Category Archives: inflammatory bowel disease

Thiopurine Metabolite Testing -NASPGHAN Consensus Recommendations

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The inflammatory bowel disease committee of NASPGHAN has published a review and recommendations for the use of thiopurine metabolite testing (JPGN 2013; 56: 333-40).

The effectiveness of thiopurines is reviewed with a few key points:

  • Cochrane reviews have shown that azathioprine and 6-mercaptopurine are effective in inducing remission in Crohn’s disease.  For active disease the overall response rate has been reported as 54% compared with 33% for placebo.
  • For ulcerative colitis, a Cochrane analysis deemed the methodologic quality of 4 of the 6 studies as unsatisfactory and that all studies were small.  “The reviewers concluded that azathioprine may be effective treatment for patients with ulcerative colitis.”

The review covers the potential adverse effects of the thiopurines: myelosuppression, pancreatitis, elevated transaminases, susceptibility to infection, and malignancy.  The review suggests that the risk of non-Hodgkin lymphoma is probably increased up to 4-fold. Though, it is difficult to determine how much of the risk is truly due to the usage of thiopurines or other confounding factors.  The studies about the risk of non-melenoma skin cancer are not discussed.

Other covered topics: advantages of thiopurine metabolite testing (6-thioguanine [6-TGN] and 6-methylmercaptopurine[ 6-MMP]), potential disadvantages of metabolite testing (e.g.. cost), use of genotype versus phenotype (phenotypic testing is generally preferred), thiopurine metabolism, devising target levels, use of allopurinol, and misinterpretation of metabolite testing.

Specific Consensus Recommendations:

  • Obtain thiopurine methyltransferase (TPMT) testing prior to initiation of thiopurines.
  • Avoid use of thiopurines in individuals with extremely low TPMT activity or who are homozygous recessive for TPMT activity
  • TPMT testing does not predict all cases of leukopenia.  All individuals receiving thiopurines should have routine monitoring with CBCs.  “Most adverse effects from thiopurines are not directly related to 6-TGN or 6-MMP levels.”
  • Metabolite testing can help determine adherence to therapy
  • Metabolite testing may be helpful in guiding dose adjustment and/or adding allopurinol treatment
  • Routine and repetitive testing of metabolites is not recommended in patients who are doing well on an acceptable thiopurine dosage.

Related blog posts:

Anti-TNFs and Pregnancy

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While pregnancy does not occur commonly while patients are in a pediatric gastroenterology practice, the possibility of becoming pregnant certainly influences our choice of medications.  With inflammatory bowel disease (IBD), I rarely recommend methotrexate in young women due to its teratogenicity.  With regard to the anti-TNF agents, there is less data available.   Two recent studies add some insight into this issue.

The first study ((Clin Gastroenterol Hepatol 2013; 11: 318-21) followed 31 pregnancies in 28 women with IBD (2006-2011).  18 patients received infliximab (IFX) and 13 adalimumab (ADA).  Most were receiving lower doses; only one IFX patient was receiving 10 mg/kg/dose and only two ADA patients were receiving weekly dosing.  Levels of anti-TNF agents were measured from cord blood from 18 newborns (12  IFX, 6 ADA).

Results:

  • 28 live births.  3 miscarriages (1 IFX, 2 ADA).  No congenital malformations were noted.
  • Mean cord IFX level was 6.4 mcg/mL.  A level of 2.8 mcg/mL was noted in the early discontinuation group –stopping 10 weeks prior to delivery .
  • Mean ADA level was 1.7 mcg/mL in five infants.  One infant had an undetectable level. All mothers had stopped ADA at gestational week 22.

