NASPGHAN VIRTUAL IBD CASE STUDY Evidence and Art: Anti TNF Antibody - - PDF document

9/17/2013 1

NASPGHAN VIRTUAL IBD CASE STUDY

Evidence and Art: Anti‐TNFα Antibody Therapy for Pediatric Crohn’s Disease

Moderators

• Brendan Boyle, MD
• Ted Denson, MD
• Neera Gupta, MD
• Anne Griffiths, MD
• Subra Kugathasan, MD
• David Mack, MD
• James Markowitz, MD
• Maria Oliva‐Hemker, MD
• Anthony Otley, MD
• Joel Rosh, MD
• Cary Sauer, MD
• Michael Stephens, MD
• Tom Walters, MD

Case

• B.A. is a 14 year old boy who presents with 6

month history of weight loss (12 pounds), intermittent abdominal pain and diarrhea without blood, arthralgias, and for the past 2 weeks fever daily to 38.5oC, and erythema nodosum

• Exam normal with exception of tender nodules
• n anterior shins, mild clubbing, pallor. Abdomen

not tender, no perirectal disease

• Weight 39 kg (<5%), Height 153 cm (10%), Tanner

2

9/17/2013 2

Case

• Seen initially in rheumatology clinic where labs reveal:

Hb 9.9 g/dl, CRP 14.35 (nl <0.5 mg/dl), ESR 52 mm/hr, albumin 2.9 g/dl, vitamin D 13 ng/ml

• Referred to GI:

EGD: normal grossly, biopsies reveal patchy inflammation with granuloma in stomach and duodenum Ileocolonoscopy: extensive ulceration of terminal ileum and right colon, grossly normal transverse colon, patchy inflammation in

• rectosigmoid. Biopsies confirm chronic

inflammation, rare granuloma MRE: extensive distal ileal disease, no stricture or abscess

Case – Terminal Ileum

• Show endoscopic photos

Case: MRI Axial contrast enhanced image. Diffuse enhancement of terminal ileum

9/17/2013 3

Case: Summary

• 14 year old, extensive ileal and right colonic

disease

• Tanner II, height <5%, wt 10%
• Is there any further information you want

before deciding on this patient’s therapy?

Potential Further Evaluation (Vote):

• A. I don’t need any further testing
• B. Antibodies to microbial antigens (ASCA,

OmpC, CBir, etc.)

• C. Video Capsule Endoscopy
• D. Both B andC

Results of Additional Tests

• Serology shows: ASCA IgA 61 (<8.5), ASCA IgG

18.8 (<17.8), anti‐OMP C IgA 8.9 (<10.9), anti‐ Cbir1 IgG 21.5 (<78.4)

• Video Capsule – not done

9/17/2013 4

20 40 60 80 100

Frequency of Disease Behavior % Number of Immune Responses

Antibody Sum and Disease Behavior

NPNS IP S

* Odds Ratio N=199 1 N=262 2 N=194 3 N=57

Surgery

P trend < 0.0001 * 2.2 * 1.0 * 5.0 * 9.5 * 1.7 * 1.0 * 4.2 * 6.1 P trend < 0.0001

Dubinsky MC et al CGH 2008;6:1105

100

Case 1: Therapeutic Options (Vote)

• Option 1: Prednisone followed by 5‐ASA
• Option 2:Prednisone followed by 6‐MP/Aza
• Option 3: Prednisone followed by methotrexate
• Option 4: Exclusive enteral nutrition followed by

IM

• Option 5: Anti‐TNFα monotherapy
• Option 6: Anti‐TNFα plus thiopurine
• Option 7: Anti‐TNF α plus methotrexate
• Option 8: Intensive helminth therapy

Natural History (Vote)

• Which of the following therapies do you

believe is most likely to alter the natural history of Crohn’s disease

• A. Immunomodulators
• B. Anti‐TNFα
• C. Neither

9/17/2013 5 Which of these therapies has greatest risk: (Vote)

• A. Biologics
• B. Thiopurines
• C. Methotrexate
• D. Biologics and thiopurine combination
• E. Biologics and methotrexate combination

If you had felt strongly about starting anti‐TNFα and a concomitant IM which

• ne: (VOTE)
• A. Thiopurine
• B. Methotrexate

Effect of Co‐Treatment with Immunomodulators on Disease Outcome During Scheduled Maintenance Therapy With Infliximab

Sokol et al. Gut 2010;59:1363

9/17/2013 6

Effect of Co‐Treatment with Immunomodulators on Disease Outcome During Scheduled Maintenance Therapy With Infliximab

Sokol et al. Gut 2010;59:1363

Case

• Started on 40 mg prednisone while prior approval
• btained for infliximab.
• After discussion with the family of potential

benefits and risks of anti‐TNFα and IM therapy they feel most comfortable starting infliximab

• monotherapy. Started 1 week after diagnosis
• Weight 39kg. Given 200 mg at 0, 2, and 6 weeks.

