Tag Archives: budesonide

Higher Doses of Topical Steroids for Eosinophilic Esophagitis

Posted on by

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

Posted on by

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

Posted on by

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.

Budesonide for Ulcerative Colitis

Posted on by

Budesonide (Uceris) has been formulated with the MMX delivery technology and now has been FDA approved for mild to moderate ulcerative colitis in adults.  The potential advantage of budesonide compared with conventional corticosteroids is for targeting anti-inflammatory activity to the colon with less systemic side effects.  The potential downside includes the high cost.  According to one website (see below), the average wholesale cost is just below $1500 per month.  In addition, only a minority of individuals responded to budesonide in published studies:

Induction of Remission in Studies 1 and 2 (reference below)

Treatment Group

Study 1 n/N (%)

Study 2 n/N (%)

UCERIS 9 mg

22/123 (17.9)

19/109 (17.4)

UCERIS 6 mg

16/121 (13.2)

9/109 (8.3)

Reference Arm*

15/124 (12.1)

13/103 (12.6)

Placebo

9/121 (7.4)

4/89 (4.5)

Treatment Difference between UCERIS 9 mg and Placebo (95% CI)†

10.4% (2.2%, 18.7%)

12.9% (4.6%, 21.3%)

Data for budesonide for pediatric patients with ulcerative colitis is not available.

Fontan and PLE

Posted on by

In my practice, I am asked to give input on patients with Fontan procedure infrequently.  A few recent articles though are a good resource:

  • Nutr Clin Pract 2012; 27: 375-84
  • J Pediatr 2012;161:186-90

Both articles review the physiology and therapies available.  In essence, the Fontan operation establishes a passive connection between the systemic venous return and the pulmonary circulation.  When there are elevated inferior vena cava pressure, this can lead to hepatic dysfunction and protein-losing enteropathy.  The latter is related to engorged intestinal lymphatics, similar to that in congenital intestinal lymphangiectasia.  When lymphatic proteins leak, PLE only develops when the intestinal leak exceeds the patient’s ability to resynthesize lost proteins.

PLE presenting features: edema, diarrhea, bloating, pain, and pleural or pericardial effusions.  PLE places patient at risk for growth failure and associated problems. In more severe cases, hypocalcemia and infections due to lymphopenia can be present.

Potential treatments:

  • Agents that improve heart function -diuretics, pulmonary vasodilators (eg. sildenafil)
  • Corticosteroids including budesonide.  While improvement is common, hypoproteinemia returns after weaning of medication.  Systemic side effects occur even with budesonide.
  • Low molecular weight heparin.  Heparin likely helps by acting as a barrier to large molecules by improving the integrity of the basement membrane
  • Octreotide -has shown some effectiveness as an adjunct to other therapies in small studies
  • Albumin infusions
  • Diet: high protein (≥ 2 g/kg/day), low-fat (<25% of calories from fat), increase medium-chain triglycerides, & sodium-reduced
  • Surgical treatment (eg. atrial baffle fenestration) and cardiac transplantation

The second reference notes that many centers are delaying the Fontan procedure and accepting some degree of hypoxemia.  The problems with this approach include symptoms like headaches and decreased energy levels and the likelihood of developing pulmonary arteriovenous malformations.  Ultimately, the authors hypothesize that biomedical engineers may develop better solutions with miniaturized mechanical support devices to improve pulmonary blood flow.

Additional references:

  • Ann Thorac Surg 2010; 89: 837-42.  Budesonide for Fontan-associated PLE
  • Ann Thorac Surg 2011; 92: 1451-56.  Budesonide for Fontan-associated PLE
  • Congenit Heart Dis 2009; 4: 107-11.  Use of sildenafil for failing Fontan.

Choosing topical therapy for EoE

Posted on by

A brief report adds useful information for topical therapy for eosinophilic esophagitis (EoE) (Gastroenterol 2012; 143: 321-24).  This study involved 25 subjects in a prospective randomized open label design that compared budesonide delivered via either as a metered nebulized form (NEB) or as oral viscous solution (1 mg BID).  The mean age of the subjects was 35 years, 60% were male, 88% were caucasian, and all had dysphagia.

Findings:

  • Orally administered viscous budesonide (OVB) was more effective at lowering esophageal eosinophilia.  After treatment, eosinophil count per high power field was 11 for OVB compared with 89 for NEB formulation.
  • Nuclear scintigraphy showed that OVB had a significantly higher level of esophageal exposure to the therapeutic agent than NEB and did not result in lung exposure (which occurred in NEB group)
  • Both groups had improvement in dysphagia.  Poor correlation of symptoms and histology has frequently been reported.

These findings along with the fact that budesonide has less systemic corticosteroid effects, due to a high first-pass metabolism, makes OVB a logical choice for patients treated with topical steroids.

Previous related blog entries:

Guidelines for Eosinophilic Esophagitis

Looking better or feeling better in EoE?