In the second study (Clin Gastroenterol Hepat 2013; 11: 286-92) there were 31 pregnant patients. Anti-TNF treatment: Certolizumab (CZP) (n=10), IFX (n=11), ADA (n=10).  Serum levels were measured at birth in the mother, infant, and in cord blood. Then, levels were followed monthly until undetectable.  Among women receiving IFX, two were receiving 10 mg/kg/dose.  Women were identified through the Crohn’s Colitis Foundation of America Pregnancy IBD and Neonatal Outcomes (PIANO) Registry.

Results:

  • IFX was detectable for 2-7 months postpartum (median interval prior to delivery and last dose was 35 days).  Median IFX level in the cord was 160% that of the mother.
  • ADA was detectable for at least 11 weeks in infant’s circulation (median interval prior to delivery and last dose was 5.5 weeks). Median ADA in the cord was 153% of the mother.
  • Median CZP in the cord was 3.9% that of the mother.
  • No congenital anomalies or complications were reported in any of the infants.

Bottomline from these studies:

Stopping these drugs after the second trimester lowers the level of these medications in the infant.  This likely results in a lower likelihood of the infant developing an opportunistic infection but also results in a low risk for the mother of an IBD flareup.  Certolizumab pegol has very low levels of placenta transfer.

Related references:

  • -J Am Acad Dermatol 2011; 65: 870.  Death noted in infant whose mother took IFX after BCG vaccination.
  • -J Crohns Colitis 2011; 5: 555-8.  Low levels of IFX detected in infants from nursing mothers with IBD  (1/200th of the maternal level in serum 2 to 3 days after infusion).
  • -Clin Gastroenterol & Hep 2010; 8: 509. n=2377. Crohn dz assoc w prematurity but not birth defects.
  • -Gastroenterol 2003;124: 9-17. Safety of 6-MP in pregnancy. n=155, at least 1 pregnancy. No adverse effect noted.
  • -Clin Gastroenterol & Hepatology; 2006: 4: 1255.  Infliximab crosses placenta but was not detected breastmilk.

Early antibiotic use and the development of inflammatory bowel disease

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Another study adds weight to the idea that early antibiotic use may increase the risk of developing inflammatory bowel disease (IBD) (J Pediatr 2013; 162: 510-4).

Using a nested case-control design, the authors matched 2377 controls to 294 children with IBD in a population-based database from Manitoba, Canada.  Specifically, the authors looked at the frequency of otitis media diagnosis and the likelihood of subsequent IBD.  By age 5 years, 89% of IBD cases had at least one diagnosis of otitis media, compared with 82% of the controls.  Despite the high frequency in both groups, the authors determined that individuals with a diagnosis of otitis media before age 5 years were 2.8-fold more likely to be an IBD case.

Some of the strengths of this study included the fact that it was a population-based analysis dating back to 1984 and likely captured almost all pediatric IBD cases (<19 years).  Nearly all physicians in Manitoba submit billing claims to a single publicly funded source.  Due to the nature of administrative data, this eliminates recall bias.

However, administrative data have several limitations as well.  Other confounding conditions may have been present and not identified; this could include family history and autoimmune diseases.

The authors “suspect” that the linkage between otitis media and IBD relates to the usage of antibiotics and subsequent alterations of the intestinal microflora.  Otitis media may serve as a “sensitive proxy measure” of antibiotic use.  Also, as boys are more frequently treated for otitis media, this may relate to the generally higher incidence of pediatric IBD in males.

For anyone interested in the association between antibiotic exposure and IBD, this study is useful and provides a number of references as well.

Related blog entries:

Mortality from IBD

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A large Danish cohort provides useful information on the mortality effects of having inflammatory bowel disease (IBD) and how this has changed over the last three decades (Clin Gastroenterol Hepatol 2013; 11: 43-48).

Using a national cohort of all individuals living in Denmark between 1982-2010 (on average 5.3 million), the authors studied 36,080 patients with ulcerative colitis (UC) and 15,361 with Crohn’s disease (CD) in comparison to data from 2,858,096 matched controls (50 controls from each IBD patient) from the general population.  For UC, the median age was 45.2 years and for CD 36.3 years.

