treating the outpatient with severe ibd: case study alan c. moss md, febg, facg, agaf associate...

Treating the Outpatient with Severe IBD: Case Study

Alan C. Moss MD, FEBG, FACG, AGAF

Associate Professor of MedicineDirector of Translational Research

Disclosures

• Consultant; Janssen, Theravance, Bayer, Roche

• Research Support; Pfizer, NIDDK, Salix, Shire

Case - 42 yr old male patient

• Left-sided ulcerative colitis for 8 years

• Failed mesalamine 4.8g/day, azathioprine 100mg/day• Recurrent flares responsive to prednisone

• Now steroid-dependent; gets more diarrhea / abdominal pain / fevers when dose lowered to 20mg

• CRP 56 / ESR 80 / Hct 28 / Stool negative for C.difficile

• High-grade B-cell lymphoma 3 years ago – now in remission

Sigmoidoscopy

What would you recommend?

A. Colectomy

B. Infliximab

C. Vedolizumab

D. Methotrexate

E. Tacrolimus

F. Tofacitinib

G. Budesonide

‘Knowns & Unknowns’ in IBD Patients

Drug Early “Response” Rate in UC#

Lymphoma Risk*

Infliximab 67% (RCT, all)

Similar to IBD Population

Vedolizumab 49% (RCT, on steroids)

None in clinical trials

Methotrexate 58% (RCT, steroid-dependent)

Similar to General Population

Tacrolimus 60% (OL, refractory)

Similar in Transplant Population

Tofacitinib 53% (RCT, on steroids)

Case Reports

Lichtenstein, Am J Gastroenterol, 107 (2012), pp. 1409–1422 Mariette X, Blood, 99 (2002), pp. 3909–3915Caillard S, Transplantation. 2005 Nov 15;80(9):1233-43Lee B, N Engl J Med. 2014 Jun 19;370(25):2377-86

Sandborn W, N Engl J Med. 2012 Aug 16;367(7):616-24Boschetti G, Dig Liver Dis. 2014 Oct;46(10):875-80 Mate-Jimenez J, Eur J Gastroenterol Hepatol. 2000 Nov;12(11):1227-33 Feagan B, N Engl J Med. 2013 Aug 22;369(8):699-710

# week 6-8 clinical response * in patients without prior history of lymphoma

ECCO Recommendations

• Few data exist in using immunosuppressants (IS) in IBD patients with prior cancer

• Recommended “waiting period” before IS starts ;• 2 years for invasive cancers• 5 years for aggressive cancers (lymphoma, melanoma,

breast, sarcomas, urinary tract cancers, and myeloma)

Beaugerie L, Dig Dis Vol. 31, No. 2, 2013Magro F, J Crohns Colitis. 2014 Jan;8(1):31-44

Feagan B, N Engl J Med. 2013 Aug 22;369(8):699-710

Vedolizumab - Efficacy in Patients with UC on Steroids

Treating the Outpatient with Severe IBD: Case Study

Joshua Korzenik, MDDirector, BWH Crohn’s and Colitis Center

Brigham and Women’s HospitalBoston, MA

Disclosures

• Consultation: Abbvie, Roche, Vithera, Shire• Research support: Abbvie, Takeda, Pfizer,

Transparency

43 yo woman with Crohn’s

• Mid-jejunal, ileocolonic Crohn’s dx in 1994 at age 23• Multiple resections:

– Ileocolonic in 2001– Mid-jejunal resection 2003– Poor response to 6-MP

• Perianal disease developed post-resection– Responded to infliximab then anaphylaxis– Rectovaginal fistula– Adalimumab- rash– Certolizumab

Psoriasis

• Paradoxical but not rare occurrence• Report of 30 patients

– Occurs on all anti-TNFs– Nearly half responded to topical therapy– 17/30 no response to topical therapy– 9/30 discontinued anti-TNF due to psoriasis– Eight patients were treated with an alternative anti-

TNF with recurrence in two (25%).

Cullen et al, IBD Journal, 2011

FDA Adverse Event Reporting System(FAERS)

• 5,432 reports (2004-2011)1

– Infliximab 1789 – Adalimumab 3475– Certolizumab 168

• British Society for Rheumatology Biologics Register2

– 9826 anti-TNF-treated – 2880 DMARD-treated patients

• 25 cases of psoriasis in anti-TNF/ 0 in DMARD-treated• 1.04 (95% CI 0.67 to 1.54) per 1000 person years

1) Kip et all, IBD, 2013 2) Harrison, Ann Rheum Dis, 2009

Other Auto-Immune Diseases Provoked by Anti-TNF Agents

• Drug-induced lupus• Psoriasis• Alopecia areata/totalis• Autoimmune hepatitis• Sjogren’s syndrome• Demylinating diseases• Vasculitis• IBD

Treatment options?

A) SurgeryB) MethotrexateC) GolimumabD) UstekinumabE) Cyclosporine

Sandborn WJ et al. N Engl J Med 2012;367:1519-28

CERTIFI: Ustekinumab Phase IIb for Response Induction in CD

CASE #2

Crohn’s disease

• 27 yo man with a hx of ileocolonic Crohn’s disease for 6 years

• 6-MP partial response, infliximab added• Sustained remission for 4 years on dual

therapy• He wants to discontinue all medications• CRP/ESR normal• All other routine labs are normal

You recommend:A) Discontinue 6-MPB) Discontinue InfliximabC) Discontinue both

D) Colonoscopy or imaging1) If normal:

a. Discontinue 6-MPb. Discontinue Infliximabc. Discontinue both

2) If not normal:a. Discontinue 6-MPb. Discontinue Infliximab

“STORI”: What happens when IFX is withdrawn?

