Ustekinumab for Crohn’s Disease

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Ustekinumab is emerging as an option for inflammatory bowel disease.  A study examining its effectiveness for TNF-refractory Crohn’s disease has been published (NEJM 2012; 367: 1519-28).

In this trial, members of CERTIFI (Crohn’s Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction) from 153 centers in 12 countries assessed the efficacy of Ustekinumab in 526 adult patients.  The primary outcome was a clinical response (CDAI >100 point drop) at 6 weeks.

Ustekinumab (currently approved for plaque psoriasis) is a ‘fully human IgG1κ monoclonal antibody’ which blocks the activity of interleukin-12 (IL-12) and interleukin-23 (IL-23) by inhibiting receptors on T cells, natural killer cells, and antigen-presenting cells.  IL-12 and IL-23 have been implicated in the pathophysiology of Crohn’s disease.

This study of ustekinumab was a 36-week randomized, double-blind, placebo-controlled phase 2b trial.  The first 8 weeks were for induction.  After induction, based on response, patients were enrolled in a 28-week maintenance phase.  Initial dosing was 1, 3, or 6 mg/kg of intravenous ustekinumab or placebo.  Maintenance dose was 90 mg subcutaneously.

Patients were permitted to continue receiving stable doses of drugs.  However, entry requirements included a washout period for intravenous glucocorticoids (3 weeks), TNF antagonists (8 weeks), and natalizumab (12 months).

Results:

  • 36.6%, 34.1% and 39.7% of ustekinumab patients (1, 3, and 6 mg/kg respectively) responded at 6 weeks compared with 23.5% of placebo.  The difference was statistically significant for 6 mg/kg/dose.
  • Maintenance therapy (among responders) noted increased clinical remission with ustekinumab compared with placebo 41.7%  vs 27.4%.
  • Overall rates of infection were similar. Serious infections were noted in 6 patients receiving ustekinumab compared with 1 placebo-treated patient.  Infusion reactions were uncommon.
  • Patients who did not have a response to ustekinumab in the induction phase did not benefit from additional ustekinumab in the maintenance phase.

Overall, in this study, patients dosed at 6 mg/kg during induction were more likely to have a response but not more likely to have a remission.  Since all patients in this study had failed at least one TNF antagonist and 50% had failed at least two, the benefit of ustekinumab in other Crohn’s disease patients remains undefined.

Related blog entries:

CHOOSE TNF TRIAL | gutsandgrowth

Vedolizumab -another new IBD treatment | gutsandgrowth

Adding Methotrexate to anti-TNF therapy | gutsandgrowth

Targeted aspirin therapy to improve colorectal cancer survival

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A recent study shows that a specific subset of patients with colorectal cancer are most likely to benefit from aspirin therapy (NEJM 2012; 367: 1596-606).

This study used data from two prospective cohort studies, the Nurses’ Health Study (n=121,700) and the Health Professionals Follow-up Study (n=51,500).  Among these patients, data was analyzed from 964 in whom there was known information on the presence or absence of the PIK3CA mutation.  In total, only 161 of these 964 patients had mutations in PIK3CA; 66 of these took aspirin and 95 did not.

Mutations in PIK3CA affect the gene encoding phosphatidylinositol-4,5-bisphosphonate-3-kinase and occur in 15-20% of colorectal cancers.  Up-regulation of this gene enhances prostaglandin E2 synthesis and prostaglandin-endoperoxide synthase 2 (also known as cyclooxygenase-2) which results in the inhibition of apoptosis in colon-cancer cells. Due to this mechanism, the authors hypothesized that blocking this pathway with aspirin would have a beneficial outcome with regard to tumor molecular characteristics and patient outcomes.

Mutations in PIK3CA were detected with PCR and pyrosequencing after DNA extraction from paraffin-embedded tissues.

Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with better survival.  Hazard ratio for cancer-related death was 0.18 and overall death rate also was lower with hazard ratio of 0.54.  In patients without this mutation (wild-type PIK3CA), regular use of aspirin was not associated with a survival advantage; hazard ratio of cancer-specific survival was 0.96 and overall survival hazard ratio was 0.94.

While this study had data on a large number of other characteristics, including BRAF, KRAS, CIMP, LINE-1, and microsatellite instability, it lacked statistical power to examine many of these other modification effects.

These data, if confirmed, indicate a role for aspirin in colorectal cancer patients with PIK3CA mutations.

Related blog entries:

Microbial transfer for metabolic syndrome?