Findings:

  • With UC, the first year of diagnosis carried a higher risk of dying (HR 2.43) then rapidly declined to around HR 1.1 after 2 years.  Overall, long-term mortality was increased 10% among UC patients.  Mortality from UC decreased from 1982 to 2010 due to decreased mortalities from gastrointestinal disorders, including colorectal cancer.
  • Mortality was higher among patients diagnosed at younger ages.  Patients diagnosed with UC in childhood or adolescence had a 2.15-fold higher relative mortality than patients diagnosed with UC at 60-79 years.
  • Cause-Specific Mortality: during the first year after UC diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 13.3) and infection (HR 9.17).  These areas were most prominent at 10+ years, but the HR ratios had decreased to 1.95 and 1.64 respectively at that time.
  • For CD, mortality was markedly increased in the first year with HR 3.69 and declined to HR 1.53 during years 2-4; HR was 1.49 at 10+ years following diagnosis.  Overall, long-term mortality was increased 50% among CD patients.  Unlike UC, no improvement in mortality rate occurred during the study.
  • Cause-Specific Mortality: during the first year after CD diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 23.02) and infection (HR 10.19). These areas were most prominent at 10+ years, but the HR ratios had decreased to 3.67 and 2.70 respectively at that time.  Infections were not increased in the most recent decade, indicating that thiopurines and biologics have not increased the overall risk of fatal infections.
  • While the relative risk of cardiovascular disease was only slightly increased (HR 1.11 for both CD and UC), this is important given the overall frequency of cardiovascular disease in the population.  Presumably, systemic inflammation contributes to the formation of atherosclerosis.
  • Suicide was also increased, especially in the first year after diagnosis (HR 2.05 for UC and HR 1.37 for CD)

Strengths of study: since Denmark has free access to health care and all citizens have a unique 10-digit personal identification, this enables capture of virtually all patients with IBD.  Previous studies have validated the database to be accurate and that the IBD diagnoses have been validated.

Related blog entries:

Where is the Journal Editor?

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A recent article is titled “Determination of Bone Age in Pediatric Patients with Crohn’s Disease Should Become Part of Routine Care” (Inflamm Bowel Dis 2013; 19: 61-65). (Thanks to Ben Gold for suggesting this reference.)

Does the study merit the authors’ conclusion that ‘determination of bone age (BA) should become the standard of care in pediatric Crohn’s disease (CD) patients, allowing clinically meaningful interpretation of growth…leading to improved treatment recommendations?’

No.  This small study (n=49, 84% Caucasian) simply showed that a lot of pediatric CD patients have a delayed bone age.  This is not a novel finding.

Specifically, the mean BA Z score was -1.40 ± 1.5 in this population and 41% had a BA Z score of < -2.0.  This cross-sectional study was conducted between 2007-2009.  Patients were consecutively approached for enrollment during this time period.

Clinical factors associated with delayed bone age included Caucasian race, Tanner stage 1-3, history of steroid exposure, colonic disease location, azathioprine/6-mercaptopurine usage, and female sex.  Interestingly, these variables are not entirely consistent with prior studies in which male sex was associated with delayed bone age.

The reason why the conclusion is a far-reach is that there is no data in the study showing how bone age influences any clinical decision-making in these patients.  There is no information on cost-effectiveness of their proposed “standard of care.”  There is no longitudinal data to suggest that the delayed BA or the recognition of a delayed BA  resulted in a different outcome.

My conclusion:

Many pediatric patients with CD have delayed BA and some may benefit from a BA determination.  I think extrapolating a much broader conclusion from this study is not warranted.

T-cell therapy for Crohn’s disease

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Data from the Crohn’s and Treg Cells Study (CATS1) are very preliminary but indicate that administration of antigen-specific T-regulatory cells (Tregs) to refractory Crohn’s disease (CD) patients could be effective (Gastroenterol 2012; 143: 1207-17).  Tregs are specialized subpopulations of T-cells.

