Acid Suppression/C difficile and Adrenal Suppression/Topical Steroids

Briefly noted:

J Jimenez et al. (JPGN 2015; 61: 208-11) provide more data that gastric acid suppression is associated with an increase risk of Clostridium difficile infection (CDI). This was a retrospective case-control study with 138 children with CDI and 276 controls. After adjustment, acid-suppression therapy had a 1.8 Odds Ratio association with CDI.

S Harel et al. (JPGN 2015; 61: 190-3) in this retrospective ‘pilot’ study of  patients receiving topical budesonide for eosinophilic esophagitis, 6 of 14 (43%) had mild biochemical evidence of adrenal suppression, as measured by ACTH testing. Bottomline: a prospective study is likely needed to confirm or refute these findings. In the meanwhile, stress steroid coverage could be considered in patients on prolonged budesonide.

How to Incorporate Budesonide Foam into UC Treatment Algorithm

A recent study (Sandborn WJ, et al. Gastroenterol 2015; 148: 740-50, editorial 701-4) shows that budesonide foam can be helpful for patients with ulcerative proctitis and ulcerative proctosigmoiditis.

Design: Two identical randomized, double-blind, placebo-controlled trials examined the use of budesonide foam in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis.  Patients had at least 5 cm of involved mucosa but no more than 40 cm. Dosing: 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks. The primary endpoint of remission was defined as an endoscopy subscore of ≤1, rectal bleeding subscore of 0, and improvement or no change from baseline in stool frequency subscore of the Mayo score. It is noted that about 90% of patients had moderate Mayo endoscopy subscore at baseline.

Key findings:

  • Combining the results of the studies, 41.2% achieved the primary end point of remission at the end of 6 weeks, compared with 24.0% of placebo patients.
  • There were 10 patients (3.7%) with low morning cortisol (compared with 0.7% of placebo-treated patients) and 14% who had abnormal ACTH testing at 6 weeks (compared with 4% of placebo-treated patients), though there no reported signs/symptoms of adrenal suppression present.

The associated editorial suggests that budesonide could be implemented in patients who did not respond to 5-ASA topical therapy (suppository for proctitis and enema for proctosigmoiditis).  In addition, the editorial questions whether a single night-time administration may be more effective by maximizing adherence.

Bottomline: Budesonide foam was superior to placebo in this study and may eliminate the need for systemic steroid use.  As the editorial suggests, 5-ASA topical therapy likely should be considered as first-line treatment.

Related blog post: Budesonide for Ulcerative Colitis

Predicting Response to Topical Steroids in Eosinophilic Esophagitis

A recent study (Wolf WA, et al. Clin Gastroenterol Hepatol 2015; 13: 45-58) examined 221 patients in a retrospective cohort study to determine how effective topical steroids were in the treatment of eosinophilic esophagitis (EoE).  The authors studied these patients from 2006-2013; the majority received budesonide (63%) and the remainder received fluticasone; the typical dosing was 0.5 mg-1 mg twice daily and 440-880 mcg twice daily, respectively. 129 (58%) of the participants were >18 years.

Key findings:

  • 57% had histologic response with <15 eos/hpf
  • Refractory patients “were difficult to treat with dietary and second-line pharmacologic therapies, with less than half responding even after multiple second-line therapies.” The most successful second-line approach was diet: 6 of 16 (38%) had improved histology (<15 eos/hpf).  Higher doses of topical agents were effective in 2 of 14 (14%) and alternative topical agent was effective in 2 of 7 patients (29%).
  • Dilatation at the time of disease presentation (25% of the study cohort) correlated with poor clinical outcome.  Only 40% (20 of 50) had a histologic response.
  • High tissue levels of tryptase and eotaxin-3 increased the likelihood of a steroid response.

As this was a retrospective study, there were several weaknesses.

Take-home message: The findings from this large cohort show that more than 40% of patients did not have a favorable histologic response.  Some recent studies indicate that higher doses of steroids may be effective, but this may be influenced by the proportion of individuals with advanced fibrostenotic disease.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Chicago's Bean

Chicago’s Bean

Sweet Alternative to Splenda for Budesonide

A recent article (JPGN 2014; 59: 317-20) has shown that Neocate Nutra is a good alternative to splenda as a delivery vehicle for budesonide for children with eosinophilic esophagitis.

This retrospective review of 60 children treated with oral viscous budesonide (OVB) who used either splenda (n=46) or with Neocate Nutra (n=14).  With regard to budesonide, in patients less than 10 years, the dose was 1 mg/day and older children received 2 mg/day.  For splenda patients, 10 packets were used to create a slurry whereas with Neocate Nutra powder the amount was 2.5 cm3 per milligram of budesonide.  Followup endoscopy took place at least 10 weeks after the start of treatment.

Key findings:

  • 13 of 14 Neocate Nutra patients achieved a histologic response (peak eosinophils <15/hpf) compared with 30 of 46 Splenda patients.
  • Mean eosinophil count dropped from 62 to 9 for Neocate Nutra patients and from 59.5 to 25.5 for Splenda patients.

Limitations of study: small number, retrospective study.

Take-home message: Neocate Nutra is at least as effective as Splenda as mixture with budesonide.  In addition, many parents may prefer to avoid Splenda.

Related blog posts:

Higher Doses of Topical Steroids for Eosinophilic Esophagitis

A recent randomized, double-blind, placebo controlled study (Gastroenterol 2014; 147: 324-33) examined “high-dose” fluticasone propionate (FP) for patients, aged 3-30 years, with eosinophilic esophagitis (EoE).  FP patients received 1760 mcg divided into two doses for three months, then the dose was reduced in half.