Look of improvement on an EoE diet

Eosinophilic Esophagitis -Six Food Group Diet

MicroRNA signature for eosinophilic esophagitis

The undiscovered country

Guidelines for Eosinophilic Esophagitis

Posted on by

For a little while, I’ve meant to complete a post on the EoE guidelines published last fall (J Allergy Clin Immunol 2011; 128: 3-20).  This article, based on the input of 33 physicians with EoE expertise, provides a lot of depth to this unfolding area in pediatric gastroenterology.

Diagnosis of EoE. The authors caution that this diagnosis is not a histologic diagnosis as a number of entities can cause esophageal eosinophilia; at the same time, a minimum number of eosinophils, 15/hpf, is a necessary diagnostic threshold.  A small number of patients may have EoE with fewer than 15/hpf, including PPI-responsive EoE, inadequate biopsy sampling, seasonal variation, or partial treatment (eg. patient on corticosteroids).

How many biopsies?  In one cited study in the article, 2, 3, and 6 biopsies had sensitivity of 84%, 97%, and 100% respectively.  Endoscopic biopsies remain the only reliable diagnostic test.

Why are there a subset of PPI-responsive EoE patients?  Potential explanations include improvement in immune-activation after healing of esophageal mucosa, inherent anti-inflammatory property of PPIs, or due to pitfalls in current diagnostic testing.  Due to recognition of this disorder, pH testing may be needed in many patients with suspected EoE.  Even still, the authors note that “PPI responsiveness or diagnostic testing (pH monitoring) might not adequately distinguish GERD and EoE.”

How useful are genotypic features?  Clinical  use of genotypes is not feasible at this time.  However, it is anticipated that esophageal gene expression will emerge as one way to differentiate EoE from other conditions and to determine optimal treatments.

What type of allergy evaluation? The majority of EoE patients have concurrent atopic diseases, including rhinitis, asthma, and eczema.  Thorough evaluation by an allergist (or immunologist) is recommended.  Specific recommendations: skin prick testing (SPT), serum IgE for immediate-type food allergy.  Atopy patch testing (APT) has high negative predictive values, >90%, except for milk which is ~50%.  APT needs to “be standardized and validated.”

Biomarkers? “Insufficient evidence to support any peripheral marker” including cytokines, and IgE (total).

Treatment –PPI: PPIs are useful to distinguish GERD as well as PPI-responsive EoE from EoE requiring other treatments.  They also help with symptomatic treatment in some patients who have secondary GERD.  Recommended dose in children 1 mg/kg/dose BID.

Treatment –Dietary: Three dietary regimens have potential effectiveness: 1) selective food diet based on allergy testing, 2) dietary restriction of the most likely food antigens (eg. six food group diet elimination) and 3) strict amino acid based diet.  Tolerance of foods that have been shown previously to provoke EoE is unlikely to develop in the majority of EoE patients.

Treatment –Corticosteroids: Corticosteroids are effective but when discontinued EoE almost always recurs.  Systemic corticosteroids can be particularly useful when severe dysphagia is present.  With severe endoscopic findings, a course of corticosteroids may help reduce the need for dilatation or lessen the risk.  Long-term use of systemic steroids is not recommended.  Topical steroids should be considered in all patients with EoE.  Recommended doses are given.

  • For fluticasone:  88-440 μg 2-4 times per day (max 880 μg BID)
  • For budesonide: 1mg daily (<10 y) and 2 mg daily (≥10 y)
Treatment –Dilation:  Dilation can provide relief of dysphagia.  In most cases, medical or dietary therapy should be attempted prior to use of dilation.  Goal of 15-18 mm.  Practical advice (not validated in studies): Limit dilation progression per session to 3 mm or less after resistance has been encountered.
Treatment –Alternatives:  Cromolyn, leukotriene receptor antagonists, or immunosuppressive agents (eg azathioprine, 6-mercaptopurine) are “not recommended.”
Complications: Perforations (spontaneous & procedure-related), food impactions, strictures, and narrow caliber esophagus.  There has not been evidence of an increased esophageal cancer risk in EoE patients to date.
Unresolved issues: Despite the extensive consensus on many of these issues, the conclusions inform the reader of how far we need to go.  Some of the unresolved questions include such basic problems:
  • “Importance of treating asymptomatic patients”
  • “Natural history of EoE and rates and predictive indexes of complications”
  • “Accuracy of skin prick and patch testing”
  • “Optimal end points of treatment”

Previous related blog posts:

The undiscovered country

Eosinophilic Esophagitis -Six Food Group Diet

Practical information on EoE for families:

http://www.ccdhc.org/diseases/EoE.html

The undiscovered country

Posted on by

The title of this blog is derived from a Star Trek movie.  I think that when we see patients with eosinophilic esophagitis that we are often seeing something new and poorly characterized.

Despite so many unanswered questions, particularly on an individual basis, this topic has seen a lot of interest and there are many advances in both bedside and basic research.  The review article  (Allergy 2012; DOI: 10: 10.1111/j.1398-9995.2012.02787.x) focuses on many of the similarities and differences between pediatric and adult patients.  Is it the same disease? (Probably yes)

With regard to medical history, the article reminds clinicians to ask about coping strategies:

  • do you wash food down with liquid?
  • are you the last one to finish your food?
  • do you chew your food a long time?
  • do you avoid foods like meats or breads?

