Tag Archives: Crohn’s disease

Coming Soon to a Pharmacy Near You (part 2)…

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While yesterday’s post reviewed the data that indicate that vedolizumab is likely to be helpful for ulcerative colitis, only small improvements were noted for patients with Crohn’s disease (NEJM 2013; 369: 711-21, GEMINI 2 studies).

Vedolizumab, “a humanized immunoglobulin G1 monoclonal antibody to α4β7 integrin, modulates gut, but not brain, lymphocyte trafficking.”  The GEMINI 2 studies for Crohn’s disease were similar to the GEMINI 1 studies for UC.  However, even more medical centers (n=285) in more countries (n=39) and more patients (n=1115 with 967 receiving study drug) participated.

Baseline characteristics:

  • Median age: 36.1 years
  • Current Smokers: 26.7%
  • Disease location: 16.2% ileum only, 28.3% colon only, 55.4% ileum/colon
  • Median fecal calprotectin: 686 mcg/gram
  • Concomitant medications: 34.2% steroids only, 16.2% immunosuppressives only, 17% both steroids and immunosuppressives, 32.6% neither steroids or immunosuppressives
  • Median steroid dosage: 20 mg
  • Prior TNF antagonist ≥1:  61.8%
  • Prior surgery for Crohn’s disease: 41.8%
  • Prior fistulizing disease: 36.8%

Results:

  • At week 6, 14.5% of vedolizumab-treated patients and 6.8% of placebo-treated patients were in clinical remission (CDAI ≤150).
  • At week 6, 31.4% of study drug group and 25.7% of placebo group had a CDAI-100 response (≥ 100 point decrease in CDAI score).
  • Among patients with an induction response, 39% and 36.4% of vedolizumab every 8 weeks and every 4 weeks, respectively were in clinical remission at week 52, compared with 21.6% of patients assigned to placebo.
  • Vedolizumab-treated patients had increased serious adverse effects including serious infections.  Nasopharyngitis occurred more frequently.
  • Five deaths were noted during the study, four among the treatment group (Crohn’s/sepsis, intentional overdose, myocarditis, and septic shock).
  • No PML cases have been reported among the 3000 patients exposed to vedolizumab

While the response rate to vedolizumab was modest in Crohn’s disease patients, there are some factors that need to be considered in interpreting this data. Unlike in many trials (According to the study which you would never … – gutsandgrowth), this trial included patients with more disease severity.  The authors note that the effects of anti-integrin therapy could be relatively slower acting in Crohn’s disease due to the transmural nature of the disease.  An alternative explanation would be that the gut-selective targeting by vedolizumab is ineffective in most patients with Crohn’s disease due to the need for a more systemic inhibition with transmural disease.

Bottom-line: Among the small percentage of patients who have a response to vedolizumab at week 6, the rates of clinical remission at week 52 were significantly higher than those who received placebo.

Probiotics for Crohn’s Disease –No Beneficial Effects Noted

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With all the buzz regarding how a patient’s microbiome seems to affect everything from metabolic syndrome and colic to autoimmune diseases and inflammatory bowel disease, more attention has been paid in attempts to alter the microbiome for therapeutic benefits.  In Crohn’s disease (CD), the fact that antibiotics have shown beneficial effects have led to a number of studies of probiotics.  A recent study, like previous ones, did not demostrate any benefit with Saccharomyces boulardii (Clin Gastroenterol Hepatol 2013; 11: 982-87).

In this prospective double-blind, placebo-controlled study of 165 patients who achieved remission after steroids or salicylates, subjects were randomly assigned to groups given S boulardii (1 gram per day) or placebo for 52 weeks.

Results:

  • CD relapse occurred in 80 patients: 38 (47.5%) in the probiotic group  and 42 (53.2%) in the placebo group
  • Time to relapse did not differ significantly: 40.7 weeks in probiotic group vs 39 weeks in placebo group
  • No differences were seen in disease activity scores or serum inflammatory markers
  • In post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse compared with nonsmoker control patients (34.5 % vs. 72%)

One important limitation of this study was not examining the effects of the probiotic on the microbiome of these patients.  Perhaps, other probiotics would be more effective in restoring a “healthy” flora.

Based on these results, and others, the accompanying editorial (pg 988-89), advocates use of probiotics only for prevention of antibiotic-associated diarrhea, prevention of recurrent Clostridium difficile, and treatment/prevention of pouchitis.

Bottom-line: Probiotics have not been demonstrated to be helpful for Crohn’s disease.

Related blog posts:

NASPGHAN: Enteral Nutrition for Crohn’s Remission

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A new document from NASPGHAN highlights the potential for enteric formulas (oral and nasogastric) as an alternative 1st line therapy for Crohn’s disease remission.  The following is a link with specific case examples along with background information and practical advice:

http://goo.gl/p19o0z 

Related blog post:

Rest easy with enteral nutrition | gutsandgrowth

Thiopurines associated with reduced risk of colon cancer

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A recent study provides some good news for those using thiopurines (6-mercaptopurine and azathioprine) (Gastroenterol 2013; 145: 166-75).

