Tag Archives: Crohn’s disease

Frequency of Functional Pain Overlap in Pediatric Crohn’s Disease

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If a patient with Crohn’s disease has pain, it may signal a flare-up of the inflammatory process.  Other causes like secondary infections, strictures, and functional pain need to be considered as well.  Functional pain can be particularly challenging.  A recent study reports on the prevalence of functional pain overlap in this setting (Inflamm Bowel Dis 2013; 19: 826-31).

This study prospectively enrolled 307 patients from two centers; it was a substudy to a cognitive behavioral therapy trial.

Patients in remission were defined by the following:

  • all normal laboratory findings:erythrocyte sedimentation rate <10, albumin >3.5, C-reactive protein <1 mg/dL
  • absence of clinical signs/symptoms of inflammatory bowel disease: 3 or less stools per day, no bloody stools, no nocturnal stools, no strictures, no concurrent steroid therapy
  • no escalation in medical therapy or clinical relapse in previous 6 months

Results: 139 of 307 patients had abdominal pain.  Among those with pain, 18 (13%) patients had functional abdominal pain (FAP). 10 of the 18 had either a colonoscopy or MRI in the previous year.  In these patients, the median PCDAI was 10.

This study noted a higher rate of depression in patients with both FAP and Crohn’s: 56%. This is compared with 29% of Crohn’s patients in remission without pain and 45% of Crohn’s patients with pain due to active disease.

Key points:

  • Pain with or without active disease can lead to an overestimation of disease activity based on PCDAI.
  • Depression is common in patients with pain, regardless of etiology
  • Current diagnostic criteria for FAP are flawed.  In fact, the Rome III criteria for FAP which specify absence of organic disease.
  • Biomarkers and imaging modalities are the best tools to exclude active disease.

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Treating Allergic Reactions to Infliximab

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This week on the GI bulletin board there was a brief discussion about overcoming allergic/anaphylactic reactions to infliximab.  A reference and a thoughtful response by Athos Bousvaros (in italics) follows:

Inflamm Bowel Dis. 2001 Feb;7(1):34-7. Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn’s disease patients with prior anaphylactic reaction. Puchner TC, Kugathasan S, Kelly KJ, Binion DG.   

 IN summary:

1.  Premed with 4 days of steroids (1mg/kg up to 40mg), and hydrocortisone day of the infusion.

2.  Give two test doses (0.1 mg, 1 mg), each over 10 minutes,

3.  If no problems, run the infusion over 4 hours instead of two.

 

Getting antibodies to infliximab before the challenge may also be helpful.  If high levels of antibodies are present, the patient may be more likely to fail the challenge. WE can “rescue” about half our patients using this protocol, and keep them on infliximab. IMPORTANT that a physician is around during the challenge.

Given the potential for adverse reactions and the importance of not depleting useful treatments, it is definitely worthwhile to read the entire cited reference rather than the aforementioned summary.

Related blog entry:

Overcoming ATIs | gutsandgrowth

Microparticles and Pediatric IBD

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Before reading a recent publication (JPGN 2013; 56: 401-07), I was not aware of microparticles; microparticles may play an important role in the development of venous thromboembolism (VTE).  Pediatric patients with inflammatory bowel disease (IBD) have a higher relative risk of VTE compared to their peers than individuals >60 years of age, though the absolute risk is low.  Much of the pathophysiology underlying the increased VTE risk remain uncertain.

Microparticles have been called “platelet dust” and are microvesicles that are released from the plasma membrane of many cells (leukocytes, red blood cells, endothelial cells, and platelets).

This study examined plasma samples from 33 pediatric patients with Crohn disease (CD), 20 pediatric patients with ulcerative colitis (UC), and 60 healthy controls. Subsequently, microparticles’ procoagulant activity was measured.  The CD and UC patients were consecutively enrolled from the outpatient clinic.  Only 3 patients in each IBD group was receiving a biologic therapy (infliximab). The disease activity and extent were compared with measures of procoagulant activity.

Several assays were undertaken to assess microparticles and thrombin generation. Key findings:

  • Increased procoagulant function of microparticles was identified in all CD patients (active and quiescent) and in UC patients with active disease.
  • A positive correlation was found between disease activity scores and procoagulant activity.

The authors note that elevated microparticles “may play a role in inflammation.” Inflammation and coagulation likely influence each other.  The authors note that VTE risk is greatest during flares but is still increased in patients in remission compared with controls.

