Complex EoE patients. EoE is complicated

Transcription

1 Complex EoE patients ACG Annual Meeting 10/17/2016 Evan S. Dellon, MD, MPH Center for Esophageal Diseases And Swallowing EoE is complicated Page 1 of 21

2 Overview 4 complex cases EoE non-response a diagnostic dilemma EoE non-response an outcomes dilemma EoE non-response a therapeutic challenge EoE fibrostenosis a therapeutic challenge Case #1 21 yo M with dysphagia, heartburn, environmental allergies, and food intolerances referred for refractory EoE Prior EGD (prn PPI use): mid and distal esophageal furrows, edema, erythema Biopsies: 82 eos/hpf Allergy testing (SPT) positive to 33 foods Started on dexlansoprazole 60 mg, targeted elimination diet to 33 foods, fluticasone 220 mcg BID Minimal symptom improvement, but lost 20 pounds and overall feels worse Page 2 of 21

3 Case #1 Billed as refractory case but EoE never confirmed More history: anxiety and heartburn most prominent Rec d: c/w Dexilant 60; liberalize diet; D/C flutic Repeat EGD/bx after 8 wks: Bx nl (0 eos/hpf) Sx persist ph/imp negative manometry normal Suspect functional issues predominate Centrally acting med started with good effect Case #1 key points Esophageal eosinophilia EoE Consider the DDx for eos Following the diagnostic guidelines is key If someone is refractory, consider if EoE is the correct diagnosis Are the patients symptoms actually due to eos? Page 3 of 21

4 ACG EoE clinical guidelines EoE diagnostic criteria: Symptoms related to esophageal dysfunction Eosinophil-predominant inflammation on esophageal biopsy, characteristically with 15 eos/hpf Mucosal eosinophilia is isolated to the esophagus and persists after a PPI trial Secondary causes of esophageal eosinophilia excluded Am J Gastroenterol, 2013 Case #2 33 yo M with asthma, allergic rhinitis, and longstanding dysphagia referred for refractory EoE. Prior dx was confirmed after a BID PPI trial Prescribed fluticasone MDI 880 mcg BID Did not feel better, so stopped the medication Page 4 of 21

5 Case #2 EGD on no treatment EGD after fluticasone Bx show 96 eos/hpf Symptomatic Bx show 0 eos/hpf Still symptomatic! Case #2 key points Be aware of symptom/histology discordance Inflammation improves but symptoms persist Strictures Infections Symptoms improve but inflammation persists Diet modification Dilation Be aware of different treatment outcomes Symptoms, endoscopy, histology Page 5 of 21

6 Case #3 30 yo M w/ 4 yr h/o solid food dysphagia and multiple food impactions with ER visits. EGD on BID PPI: Bx: 60 eos/hpf Case #3 After budesonide slurry, 1 mg BID: - Dysphagia persists - Bx: 78 eos/hpf Page 6 of 21

7 Case #3 After budesonide 2 mg BID: - Dysphagia persists - Bx: 55 eos/hpf Case #3 After six-food elimination diet (SFED): - Dysphagia persists - Bx: 70 eos/hpf Page 7 of 21

8 Case #3 key points This patient is truly refractory to both first line treatments of topical steroids Next steps are not well defined Depends on patient preferences Depends on availability of other options Clinical trial would be a great choice Treatment algorithm New EoE diagnosis Stricture present Topical steroids or dietary elimination Dilation Response Non-response Stricture present Maintenance therapy Assess compliance Further diet restriction Increase steroid dose or change formulation Switch from steroids to diet or from diet to steroids Consider second line agents or clinical trials Exclude infection and reconsider other causes of esophageal eosinophilia Dellon & Liacouras, Gastro, 2014 Page 8 of 21

9 What is steroid non-response? Conceptually: persistent eosinophilic inflammation and persistent symptoms Practically: Any eosinophil still there? Topical steroid non-response is not defined in any paper or in any of the guidelines! >15 eos? >5? No decrease from baseline? Less than a 50% or 90% or xx% decrease? Possible causes Medication dose too low Medication not properly administered or sub-optimal formulation ( low dwell time ) Medication or diet non-adherence Superimposed infection (candida; HSV) Allergen exposure (food; environmental) It s not EoE Page 9 of 21

10 Some real life examples Medication issues: Fluticasone 44 mcg MDI Fluticasone MDI inhaled (or spacer used) Fluticasone MDI sprayed on hand and licked (!) Fluticasone 50 mcg nasal Albuterol MDI swallowed Enteric-release capsules of budesonide Dietary issues Did not know whey protein was dairy Did food challenges rather than elimination ( ice cream diet ) Topical steroids non-response Author Med Subjects NON-response Outcome Konikoff, 2006 Flutic 880/d Peds 50% 1 eos Dohil, 2008 OVB 1-2/d Peds 13% 5 eos Straumann, 2008 OVB 2/d Adults 28% < 5 eos Few predictors of nonresponse identified?baseline dilation?genetics Alexander, 2012 Flutic 1760/d Adults 38% >90% decrease Dellon, 2012 OVB 2/d Adults 36% < 1 eos Gupta, 2014 OBS 2/d Peds 23% <1 eos Butz, 2014 Flutic 1760/d Adoles/Adul 35% 1 eos Miehlke, 2015 BET/BVS 2-4/d Adults 0-6% < 16 eos/mm 2 Dellon, 2015 OBS 4/d Adoles/Adul 39% 6 eos Page 10 of 21