In this study, the investigators, performed a 12-week open-label multicenter single injections study of 20 patients with refractory CD.  After withdrawing blood from patients, mononuclear cells were isolated and cultured.  Subsequently, T cells were cloned.  A specific subset with high IL-10/IL-13 production and low IL-4 production were selected.

Key findings:

  • 8 of 20 (40%) patients had a CDAI reponse at 5 and 8 weeks.  This was associated with a reduction in serum CRP and a trend of decreasing fecal calprotectin.
  • Remission was noted in 3 patients at week 5 and in 2 patients at week 8.
  • Overall, regardless of dose used, the safety profile was “in line” with severe active refractory CD.  Gastrointestinal adverse events were common.  7 patients had CD flares. One patient died due to suicide.

To understand this study more fully, an accompanying editorial is in the same issue (pages 1135-38).  A more complete discussion of the function of Treg cells is given, included their physiologic role of patrolling the gut lamina propia for antigens ‘derived from food and commensal flora.’  Circulating Treg cells may be deficient in IBD patients and thus contribute to the pathogenesis.

While injecting Treg cells may become a useful therapy, other ways of boosting Treg cells may be enhanced as an alternative.  Currently, granulocyte colony-stimulating factor (GCSF), anti-TNFα agents, and IL-2 all have the potential to enhance Treg cell function.  This supports the editorial’s conclusion that ‘Treg cells are rapidly moving from the bench to the bedside.’

Given the experimentation with stem cell therapy and bone marrow transplantation for CD, Treg cells show promise of a much more targeted effect on the immune system.

Additional references:

  • -Blood 2010; 116:6123-32.  Autologus stem cell transplantation in patients with refractory CD.
  • -Gut 2008; 57: 211-17.  Autologus stem cell transplantation for refractory CD.
  • -Gut 2010; 59: 1662-69.  Mesenchymal stromal cell treatment for luminal Crohn’s.

Predictors of colectomy in pediatric UC

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A recent review of children in the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) examined risk factors for proctocolectomy in children with Ulcerative Colitis (UC) (JPGN 2012; 55: 534-40).  Two of the investigators (Stanley Cohen and Ben Gold) are colleagues of mine at GI Care for Kids.

In total, 406 children with UC were reviewed.  The average age at diagnosis was 10.6 years.  The average followup was 6.8 years.  57 (14%) underwent surgery with a median time to surgery of 3.8 years.  Overall risk factors for colectomy included the following:

  • Presenting with weight loss, HR 2.55
  • Presenting with hypoalbuminemia (<3.5 g/dL), HR 6.05
  • First-degree relative with UC, HR 1.81
  • Treatment with cyclosporine, HR 6.11
  • Treatment with tacrolimus, HR 3.66

While this data expands on the knowledge of these factors in children, the findings are not unexpected.  Low albumin levels and poor nutritional status have been identified in other studies as risk factors for UC relapse and for colectomy.

With regard to first-degree relatives, the findings imply that children with a first-degree relative are more likely to have a more severe form of UC.

The use of calcineurin inhibitors, cyclosporine and tacrolimus, are given only in the presence of severe disease.  Thus, while use of these agents is associated with an increased risk of colectomy, it is unlikely that this is a causal relationship.  Interestingly, the use of infliximab was not identified as a risk factor.  However, this retrospective study examined patients between 1999-2003.  Since this timeframe, there has been increased use of infliximab for refractory UC.

Going forward, it is likely that contemporary studies would incorporate PUCAI (pediatric UC activity index) measurements and would have the ability to enroll far greater numbers of patients from database consortiums.

Related blog posts:

Predicting long-term response with calprotectin levels

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This blog has been a fan of calprotectin levels (see related posts below) as both a screening test for inflammatory bowel disease and as a marker of disease activity.  Now more data is available indicating that calprotectin levels, much like endoscopic mucosal healing, after induction therapy correlates with long-term response (Inflamm Bowel Dis 2012; 18: 2011-17).