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Animal models have demonstrated an association between microbiota composition and obesity.  Now, a study shows that the transfer of intestinal microbiota from lean human donors to individuals with metabolic syndrome can improve insulin sensitivity (Gastroenterology 2012; 143: 913-16).

It is known that the small intestine has sensing mechanisms to improve insulin sensitivity via neuronal circuits and changes in microbe composition may be one of the stimuli for this mechanism.  Given the association of altered microbiota with obesity, the investigators divided 18 patients with metabolic syndrome to receive either an allogenic infusion (n=9) of gut microbiota or an autologus infusion (n=9) of gut microbiota.

All subjects underwent small bowel biopsies and then subsequently had lavage through a duodenal tube.  In the allogenic group, the infusate was derived from lean male donors (BMI <23 kg/m-squared).  Insulin sensitivity was measured before and 6 weeks after infusions.

Results:

  • Fecal microbiota of obese subjects was characterized by lower microbial diversity and higher amounts of certain microbes (eg. Bacteroidetes).
  • Peripheral insulin sensitivity improved after allogenic infusion with a median of 26.2 μmol/kg/min prior to 45.3 μmol/kg/min at the six-week measurement.  It was unchanged in those with the autologous infusion as noted in Figure 1.
  • Gut microbial diversity increased significantly after allogenic infusion 178 ± 62 –>234 ± 40 species.  It was essentially unchanged in the autologous group (from 184 ± 71 to 211 ± 50).  Heat maps (Figure 2) help illustrate the microbial changes in the subjects.
  • The authors conclude that butyrate derived from many of the increased bacterial group probably has a regulatory role in improving insulin sensitivity.  Butyrate can prevent translocation of endotoxic compounds derived from gut microbiota which can promote insulin resistance.

Perhaps in a few years, besides limiting the consumption of sugary beverages in places like NYC, beverages with “lean” microbes and or “lean” probiotics may become important.

Do we need clinical scores in pediatric pancreatitis?

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A retrospective study (2003-2007) confirms the limited utility of severity scores in pediatric pancreatitis (JPGN 2012: 55: 266-67). The authors collected data from 48 children; 13 were considered to have severe acute pancreatitis (AP).

Three clinical scores, Ranson, Glasgow modified, and DeBanto, were compared; in addition, the Balthazar computed tomography (BCT) severity index was examined.  Based on their cohort, the clinical scoring systems had a specificity of about 85% but a poor sensitivity of about 55% (53-62%).  The BCT had a sensitivity of 80% and a specificity of 86%. Though, to limit radiation exposure, ultrasonography is preferred over routine use of CT scanning for most pediatric patients.

These data indicate that it is not necessary to remember Ranson’s criteria (or to download a app for that).

More “Survivin” in Crohn’s disease

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Survivin is a member of the inhibitors of apoptosis family.  It helps regulate cell division and prevents cell death.  (Gastroenterology 2012; 143: 1017-26).  While survivin has been shown to be important in cancer, it appears to be important in inflammatory and autoimmune disorders.

In the referenced study, lamina propria T cells (LPT) were isolated from mucosal samples of patients with Crohn’s disease (CD), ulcerative colitis (UC), and controls.  Expression of survivin was assessed by immunohistochemistry, confocal microscopy, and immunoblotting.

LPTs from patients with Crohn’s disease had increased survivin levels; this was not seen in control patients or UC patients.  Furthermore, the investigators showed that the survivin (bound to heat shock protein) was resistant to proteasome degradation.

Implications of this study: 

Survivin may have crucial consequences for CD and other inflammatory/autoimmune diseases; cell proliferation and apoptosis alteration may be important in the pathogenesis of  in these disorders.

Two new drugs for obesity

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Undoubtedly, a safe, effective medication for obesity would be a pharmaceutical blockbuster.  The record so far on previous medications has been dismal.  Many have been abandoned due to safety concerns, including sibutramine (myocardial infarction and stroke) as well as dexfenfluramine/fenfluramine (valvulopathy).  Two new FDA-approved agents have shown promise but caution in their use will be needed (NEJM 2012; 367: 1577-79).  Neither agent has approval for pediatric usage.

Belviq (lorcaserin) is a selective agonist of the serotonin 5-HT-2C receptor and Qsymia (phentermine with topiramate) is a combination sympathomimetic amine (anorectic agent) with an antiepileptic drug.