Efficacy: Among the 28 FP patients, a complete remission (CR) (≤1 eosinophil/hpf on histology) was evident in 65% compared with 0% CR in 14 placebo patients.  Furthermore, partial response (PR) (multiple definitions of responsiveness -see Figure 2) evident in about 75%.  Reduction in dose to 880 mcg/day resulted in 93% of EoE participants maintaining CR or PR.

Molecular response: The authors also studied the transcriptome prospectively in these patients with the “Eosinophilic esophagitis diagnostic panel” (EDP). “A large portion of the participants receiving FP in phase 1 showed a normalized signature compared with the dysregulated screening and placebo signatures….notably, the 6 FP participants with histologic PR or no remission also had a partial reversal with a signature different from the placebo group…However, there were still a few molecular nonresponders whose signatures failed to normalized upon FP treatment.”

Based on their study findings: the authors recommend assessment at 3 months after initiation of topical steroids because “extending the timeframe for high-dose FP to 6 months does not increase remission status.”

The authors could not identify any demographics or signs/symptoms that predicted response to high-dose FP. In addition, in this small cohort, no difference in adverse effects compared to placebo were found.

My take on this study is that it raises more questions than it answers.

  • Is the higher induction dose of FP really needed or would 880 mcg/day over a 6 month period result in the same findings?
  • Is FP superior to budesonide which is considered to have less systemic absorption?
  • Should we be using higher doses of budesonide as well?
  • Would patients be better off receiving systemic steroids and transitioning to topical steroids?
  • What are the long-term consequences, good and bad, in using higher steroid doses?

Take-home message: In a carefully designed study with molecular correlation, higher doses of Fluticasone achieved high rates of complete remission in EoE patients.  Except for elemental diets, no dietary therapies have shown to have a higher response rate.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

 

Microscopic, Lymphocytic and Collagenous Colitis

Microscopic Colitis (MC) is a rare pediatric problems and occurs when chronic diarrhea occurs in the presence of a normal-appearing endoscopic exam but with abnormal histology.  In adult populations, microscopic colitis is seen more frequently and can be confused with irritable bowel syndrome.  The two subtypes:

  • Lymphocytic Colitis (LC):  >20 intraepithelial lymphocytes/100 colonocytes
  • Collagenous Colitis (CC): thickened subeptihelial collagen band in addition to changes seen with LC

In a recent study (JPGN 2013; 57: 557-61), 27 MC cases were identified from a pathology database between 1995-2011.  5 were excluded due to an enteric infection.  Among the 22 other cases, 19 had LC and 3 had CC.  Association with celiac disease was evident in 4 patients and many had preceding drug exposures.

Treatment included steroids, melamine, an bismuth.

Additional references:

  • -JPGN 2011; 53: 579. lymphocytic colitis case report
  • -Clincal Gastro & Hep 2011; 9: 13.  Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gut 2009; 58: 68-72. Collagenous colitis: Budesonide at 6mg/day maintained remission in ~25%.
  • Gastro 2008; 135: 1510.  Budesonide effective for collagenous colitis; n=48, 9mg/day.
  • -Gastro 2011; 140: 1155. Review of microscopic colitis/collagenous colitis.
  • -Am J Gastroenterol 2010; 105: 859-865.  n=466 & 451 controls.  Microscopic colitis present in 1.5% of IBS patients.  IBS pts with lower incidence of adenomas (7.7.% vs 26%).  9% had diverticulosis (lower).
  • -Clin Gastro & hep 2009; 7: 1210. 4.3% of pts w microscopic colitis had celiac. 44/1009.

Adult versus Pediatric Data: Autoimmune Hepatitis

Recent data in adults indicate that budesonide may be more effective than prednisone for treating autoimmune hepatitis (AIH) (Gastroenterol 2010; 139: 1198-206).  Is this true in pediatrics? A small study and an associated editorial indicate that budesonide may be inferior (J Pediatr 2013; 163: 1347-53 & editorial 1246).

The study consisted of 46 pediatric patients with AIH (35 females) who were enrolled in a prospective double-blind, randomized, active-controlled trial with budesonide at a dose of 3 mg TID or prednisone (starting at 40 mg and tapered to 10 mg); all patients received concomitant treatment with azathioprine (1-2 mg/kg/day).  After the initial 6 months, a further 6-month open-label treatment with budesonide (n=42) followed.  Approximately 70% of the patients had type 1 AIH.

Results:

  • Normalization of aminotransferases occurred in only 16% of budesonide group and 15% of prednisone group after 6 months.
  • At 12 months, 46% of those on budesonide had biochemical remission

The editorial explains why these results are unlikely to affect current management and provides succinct summary of AIH management.

Key points:

  • “The juvenile form of AIH is particularly aggressive…between 40% and 80% of children are reported to have cirrhosis at diagnosis”
  • Standard treatment for juvenile AIH: Prednisone 2 mg/kg/day (max 60 mg) which is tapered over 4-8 weeks with the decline of aminotransferase levels to a maintenance dose of 2.5-5 mg/day.  80% of the improvement (in ALT values) occurs within the first two months.  Typically, azathioprine is added after some improvement in aminotransferases.  In the absence of toxicity, the dose is increased to 2-2.5 mg/kg/day.
  • Remission is defined as complete normalization of aminotransferases along with normalization of serum immunoglobulin G levles, negative or very low autoantibody titer, and histologic resolution of inflammation.
  • Histologic remission lags biochemical response, “though 95% of patients have a marked histologic improvement after a mean duration of 4 years of effective therapy.”
  • Budesonide is not used in the presence of cirrhosis
  • Problems with current study are detailed in the editorial.  The design likely contributed to remission rates which were significantly lower than reported with standard prednisone/azathioprine.

Related posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.