The authors do not discuss the relationship of mucosal healing to microparticles or VTE. However, given that clinical remission is not defined currently based on mucosal healing, it would be of interest to know the status of these microparticles and the risk of VTE with mucosal healing. Perhaps the “quiescent” CD patients have ongoing disease contributing to their increased risk of VTE and increased procoagulation function of microparticles.

Related blog entry:

VTE with IBD | gutsandgrowth

**According to previous expert consensus guidelines, “routine heparin prophylaxis cannot be justified in children until better evidence is available to suggest that the benefit outweigh the risks”  (Turner D, et al. Am J Gastroenterol 2011; 106: 574-88).

Switching from Thiopurines to Methotrexate

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Data regarding methotrexate treatment for Crohn’s disease (CD) is limited.  A fairly large retrospective study provides a better idea about its effectiveness over a five-year period (Clin Gastroenterol Hepatol 2013; 11: 667-72).

In total 174 consecutive CD patients (age 35 ±12 y) from 3 hospitals were analyzed.  All of these patients received methotrexate (MTX) after thiopurine therapy. 23% had not responded to an anti-TNF agent.  Most of the patients who had failed thiopurine treatment had an intolerance to thiopurine rather than loss of clinical response.  Data on patient characteristics including smoking status, disease behavior/location, previous treatments, and indication for MTX are detailed in Table 2.  Interestingly, 113 patients were female.  The authors noted that 90% of their patients received MTX parenterally.

Key findings:

  • Patients with sustained clinical benefits from methotrexate monotherapy:  98 (86%) at 6 months, 50 (63%) at 12 months, 27 (47%) at 24 months, and 3 (20%) at 60 months.
  • 45 (26%) discontinue methotrexate due to intolerance, mostly within the first 6 months.  However, adverse effects were generally mild.  Only one patient required hospital admission for an infection (cytomegalovirus).

There are many limitations of this retrospective study.  Nevertheless, a significant portion of patients derived clinical benefit for at least 2 years.

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Neurological Complications Associated with Inflammatory Bowel Disease

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Though I have not seen much in the way of neurological complications in our pediatric inflammatory bowel disease (IBD) population, nevertheless I worry about them.  A recent article provides some insight into the incidence, the pathophysiology and approach to these complications (Inflamm Bowel Dis 2013; 19: 864-72).

Types of neurologic complications: The most common neurologic complication is peripheral neuropathy.  The frequency is quite variable based on data collection method.  In large administrative healthcare data, the prevalence has been reported around 2% whereas in cohort studies the range has been 8-15%. Other complications include meylopathy, cerbrovascular disease, cranial nerve palsy (eg. Melkersson-Rosenthal syndrome), seizures, and demyelinating diseases.

With regard to demyelinating diseases, this has gained additional attention in the setting of biologic agents which have been associated with this complication.  However, the authors note that a pre-biologic treatment study from Olmstead County, observed a prevalence of multiple sclerosis of 1% which was 3.7 times higher than expected.  In addition, similar studies have confirmed this finding.

Potential mechanisms vary greatly depending on the neurologic complication. With regard to cerebrovascular disorders, “venous thromboembolism (VTE) has been shown to occur 3 times more frequently in patients with IBD (the risk increases to 8-10-fold in patients with active colitis) than the general population.”  Hence, VTE prophylaxis is recommended by the authors in hospitalized IBD patients, especially if they are experiencing a disease exacerbation.

In addition to the underlying disease, vitamin deficiencies (eg. Vitamin B12) and medications can trigger neurologic complications.

  • Natalizumab: progress multifocal leukoencephalopathy (PML)
  • Metronidazole: peripheral neuropathy (typically reversible with drug discontinuation)
  • Anti-TNF-α agents (infliximab, adalimumab, certolizumab): demyelination, rarely seizures, and rarely PML
  • Cyclosporine: various neurotoxicity in ~25%

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Tacrolimus for Refractory Crohn’s Disease

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While tacrolimus has been considered a potential option for refractory Crohn’s, data on its usage are sparse, mostly small retrospective studies.  Another small retrospective study from the Mayo clinic provides data from their experience with 24 adult patients who were treated with tacrolimus for a median of 4 months (Inflamm Bowel Dis 2013; 19: 1107-11).