In studies with lorcaserin, three studies (1-year placebo-controlled) have shown that the number of patients losing >5% of body weight was increased compared to placebo.  Mean percentage body weight loss with lorcaserin was -5.8% in first two studies and -4.5% in third study.  In contrast, placebo patients who received lifestyle counseling lost  -2.5% and -1.5% respectively.  Overall, up to 47% of patients receiving medication lost more than 5% body weight.

Potential safety concerns with lorcaserin:  initially there were concerns due to increased incidence of tumors in rats and possible valvulopathy (eg. mitral or aortic valve regurgitation).  However, the FDA has concluded that it is unlikely that these are likely to occur in humans.

With phentermine/topiramate, two placebo-controlled studies have shown an increase in patients losing >5% of body weight compared to placebo.  In the first study, the mean percentage change in body weight was -10.9% combination (dosage 15 mg/92 mg) compared with -1.6% for placebo.  In the second study, this dosage led to a -9.8% reduction compared with -1.2% in placebo patients. Overall, up to 70% of patients receiving medication lost more than 5% body weight.

With regard to safety, it is known that topiramate is teratogenic and increases the risk of orofacial cleft.  Due to this, approval for this combination requires a risk evaluation and mitigation strategy (REMS) which permits only specially-certified pharmacies to dispense along with formal training for prescribers. In addition, this combination has been associated with mildly increased heart rate. Due to favorable changes in blood pressure, the FDA concluded that this medication had a good benefit-risk balance.  But, the manufacturer recommends against it use in patients with cardiac issues or cerebrovascular disease.

With both new medications, other safety concerns include the risk of increased psychiatric effects.  In addition, specific recommendations include the following:

  • Only recommended in adults with BMI ≥30 or adults with BMI ≥27 with at least one weight-related comorbidity
  • With both medications, if weight loss not adequate after 12 weeks then discontinue medication.  With lorcaserin, if weight loss is not ≥5%, then discontinue.  With phentermine/topiramate, if weight loss is not ≥3% at 12 weeks (with 7.5 mg/46 mg), consider dosage increase and/or discontinuation.

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Can NALFD be improved with bile acid sequestration?

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Probably not (Hepatology 2012; 56: 922-32).

Because bile acid sequestrants like colesevelam (& cholestyramine) lower plasma low density lipoprotein (LDL) levels and can improve glycemic control, a recent study tested the hypothesis that this would result in improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH).

Methods: 50 patients were randomly assigned to either colesevelam 3.75 g/d or placebo for 24 weeks.  All patients had a liver biopsy within 6 months as a baseline study.  The primary outcome was liver fat as measured by a MRI technique (proton-density fat-fraction or PDFF) and by MR spectroscopy. At the start and conclusion of the study patients had biochemical assays, MRI-PDFF & MR spectroscopy; also, patients had a liver biopsy at completion of study.

Results: The colesevelam group had increased fat at the conclusion of the study period by a mean difference of 5.6% with PDFF and 4.9% with MR spectroscopy, both compared with placebo group.  In addition, liver biopsy did not detect any effect of treatment.  Looking at the biochemical indices, there was also a trend of increased transaminases in the treatment group compared to the control group (Table 3 in study).

Conclusions: The authors indicate that the increased fat may be due to a compensatory increase in bile acid synthesis.  Also, as the changes in fat were only detected on MRI, future NASH studies may benefit from this technique as well.

Related blog entries:

NAFLD Guidelines 2012 | gutsandgrowth

Pediatric NAFLD Position Paper | gutsandgrowth

PEG vs. Fiber for constipation

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Which is better for childhood constipation, polyethylene glycol 3350 (PEG) or fiber? A recent study weighs in (J Pediatr 2012; 161: 710-15).

This randomized, prospective, open-label study compared PEG (with electrolytes) to a fiber supplement (acacia fiber, psyllium fiber, and fructose [AFPFF]) in 100 children with chronic functional constipation (Rome III criteria).  Mean age was 6.5 years.  Study design allowed for dosage adjustment.  Initial PEG dosing was 0.5 g/kg but could be increased to 1 g/kg. AFPFF was dosed at 16.8 g daily but could be increased to 22.4 g.  Primary outcome was ≥3 bowel movements per week and improved stool consistency (≥2 on Bristol stool scale).

Key findings:

  • Compliance was better with PEG than AFPFF: 96% for 72%.
  • After 8 weeks, improvement noted in 83% of PEG patients compared to 78% of AFPFF (P=0.788).  At this time point, PEG were having ~5.8 stools/week vs. 5.6 for AFPFF.  Mean Bristol scores were 3.7 and 3.5 respectively.
  • Conclusion: similar efficacy but PEG had better acceptance.  No mention of relative costs of these agents is noted.