11 Real world non-response Topical steroids non-response 63% (n=75; Moawad et al, ACG meeting, 2013) 43% (n=189; Wolf et al; CGH, 2014) Dietary therapy non-response 54% targeted elim, 28% SFED (Arias, Gastro, 2014) 48% SFED (Philpott, APT, 2016) Non-response 2 nd line rx CGH, 2015 Page 11 of 21

12 EoE emerging therapeutics New topical steroids and formulations Clinicaltrials.gov summer, EoE studies listed 38 actively recruiting 20 with new treatments Novel biologics Novel small molecules Kern & Hirano, Expert Opin Emerg Drugs, 2013 Topical steroids new formulations 76 adults with active EoE Four treatment groups (2 wks of treatment): Budesonide effervescent tabet (BET) 2 mg/d BET 2 mg BID Budesonide viscous suspension (BVS) 2 mg/d Placebo Gut, 2015 Page 12 of 21

13 Topical steroids new formulations Histologic outcome Endoscopic outcome (< 16 eos/mm 2 ) Symptom outcome *p < for all groups compared with placebo Miehlke et al, Gut, 2015 Topical steroids new formulation RCT of oral budesonide suspension (OBS) vs placebo 87 pts (11-40 yo) with active EoE OBS 2 mg BID x 12 wks Co-primary outcomes: Symptom response (using the DSQ, a validated instrument) Histologic response ( 6 eos/hpf) Secondary outcome of endoscopic response (using EREFS, a validated instrument) Dellon et al, & Hirano et al, DDW 2015 Page 13 of 21

14 Topical steroids new formulation Mean change in DSQ score Symptom outcome p= Proportion with 6 eos/hpf Placebo Histologic outcome p< OBS 2 mg BID Mean change in total EREFS score Endoscopic outcome p< Dellon et al, & Hirano et al, DDW 2015 Flovent diskus?? Retrospective analysis of 30 adults w/ EoE Eos: eos/hpf (p < 0.001); 77% < 15 eos/hpf EREFS: (ns) Sx score: (ns) Page 14 of 21

15 Revisiting anti-il-5 Eosinophil count (eos/hpf) 120 Pre-treatment 100 Post-treatment Straumann Assa'ad Spergel Year Design RCT RCT RCT Subjects 11 adults 59 children 226 children Med mepolizumab* mepolizumab** Reslizumab*** Rx time 2-4 doses; eval at 13 wks 3 doses; eval at 12 wks 4 doses; eval at 15 wks *750 mg x2; then 1500 mg x 2; **0.55, 2.5, or 10 mg/kg; **1, 2, or 3 mg/kg Anti-IL-13 BL Wk 16 JACI, 2014 Page 15 of 21

16 Anti-IL-13 Presentation #19; Abstract #420; 8:30 am Tues! Case #4 26 yo W with long standing dysphagia and dietary modification behavior Page 16 of 21

17 Case #4 Incomplete histologic response to topical steroids; did not want to try diet or clinical trials serial dilation approach: Case #4 key points Dilation is required for narrow caliber esophagus and esophageal strictures Dilation is effective at improving symptoms but does not impact underlying inflammation Dilation can be done safely in EoE Either balloons or bougies can be used A cautious approach is important Page 17 of 21

18 Take home points A sizable proportion of EoE patients may not respond optimally to first line treatments or present with a complex clinical picture Confirm the dx of EoE Stepwise approach to treatment Search for causes for refractory EoE Dilation for fibrostenotic disease Consider clinical trials if first line options fail Thanks! Page 18 of 21

19 DDx of esophageal eosinophilia EoE Eosinophilic gastroenteritis GERD PPI-responsive esophageal eosinophilia (PPI-REE) Crohn s disease Connective tissue diseases Hypereosinophilic syndrome Infections Drug hypersensitivity response Furuta et al, Gastro, 2007; Liacouras et al, JACI, 2011 Selecting treatment approach Anti-inflammatory Dilation Hirano & Aceves, Gastroenterol Clin N Am, 2014 Page 19 of 21

20 Other EoE treatment options? Treatment Systemic corticosteroids Leukotriene antagonist (montelukast) Comment Effective; limited by side effects Questionable efficacy Mast cell stabilizer (cromolyn) Immunomodulators (6MP; AZA) Biologics (anti-ige; anti-tnf) Endoscopic dilation Not effective Limited data; side effects Not effective Mechanical; does not impact underlying disease process Some thoughts on dilation No direct comparative data on technique Safety data published for both balloons and bougies Educate patients on post-procedural discomfort Cautious approach Balloon - after 13.5mm Balloon - after 15mm Page 20 of 21

21 Some thoughts on dilation No direct comparative data on technique Safety data published for both balloons and bougies Educate patients on post-procedural discomfort Cautious approach Savary - after 12.8mm Savary - after 14mm Page 21 of 21