Tag Archives: Crohn’s

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.

Assessing and discussing risk of lymphoma in IBD

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A recent article has shown that the absolute lymphoma risk from medications in children and young adults with IBD is quite low (Inflamm Bowel Dis 2012; 18: 838-43).

In this single center study from 1979-2008, 1374 pediatric IBD patients had charts reviewed to determine whether lymphoma developed.  In total, two male patients who had received thiopurines developed lymphoma (one Hodgkin, one anaplastic large cell) in 6624 patient-years of follow-up.  Both patients are alive after chemotherapy.  Mean follow-up was 4.8 years per patient.  The absolute lymphoma incidence rate was 3 per 10,000 patient-years; after thiopurine exposure, the rate was 4.5 per 10,000 patient-years compared to an expected 0.58 per 10,000 patient-years.

In this study, 22% of the patients had received TNF inhibitors.  None developed lymphoma.  The risk of biologics could not be fully assessed due to a limited study period: 713 person-years taking the medication.

The risk of thiopurine-associated lymphoma was similar to previous studies but did not reach statistical significance.  As related in other studies, the risk of biologic agents, like Remicade, Humira, and Cimzia, is heavily influenced by whether patients had also received immunomodulators.

One useful way to try to convey this risk has been with diagrams.  One useful diagram is a palette of one thousand people or of 10,000 people showing the absolute risk and one showing the risk for other complications like infection.  You can make your own by going to the following link:

Download Communication Tools

RiskComm

Additional references/blog entries:

Only one chance to make first impression

Biologics | Living Longer | Arthritis Today Magazine -From Arthritis magazine: biologics improve survival in Rheumatoid arthritis

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:

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.

Food as medicine

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Two recent articles add some useful information regarding enteral therapy for Crohn’s disease (Inflamm Bowel Dis 2012; 18: 246-53 & JPGN 2012; 54: 298-305).

The first article enrolled 34 children with newly-diagnosed Crohn’s disease.  Patients were divided into elemental and polymeric formula groups and followed in a prospective, double-blind randomized controlled trial for two years.  Measures of improvement included the PCDAI as well as fecal calprotectin and fatty acids.  Both groups of patients responded clinically.  93% (14/15) of the elemental formula group achieved remission based on PCDAI scores (<11) and 79% (15/19) of the polymeric formula group.  The initial treatment was use of formula (along with only clears) either by NG or oral for 6 weeks.  All patients had NG placed at time of endoscopy and if sufficient oral intake was demonstrated (for 2 days), NG was removed.  All subjects had small bowel and colonic disease.  Although calprotectin levels decreased, they remained very elevated.  In the EF group, the median calprotectin dropped from 2023 μ/g to 1113 μ/g, though only one patient had a level below 400; similarly in the PF group the calprotectin dropped from 1929 μ/g to 1134 μ/g, and only two patients had a level below 400.  Some to the reasons why changes in diet may be useful have been alluded to in a previous post: Eat your veggies…if you don’t want to get sick.

The second reference is a clinical guideline on the use of exclusive enteral nutrition EEN).  The introduction notes that 65% of European pediatric gastroenterologists use EEN compared to 4% for North American pediatric gastroenterologists.  In pediatric trials, EEN and corticosteroids were considered ‘equally effective’ in a pediatric meta-analysis which included five randomized controlled trials (n=147).  However, a Cochrane review favored corticosteroid treatment over EEN in a meta-analysis that included adult and pediatric patients (n=192 EEN, n=160 corticosteroids).  According to the authors, small studies have demonstrated other potential advantages of EEN including higher rates of mucosal healing and better linear growth.  With regard to mucosal healing, the initial cited study casts with ongoing elevated calprotectin indicates that this does not occur in the majority of children with EEN therapy.  Other caveats:

  • Disease location: some evidence favors small bowel disease rather than colonic disease
  • Formula composition: does not seem to matter whether elemental or polymeric
  • Duration of therapy: majority treat for 6-8 weeks of EEN.  The authors recommend at least 8 weeks
  • Time for response: Inflammatory markers improve in a little as a week, remission typically 2-4 weeks
  • Concomitant medications: many places initiate immunomodulator treatment; others cycle EEN
  • Start with goal 120% of ‘maintenance’ nutrient needs.  On 1st day, authors recommend starting at 1/2 goal volume and gradually increase over 1-2 days
  • Partial enteral nutrition (PEN) (eg. overnight feedings & normal daytime diet) has been helpful in improving growth and may improve remission rates.
Why not EEN or PEN? Potential barriers include cost, difficulty changing diet, fear of tube feedings, and more acceptable alternatives.  At the same time, some of these barriers could be overcome.  Quality of life measures have improved in children receiving enteral nutrition.

The use of more top-down therapy may affect all of the above considerations (Only one chance to make first impression).

Additional references:

  • -Cochrane Database Syst Rev 2007; CD000542.  Enteral nutritional therapy vs corticosteroids to induce remission in Crohn’s disease.
  • -Gastroenterology 2011; 141: 742. AGA guidelines on use of enteral nutrition in wide variety of conditions.
  • -Gastroenterology 2008; 135 : 1005. omega-3 fatty acids ineffective in Crohn’s dz for maintaining remission.
  • -Pediatr Res 2007; 61: 356-60.  Enteral nutrition effect on protein turnover in adolescents with Crohn’s disease.
  • -J Pediatr 2000; 136: 285-91. Nutritional Rx w polymeric diet is effective w/in 8 weeks in 32/37.
  • -Scand J Gastro 2001; 36: 383-8. Elemental & polymeric diets successful in maintaining remission in ~43% of adults with complete steroid withdrawal
  • -JPEN 1992; 16: 499. improved wt,ht, decreased prednisone, decreased CDAI
  • -JPGN 2000; 31 (supp 2) A291. Polymeric vs elemental diet.
  • -JPGN 2002; 35: 339-40. Lactase deficiency – same prevalence in IBD as in RAP.
  • -JPGN 2000; 31: 3 & 8. EN about as effective as steroids for primary Rx.

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.