Using the observational cohort enrolled in the French CESAME study (Cancers et Surrisque Associe aux Maladies Inflammatoires Intestinales En France), the authors followed 19,486 patients with IBD.  60.3% had Crohn’s disease, and 30.1% were receiving thiopurine therapy.  The study period was 2004-2007.  At the start of the study, 2841 patients (14.6%) had long-standing extensive colitis.

Among patients with long-standing extensive colitis, the hazard ratio for colrectal high grade dysplasia and cancer was 0.28 for those who received thiopurine therapy compared with those who never received thiopurine therapy.

Thus, this prospective study showed that while colorectal cancer (CRC) was increased in IBD patients with long-standing colitis, this risk was less among the subset who were treated with thiopurines.  Some previous studies have not found a reduction in CRC risk, though they may have been underpowered and biased as these studies came from referral centers.

The authors also cautioned that more than 1/3rd of CRC cases occurred in those without extensive colitis which may necessitate a lower threshold for screening colonoscopy.

Related blog posts:

Remission in Crohn’s Disease

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A recent article highlights the issue of remission in Crohn’s disease (CD) (Inflamm Bowel Dis 2013; 19: 1645-53).

As noted in previous blog entries (see links below), improvements in remission with ImproveCareNow and with previous drug trials have several limitations due to the current definition of remission.  Currently, even during periods of clinical remission (defined currently mainly by symptoms), laboratory or endoscopic evidence of persistent inflammation can be seen.  Persistent inflammation is likely to lead to progressive bowel damage. With the advent of more effective treatments as well as better biomarkers, a more objective measure of remission is needed.

“Remission is an evolving concept in CD. At its most fundamental level, remission should be a state with little or no risk of disease progression, likely implying the absence of biological evidence of inflammation.”

The authors proposed definitions of remission based on whether the patient has “early” disease or “late” disease.  Early disease “may be defined as disease duration ≤18 months without previous exposure to immunosuppressants or biologics.”

Early disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission in practice (symptom control): complete absence of symptoms; 1-2 formed stools per day without abdominal pain.  In a clinical trial, CDAI <150 points.
  • Outcomes: no disease progression or complications, normal quality of life

Late disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission (symptom control): a: inflammatory symptom improvement (may have residual symptoms due to previous damage or surgery). In clinical trial, CDAI 150-220 points.
  • Outcome: stabilization of noninflammatory symptoms and no progression of structural damage, improved quality of life

The authors goal is to rework remission to include symptom control and histologic/mucosal healing.  This concept is not novel.  Investigators in the adalimumab EXTEND study coined the term “deep remission.” This term referred to patients with both CDAI remission and complete mucosal healing.  Patients who achieved deep remission had improved outcomes, including fewer hospitalizations and fewer surgical resections (Gut 2010; 59: A80).

Bottomline: Improvements in both objective measures of biologic inflammation along with resolution of clinical symptoms are needed to change the long-term outcome for patients with Crohn’s disease.  The definition of remission should reflect this reality.

“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

Related blog entries:

Rethinking top-down treatment?

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Given the effectiveness of biologic therapy and the potential for disease modification, the threshold for “top-down” treatment has been lower at this time as compared with “step-up” treatment.  What about long-term outcomes, does starting soon increase or decrease the likelihood of doing well?  A recent study suggests that “early biologic therapy did not improve disease activity or quality of life” (Inflamm Bowel Dis 2013; 19: 1397-1403).

In this retrospective chart review involving 93 patient’s with Crohn’s disease (between 2004 and 2010), patients whose data was prospectively maintained were categorized into either early biologic therapy or a step-up group. For these patients, the mean age at diagnosis was 28 years.  There were no apparent differences in demographic variables between the groups; however, the early biologic therapy group had higher disease activity and lower quality of life scores at baseline. 20% were current smokers and 61% never smoked.  Disease location was similar in both groups; overall, 35% had ileal disease, 13% colonic disease, 34% ileocolonic, and 7% isolated upper tract disease.

Results:

  • Mean Harvey-Bradshaw index and Short Inflammatory Bowel Disease Questionnaire scores at 3, 6, and 12 months were not different between the groups.
  • Early biologic therapy group had more hospitalizations.
  • No difference in steroid use or surgeries was noted at one year.

Take-home message: This study suggests that differences in outcomes between “top-down” therapy and step-up therapy are more pronounced early in the treatment course but may wane after 1 to 2 years.  However, early biologic therapy “may be a more effective strategy in patients with Crohn’s disease with higher disease activity.”

Relating blog posts:

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.

Related blog links:

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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