Clinical features –main difference is greater presentation variety in children.  Adults almost always have long-standing dysphagia.  In pediatrics, painful symptoms, reflux symptoms, and feeding refusal are often seen in early stages.  In both populations, other atopic diseases are very common.

Immunopathogenesis (same in pediatrics and adults):  Th2-type inflammatory response; not just eosinophils but also IL-5-expressing T-cells, B cells, and IgE-bearing mast cells.  A break-down of all the types of quantified cells from a large number of studies is detailed (Table 2).

Allergic profile –main difference is much higher aeroallergen sensitization in adolescent & adult patients than in pediatric patients.  In children, top four allergens: milk, wheat, egg, and soy.  In older patients/adults, nuts are frequent food allergens.

Treatment strategies –basic question of whether to treat for symptomatic relief or histologic response is still debated.  Three goals of treatment are the same:

  • improve quality of life
  • reduce the risk of severe esophageal injury
  • prevent esophageal damage

3 D’s of treatment drugs, diet, dilatation:

Drugs: topical steroids (fluticasone, budesonide) are effective in ~50% of children & these agents may reverse subepithelial fibrosis, PPIs -small percentage have EoE PPI-responsive disease, & systemic steroids.  Lower doses of budesonide may be effective as maintenance treatment (0.25mg BID).  Interestingly, infliximab has not been effective clinically or histologically despite the high amounts of TNF.  Azathioprine (or 6-MP) was effective in three steroid-dependent patients in a pilot study.

Diet –review does not cover new territory (see previous blog: Eosinophilic Esophagitis -Six Food Group Diet).  States that elemental diets are not practical in adults.  Discusses the fact that food allergy identification is difficult & remains a pressing research need.

Dilatation –can provide long-lasting symptom relief.  Dilatation is infrequently utilized in pediatrics and virtually never in absence of other therapies.

On a side note, in my training I was taught that there were 3D’s to treating every patient: diet, drugs, and demeanor — a good attitude goes a long way, particularly in an uncertain world.

Additional references:

  • -Gastroenterology 2011; 141: 1593.  anti-IL-5.  partially effective for EoE.
  • -JPGN 2010; 51: 723. n=91.  Incidental gastric eosinophils does not predict a worse response to fluticasone then isolated EoE.
  • -Clin Gastro & Hepatology 2011; 9: 400 (editorial 370). Budesonide at dose of 0.25mg BID was partially effective in adult cohort of n=28.
  • -Aceves SS et al. Allergy 2010; 65: 109-116. 3 month course of budesonide can lead to resolution of esophageal remodeling. Lamina propria fibrosis resolution correlates with response to topical steroids. Examined effect on lamina propria after 3 months of Rx.
  • -Gastroenterology 2010; 139: 1526. n=36. (summary pg 1429) 15 day course of budesonide (1mg BID). 13/18 in Rx group had improved dysphagia, 72% wiht histologic remission, 92% reduction in eosinophil count. Did not seem to matter if “allergic” or not. 3 pts developed mild candida.
  • -Gastroenterology 2010; 139: 418. Randomized placebo study showed effectiveness.n=15 Rx (n=9 placebo). 87% of Rx group responded.  2ml of water with 0.5gm pulmicort and mixed it with 4-5 packets of splenda.
  • -JPGN 2007; 45: 281/370/319. Review/research symposium/subepithelial fibrosis associated with EoE & dysphagia.
  • -JPGN 2007; 45: 22-31. Th2 Immunity w Eotaxin-3/ C-C chemokine receptor in EoE.
  • -Gastroenterology 2006; 131: 1381-1391. Randomized double-blind, placebo-controlled trial of fluticasone for EoE: 880mcg divided bid; n=21 Rx, n=15 placebo. 50% (vs 9% controls) achieved histologic remission; Rx more effective in those w/o detectable food allergies. 67% (vs. 27% controls) resolution of vomiting.
  • -Clin Gastro & Hep 2007; 5: xxiv. EoE causing Boerhaave’s syndrome (spontaneous rupture)
  • INCREASED FRAGILITY: -Gastrointest Endosc 2003; 57: 407-12. -Clin Gastro Hepatolo 2003; 1: 433-37.
  • -Clin Gastro & Hep 2006; 4: 1328. absolute eosinophilia (AEC 440 vs 140 controls), eosinophil-derived neurotoxin, and eotaxin-3 act as biomarkers of EE activity.
  • -Gastroenterology2006; 131: 2018 (-J Clin Invest 2006; 116: 536-547. ) Eostaxin-3/EcE transcript signature.
  • -J Pediatr 2005; 147: 540 Picture of ringed esophagitis.
  • -JPGN 2004; 39: S8 [abstract 0005]. CHOP experience in 250 pts. NG elemental diet was most effective. ~6% of pts presenting with GER. Strict avoidance of allergens needed.