in the identification of more patients.  However, like IBD, there is likely a role for changing microbial environment contributing to an increasing case burden.  Recently, reports have shown that the risk of celiac disease can be influenced at birth (Gastroenterology 2012; 142: 39-45).  Although the absolute risk was modest, there was an increased risk demonstrated with elective but not emergent cesarean delivery among a large nationwide case-control study from Sweden.  Among the cohort of 11,749 offspring with biopsy-proven celiac (with matched control group of 53,887), elective cesarean delivery resulted in an odds ratio of 1.15 (confidence intervals 1.04-1.26).  This study confirmed other studies which have shown an increased risk with cesarean delivery (Pediatrics 2010; 125: e1433-e1440).  Some of the strengths of this Swedish study, included the fact that the deliveries were separated based on elective or emergency cesarean delivery and were controlled for whether the mother had celiac disease.  (Pregnant women with celiac disease have an increased risk of cesarean delivery.)  The authors speculate that the reason why elective cesarean deliveries increase the risk of celiac disease is that microbial exposures at birth likely influences perinatal colonization –>affects intestinal immune response and mucosal barrier function. Offspring of women with emergency cesarean delivery would be more likely to be exposed to bacteria from the birth canal and no significant increase risk of celiac disease could be identified in this group.

Thus how we are born and where we live make a big impact on the likelihood of developing these GI disorders.

Additional References:

  • -Gut 2011; 60: 49-54. n=577,627 Danish children. Use of antibiotics associated with increase risk of Crohn’s disease (but not UC), especially at younger ages (3-11month of age, & 2-3yrs of age). Each course increased risk by 18%. In children with >7 courses, relative risk was 7.3. especially penicillins.
  • -NEJM 2011; 364: 701, 769. Living on a farm decreases risk of childhood asthma.
  • -Nature 2011; 476: 393. ‘Stop killing beneficial bacteria.’  For example, killing H pylori likely increases risk of esophageal adenocarcinoma
  • -Gastroenterology 2011; 141: 28, 208. GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -Gastroenterology 2010; 139: 1816, 1844. Microbiome & affect on IBD vs mucosal homeostasis
  • -J Pediatr 2010; 157: 240. Microbiota in pediatric IBD -increased E coli and decreased F praunsitzil in IBD pts.
  • -J Pediatr 2009; 155: 781. early child care exposures lessens risk for asthma.
  • -IBD 2008; 14: 575.  Role of E coli in Crohn’s
  • -Lab Invest 2007; 87: 1042-1054. Role of E coli in Crohn’s
  • -Pediatrics 2007; 120: 354. Crohn’s less common after repeated exposure to farm animals in 1st year of life.

More practical information and links to other websites can be found at http://www.gicareforkids.com.