• Prospective multi-center study: GETAID

• Patients with luminal CD, >17 y.o., who received at least

1 year of IFX plus AZA/6-MP/MTX

• At least 2 infusions of IFX administered in preceding 6

months. Final IFX no more than 2 weeks after accrual.

• Outcome: Steroid-free remission >6 months, CDAI <150.

• CDAI at recruitment: 37 (19-61)

Louis E et al. Gastroenterology 2012; 142 (1): 63-70.

Louis E et al. Gastroenterology 2012; 142 (1): 63-70.

“STORI”: What happens when IFX is withdrawn?

What do these data mean for this patient?

• Low-to-Intermediate risk of relapse

– Male, no previous surgery

– On immunomodulator

– Normal CRP, hemoglobin

• Options:

– Stop IFX, continue 6-MP

– Continue 6-MP, then stop IFX

• Louis et al.: Re-treatment with IFX induced remission in

36/40 (96%)

Treating the Outpatient with Severe IBD: Case Studies

Corey A. Siegel, MD, MS

Geisel School of Medicine at Dartmouth

Dartmouth-Hitchcock Medical Center

CCFA Advances

December 5th, 2014

Case: 67 year old gentleman with UC

• 67 year old gentleman with recent onset of diarrhea with bleeding• 10-12x/day, up at night

• Stool studies (including C. diff) negative • Colonoscopy and biopsies consistent with moderately active

extensive ulcerative colitis

Past medical history• Hip osteoarthritis, s/p hip replacement• Pneumonia 3 months prior

• Admitted to ICU, intubated • Quit smoking at that time

Current meds: none other than occasional naproxen


• First treatment options in new diagnosis of moderately active UC?• Does “top down” apply to UC also?

• Initiated on prednisone 40mg daily + 4.8 grams of 5-ASA, Rowasa nightly

• Unable to taper down below 20mg• Now what?

Uceris Anti-TNF Immunomodulator Vedolizumab Some combination of above Surgery


• Initiated on infliximab monotherapy (with prednisone 40mg daily)• Start to taper prednisone• Week 14 infliximab concentration = 11, negative antibody• But unable to taper below prednisone 20mg• Repeat colonoscopy with moderately active extensive colitis (no

significant change)• Now what?

Increase infliximab dose Add immunomodulator Change to vedolizumab Start smoking Surgery

Cigarette Smoking in UC: Immunology

• Immunologic mechanisms for the protective effect of cigarette smoking in UC remain unclear• Immunologic and clinical studies in IBD have focused

on nicotine• Therapeutic trial experience in UC with nicotine gum,

transdermal nicotine, enemas has been inconclusive

Otterbein L et al, Nat Med 2000;6:422-8

One component of cigarette smoke, carbon monoxide (CO), possesses potent anti-inflammatory effects in

numerous models of acute inflammation

ALERT: “BAD AIR”

CO as a Therapeutic?

Other delivery vehicles?

Iskander H, et al. IBD LIVE case series. Inflamm Bowel Dis 2014.

Lee, S, et al. E-cigarettes as salvage therapy for medically refractory ulcerative colitis. Presented at Advances in IBD, 2013.


• Started to smoke ½ pack per day• Within 2 weeks started to taper prednisone• OFF ALL prednisone 4 weeks later• Continues infliximab 5mg/kg every 8 weeks• Follow-up colonoscopy with near complete

mucosal healing!!!!

Case: 41 year old woman with Crohn’s disease (2 scenarios)

• Diagnosed with ileal and perianal Crohn’s disease• At diagnosis started on 6MP + Infliximab + Cipro• Elevated LFTs – shunting with 6MP (despite

heterozygous TPMT – with half dosing!)• Infliximab monotherapy – did GREAT

• Complete mucosal healing• No further perianal lesions • Asymptomatic

41 year old woman with Crohn’s disease (2 scenarios)

• One year later – performed therapeutic drug monitoring• Prometheus ANSER assay

• Infliximab trough concentration = 0 • Antibody level = 24• Options?

Ignore Repeat the test with a different assay Increase infliximab dose Add back an immunomodulator Switch to another anti-TNF Switch class of biologic

BRIDGe “anti-TNF optimizer”

• RAND appropriateness panel• Evaluated two aspects of therapeutic

drug monitoring1. When to test?

2. What to do with the results

• When to test?• At end of induction, primary non-

response• Secondary non-response• During maintenance, responding• Restarting after drug holiday

Melmed GY, et al. Presented at ACG and UEGW 2014


www.BRIDGeIBD.com

41 year old woman with Crohn’s disease (scenario #2)

• Recurrent perianal disease, mild-moderate ileal recurrence• One year later – performed therapeutic drug monitoring

• ANSER assay

• Infliximab trough concentration = 2• Antibody level = 4• Options?

Ignore Repeat the test with a different assay Increase infliximab dose Add back an immunomodulator Switch to another anti-TNF Switch class of biologic


www.BRIDGeIBD.com

Can you make antibodies go away?

Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:444-447.

IFX levels closed squaresATI open squares

treating the outpatient with severe ibd: case study alan c. moss md, febg, facg, agaf associate...

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