17 (71%) of study participants were female and their median age was 38 years.  18 (75%) had ileocolonic disease.  All patients were either intolerant or unresponsive to at least one anti-TNFα agent.  Most patients received concurrent therapy: thiopurines (58%), methotrexate (8%) and antibiotics (46%).

Results:

  • 67% responded to tacrolimus and 21% achieved a steroid-free remission.
  • Patients with trough levels of 10 to 15 ng/mL had the highest response (86%) and remission (57%).
  • Adverse events were common (75% of patients); 8 (33%) required dose reduction and 6 (25%) led to treatment discontinuation.  Frequent adverse events included acute kidney injury (29%), paresthesia (29%), headache (17%), and tremor (17%).
  • 54% of patients in this series required surgery within a median of 10 months after starting tacrolimus.
  • Of the patients who achieved remission (n=5), 2 were transitioned to immunomodulator therapy to minimize long-term toxicity. 1 patient did well after stopping all therapy during a 6 month followup.  1 patient stopped treatment due to paresthesias and 1 patient continued therapy for 2.5 years.

The study does not describe the use of antibiotics for the prevention of Pneumocystis jiroveci pneumonia.

Take-home message: Tacrolimus doesn’t look too promising for refractory disease.

Related blog post:

Additional references:

  • -IBD 2008; 14: 7-12. Tacrolimus of minimal efficacy for UC and Crohn’s. Some achieve response (22/32 in UC and 7/15 in Crohn’s) only 3/32 UC with remission and 1/15 Crohn’s with remission
  • -Gut 2006; 55: 1255-1262. Use of prograf in refractory UC. Troughs 10-15, then 5-10 after remission; partial response in 68% at week 2 & 58% at week 10 (n=19)
  • -Gastroenterol 2003; 125: 380. Tacrolimus helped but did not cure fistulizing disease
  • -J Pediatr 2000; 137: 794-799. n=14.
  • -Am J Gastro 1997; 92: 876. Use in fistualizing Crohn’s.
  • -Am J Gastro 1998; 93: 18. Use in IBD.
  • -IBD 1999; 5: 239. Combined c azathioprine for perianal fistulae. response: initial 2.4weeks, 12.2weeks complete. 7/11 c complete response.
  • -IBD 2009; 15: 193. topical tacrolimus for proctitis. 10/12 w proctitis responded to 2 mg or 4 mg enema in 100 mL of sterile water.
  • -IBD 2007; 13: 245. Use for perianal disease.
  • -Gut 2000; 47: 436-440. Topical tacrolimus may be effective in the treatment of oral and perineal Crohn’s disease.

Overcoming ATIs

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Usually, when antibodies to infliximab (ATI) develop in combination with a loss of clinical response in an individual with inflammatory bowel disease (IBD), this often indicates a need to switch treatments.  A recent study suggests that some patients can eliminate ATIs with the addition of immunomodulators (Clin Gastroenterol Hepatol 2013; 11: 444-47).

In this small retrospective study, 5 patients (18-37 years of age) who developed ATIs were able to continue infliximab therapy after instituting immunomodulator treatment (3 with thiopurines, and 2 with methotrexate).  What makes this report interesting, was that these ATIs (prior to immunomodulator use) were identified multiple times and were associated with undetectable infliximab levels.  None of these patients had dose intensification of infliximab.  After instituting immunomodulator therapy, detectable infliximab was evident and the ATIs disappeared.  According to Figure 1, the timeframe for return of response was about 10 weeks in some of these patients.

The authors note that the addition of immunomodulators can gradually eliminate a preformed memory response to infliximab antigen.  They also note that ATIs can sometimes disappear spontaneously, though this had not been noted to occur previously when mulitple ATIs levels have been identified.

While these observations are important, a larger prospective study is needed to inform how frequently this strategy could be successful.

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Global increases in IBD incidence

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Two more studies have shown increasing incidence of pediatric inflammatory bowel disease.

First in Victoria, Australia (mostly Melbourne) (Inflamm Bowel Dis 2013; 19: 1-6).

Over a 60-year span (1950-2009), a retrospective review was undertaken of ulcerative colitis (UC) pediatric patients. In total, 342 children were diagnosed with UC. Key finding: The number of reported cases increased by 11-fold during the study period with a marked increase since 1990 (0.15 –>1.61/100,000).  In addition, recently diagnosed children have had more extensive disease.

Next in Spain (Inflamm Bowel Dis 2013; 19: 73-80).