This retrospective study (2005-2010) examined 60 patients with IBD with elevated baseline calprotectin levels.  34 patients had Crohn’s disease (CD) and 26 had ulcerative colitis (UC).  42 patients received infliximab therapy and 18 patients received adalimumab.  After induction therapy, therapy was discontinued in primary non responders or continued as scheduled maintenance therapy for at least one year if not relapsing.

The average age at induction for CD patients was 30 and the corresponding age at diagnosis was 21.  For UC patients, the average age at induction was 29 and the corresponding age at diagnosis was 26.

Median calprotectin level at baseline was 810 μg/g (n=60).  After induction, the median value dropped to 97 μg/g (n=60) and at 1 year the value dropped to 27 μg/g (n=25).  The calprotectin level normalized in 31 patients after induction.  At 12 months, the sustained remission was present in 84% (26/31).  In contrast, only 38% (11/29) who had elevated levels after induction were in remission at 12 months.

Related blog entries:

More frequent pediatric IBD

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Using a national cohort of prospective and retrospective data on pediatric inflammatory bowel diagnosis, (PIBD) a recent report indicates a rising incidence of PIBD in Scotland (Inflamm Bowel Dis 2012; 18: 999-1005).

Key findings:

  • Between 2003-2008, 436 patients were diagnosed with PIBD; this equates to 7.82/100,000; Crohn’s was 4.75 and UC 2.06 per 100,000 respectively
  • Between 1990-1995, 260 patients were diagnosed with PIBD; this equates to 4.45/100,000; Crohn’s was 2.86 and UC 1.59 per 100,000 respectively
  • Mean age of diagnosis in more recent cohort was younger: 12.7 years compared with 11.9 years

Currently, a data-base coordinated in a single center along with collaboration with regional networks enables the capture of all new IBD diagnosis (since 1999).  Prior cohort was determined by “exhaustive examination” of previous IBD records.

Running out of options

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A series of articles on natalizumab were published which give practical advice for this drug which clinicians often turn to when ‘running out of options’ (Gastroenterol Hepatol 2012; 8: 4-17).

Slides from these articles should be available soon (not online on 1/2/13):

http://www.clinicaladvances.com/index.php/our_publications/gastro_hep-issue/gh_november_2012/

According to an algorithm on page 7, in patients with moderate-severe Crohn’s disease who have failed conventional therapies and anti-TNF drugs (or unable to tolerate), the next step is to obtain anti-JCV (John Cunningham Virus) antibody status.  Patients who test negative are ‘Okay to treat with natalizumab’ due to very low risk of progressive multifocal leukoencephalopathy (PML).  Repeated testing at least once a year is then recommended.

For patients who test positive for anti-JCV at any time point, natalizumab can be considered if no other treatment options are available, but the risk of PML is much greater. Previous blog entries (below) have discussed this in greater detail and have provided additional references:

Another article published the experience in 36 Mayo clinic patients between April 2008-September 2010 (Inflamm Bowel Dis 2012; 18: 2203-08).  Consecutive patients who received natalizumab were prospectively followed.  Of the 36 treated with natalizumab, 30 agreed to participate in the study.  23 patients had failed two anti-TNF agents and 7 had failed one anti-TNF agent.  Median age was 35 years.

Results:

  • 14 (46%) had a complete clinical response, 12 had a partial response, and four had no response.  Cumulative probability of a complete response within 1 year was 56%.
  • Time to response: 10% after 1st dose, 50% of patients had complete response after 4th dose
  • Adverse events were common –though this rarely caused drug cessation. Common events included headache and infections (listed in Table 4 of article).  Some infections prompted holding natalizumab for up to 8 weeks.
  • 11 stopped natalizumab due to lack of improvement.