Additional references:

Diagnosis and management of idiopathic childhood constipation – BMJ  NICE (Nat’L institute for Health and Clinical Excellence) recommendations 2010

Also, a recent previous post (ACE report -10 year effectiveness | gutsandgrowth) has links to multiple related blog entries.

Microbiome in pediatric ulcerative colitis

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Alterations in the gastrointestinal tract microbiome may play an important role in many digestive conditions.  A recent article examines microbiome alterations in children with severe ulcerative colitis (UC) (Inflamm Bowel Dis 2012; 18: 1799-1808).

Stool samples from 26 healthy children and 27 children with severe UC were prospectively studied.  After DNA extraction, PCR amplification and microarray hybirdization were performed and analyzed.   None of the patients in the study had received antibiotics or probiotics in the preceding month.

Key findings:

  • There were substantial reductions in “richness,” diversity, and evenness of the gut microbiome in UC patients.  (Richness is a term used to reflect the number of detected phylospecies.)
  • There was a decrease in signal in almost all  phylospecies.
  • The number of phylospecies was reduced in UC (266 ± 69) vs controls (758 ± 3)
  • Steroid responders had even fewer phylospecies compared with responders (142 ± 49  vs. 338 ± 62)

It is not surprising that the stools from these children are much different.  The issues of causation and whether a snapshot of the microbiome diversity will have clinical relevance is not clear.  It is possible that antimicrobials may make an individual more susceptible to inflammatory bowel disease by altering the individual’s microbiome.

Related blog entries:

Eat your veggies…if you don’t want to get sick | gutsandgrowth

Why are we seeing so many more cases | gutsandgrowth

ACE report -10 year effectiveness

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More data is now available on the use of antegrade continence enema (ACE) for difficult-to-treat defecation disorders (J Pediatr 2012; 161: 700-4).

This study reports the 10-year (retrospective) experience of a single center.  In total there were 99 patients, median age 8 years.  Mean time for followup was 46 months.  Most procedures were undertaken by interventional radiology with temporary  8.5 Fr Dawson-Mueller catheter which was changed to a Chait Trapdoor catheter after six weeks.  All patients received triple antibiotics for 48 hours and then oral metronidazole for 7 days.  While ACE were not started for 10-14 days, the tube was irrigated with 10 mL of normal saline BID after placement.

Key findings:

  • 71% became symptom-free, and an additional 20% improved significantly
  • Patient population: 35 with functional constipation, 29 with spinal abnormalities, 8 with cerebral palsy, 8 with Hirschsprung’s, 7 with imperforate anus, 7 with combined imperforate anus/tethered cord, and 5 with other causes
  • Irrigations with a stimulant seemed to be more effective.  Specific stimulants included bisacodyl (5 mg if patient <10 years and 7.5 mg if >10 years) and glycerine (median dose 37.5 mL).
  • In the 7 patients without improvement, the stoma was closed after a median time of 7 months & 5 ultimately underwent colostomy.
  • Risk factors for poor outcome: younger age, shorter duration of symptoms, Hirschsprung’s disease, cerebral palsy, previous abdominal surgery, and abnormal colonic manometry (Previous studies have not shown that preop manometry helpful in predicting outcome of ACE).
  • 13% of patients were able to discontinue ACE without recurrence of symptoms
  • Major complications occurred in 12 patients.  12 patients had infections, 4 had abscess, and 3 had peritonitis.  Minor complications were commonplace including leakage in 21 and granulation tissue in 41 patients.

I think this report does provide a balanced view of cecostomy/appendicostomy placement; this will be helpful in counseling families.  While the majority of children will be able to irrigate their colon and thus minimize their intractable constipation, many will have issues with the tube site and particularly early on there is a risk of serious infections.

Related blog entries:

Clues about constipation and more than 2.5 million views …

Stimulants for constipation | gutsandgrowth

It’s worth the cost | gutsandgrowth

thyroid | gutsandgrowth

Additional references:

  • Percutaneous Endoscopic Colostomy (PEC) – YouTube (LEFT-SIDED PROCEDURE)

  • -J Pediatr Surg 2010; 45: 213-9.  ACE highly effective for intractable constipation
  • -JPGN 2011;52: 574.  n=117. 69% success with antegrade enemas.
  • -JPS 2002; 37: 348-51.  sigmoid irrigation.
  • -Lancet 1990; 336: 1217. Malone’s initial description.