This retrospective study from hospitals’ databases looked at the incidence between 1996-2009 in the pediatric population (<18 years).  A total of 2107 patients were identified: 1165 with Crohn’s disease, 788 ulcerative colitis, and 154 IBD unclassified. Median age at diagnosis was 12.3 years.  Key finding: in the last 14 years, pediatric IBD incidence has almost tripled (0.9 –>2.8/100,000).

Both of these studies have limitations related to large retrospective reviews in terms of potential problems with capturing all of the patients and the potential for misdiagnosis.  However, the trend is clear.  In addition, these studies show incidence rates comparable to several other Western studies.  The increasing incidence of IBD ‘argue for a common environmental factor in their pathogenesis.’  While interest has focused on microbial factors, the basis for this increased incidence currently remains elusive.

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True red flags in recurrent abdominal pain

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For pediatricians and pediatric gastroenterologists alike, identifying which children need additional workup for recurrent abdominal pain (RAP) is facilitated by recognizing “red flags.”  “Red flags” are clinical features that indicate a higher likelihood of a nonfunctional disorder.  A recent study notes that reports of waking from sleep and joint pains do not distinguish functional from nonfunctional causes of RAP (J Pediatr 2013; 162: 783-7).

This study, performed between 2005 to 2008, had patients presenting to an outpatient pediatric gastroenterology clinic for RAP prospectively complete a detailed questionnaire. Data, though, was extracted retrospectively. In this population (n=606), 85% were Caucasian.  After their evaluation, patients with functional GI diseases (FGID, n=478) were compared with patients confirmed with Crohn’s disease (CD, n=128).  All FGIDs underwent biochemical testing, 41% had upper endoscopy, and 32% underwent colonoscopy.

Additional key findings:

  • Using a tree analysis, the cumulative sensitivity for Crohn’s disease was 54% with the presence of anemia, 78% when blood in stool was added to anemia, and 94% when weight loss was added as well.
  • FGID patients were more likely to report stress and headaches, more likely to have family history of FGID, and less likely to have anemia, hematochezia, or growth issues.
  • FGID patients were more likely to experience vomiting.

The sensitivity and specificity of these symptoms/signs will vary based on the population.  For a general pediatric clinic, it is likely that the sensitivity of these red flags would remain high; the specificity would likely be lower than in a pediatric gastroenterology office due to the increased prevalence of functional diseases in the general pediatric setting.

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Paris Classification of Pediatric Crohn’s Disease

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A recent study described the phenotypic results of a prospective, web-based registry of new-onset pediatric inflammatory bowel disease (IBD) in 17 European countries and Israel (Inflamm Bowel Dis 2013; 19: 378-85).

The EUROKIDS Registry included 582 pediatric Crohn’s Disease (CD) patients classified according to Paris classification:

  • 16% with L1 involvement of the terminal ileum only
  • 27% with L2 colonic involvement only (more common in younger children)
  • 53% with L3 involvement of the ileum and colon
  • 4% with L4 isolated upper GI disease.  Upper tract disease can be further subdivided into L4A esophagogastric disease and L4B jejunal/proximal ileal disease.
  • *Upper GI disease can coexist with L1, L2 or L3.  In this study, 34 (6%) had esophageal involvement, 102 (18%) had gastric involvement, and 100 (17%) had duodenal involvement.
  • In this study, 165 of the 507 patients did not undergo small bowel imaging. Of those who did, 64% had small bowel follow-through, 38% had MRI, 6% CT, and 5% video capsule.

Other findings:

  • Perianal disease (e.g.. fistula or abscess) noted in 9% at diagnosis.
  • Granulomas were found in 43% of patients who had biopsies from at least 10 segments of the GI tract
  • 82% of CD patients had nonstricturing, nonpenetrating disease (B1), 12% had stricturing disease (B2) and 5% had penetrating disease (B3).  2% had both stricturing and penetrating disease.
  • Extraintestinal manifestations were seen in 20% of the study population.
  • The authors estimated that the diagnostic yield of upper endoscopy  in the workup for pediatric IBD was  7.5% and for intubation of the ileum/ileoscopy 13%.

Study limitations included a selection bias of centers and pediatric gastroenterologists with a special interest in IBD.  Also, in this registry, older adolescents are underrepresented. In about one-third of the centers, patients older than 15 years are seen primarily by adult gastroenterologists.