Started on Fe, Vit D. Prednisone tapered over next 5 weeks

• At 8 week visit is feeling much better, PCDAI 5

Case

• Seen at 6 months and patient states that he is

having mild abdominal pain and stools are looser for the week or two before his next infusion.

• ESR 25, CRP 2.0 (<0.8), Hb 13, albumin 3.6 g/dl

9/17/2013 7

At this point I would (Vote):

• A. Empirically increase the dose of infliximab

to 10mg/kg/dose

• B. Empirically decrease the interval between

infusions to 6 weeks but leave the dose at 5 mg/kg

• C. Check a trough infliximab level along with

antibody to infliximab (ATI)

• D. Start a brief course of prednisone and leave

infliximab schedule the same

Father of patient is hedge fund manager and $ is no object

• Infliximab level and ATI are obtained:
• Infliximab level 0 ug/ml, ATI 0 U/ml (ELISA

test)

• So minimal circulating infliximab and no

evidence of antibody.

What would you do?

• Increase the dose to 10 mg/kg and keep at

every 8 weeks

• Decrease the interval to 6 weeks and leave at

5 mg/kg

• Something in between

9/17/2013 8

Case

• Infliximab dose increased to 10 mg/kg and

interval kept at 8 weeks

• Patient does well for 1 ½ years

Case

• At next visit he comes in stating that his

abdominal pain has increased greatly, he is sleeping poorly, he is having 5‐6 stools per day and feels tired all the time, weight down 2 lbs

• Now 16 years old, weight and height are both

at 25%, Hb 13, ESR 20, albumin 3.6 g/dl, CRP 1.4 (nl <0.8)

At this point I would (Vote):

• A. Get infliximab level and antibody to

infliximab*

• B. Empirically decrease intervals between

infusions to 6 weeks

• C. Start a brief course of prednisone
• D. Repeat evaluation including

ileocolonoscopy and MRE

*Father now under investigation by SEC, bank accounts frozen, no money. States they cannot afford to do the testing

9/17/2013 9

Repeat Evaluation Performed

• Mild terminal ileal inflammation on biopsy
• nly, normal colon
• Repeat MRE shows minimal enhancement of

terminal ileum

• Patient and family state that terrible stress

secondary to father’s indictment, harassment in school

• Psychosocial support, patient improves

Case – Two Years Later

• Father exonerated of all wrong doing, making

$12 million again, family happy

• But, 17 year old patient now states he is

having increased abdominal pain, diarrhea, weight loss, fevers. Terrible stress with college applications and broke up with girlfriend

• ESR 42, albumin 3.2, CRP 7 (nl <0.8)

At this point I would (VOTE):

• A. Get infliximab level and antibody to infliximab
• B. Empirically increase infliximab dose to 10

mg/kg every 4 weeks

• B. Empirically switch to adalimumab
• C. Empirically switch to certolizumab
• D. Start a brief course of prednisone
• E. Repeat evaluation including ileocolonoscopy

and MRE

9/17/2013 10

Case

Undetectable drug, low titer antibody at trough

At this point I would (Vote):

• A. Switch to adalimumab (in class)
• B. Switch to natalizumab (out of class)
• C. Perform ileocecal resection
• D. Infliximab 10 mg/kg every 4 weeks and add

IM

What Does a Low titer Antibody Level Mean?

• Vande Casteele et al. Antibody response to infliximab and its

impact on pharmacokinetics can be transient. Am J Gastro 2013;108:962

• Use of novel mobility shift assay that detects both infliximab

and antibody whereas ELISA could only detect antibody in the absence of drug

9/17/2013 11 Transient vs. Sustained Antibodies to Infliximab

Vande Casteele et al. Am J Gastro 2013;108:962

Vande Casteele et al. Am J Gastro 2013;108:962

Patients with sustained ATI more often have to stop IFX owing to LOR or hypersensitivity reaction Time to discontinuation owing to LOR or hypersensitivity is shorter in those with sustained versus transient antibodies

Case – Can I Recapture Response at This point?

• Patient started on methotrexate
• Infliximab dose 10 mg/kg, interval every 4

weeks

• Patient clinically improves, and 3 months later

infliximab level 16, ATI 0 (ELISA) by another lab that does the old assay

• Goes off to the University of Connecticut and

and does well for his first 2 years. Life is great.

9/17/2013 12

What Assay Am I Using?

• Can I measure drug and antibody to drug

simultaneously, or does presence of circulating drug preclude such measurement?

Ordas et al. Clin Gastroenterol Hepatol 2012;10:1079

With ELISA the presence of circulating drug precludes measuring antibody levels

Mobility Shift Assay

Ordas et al. Clin Gastroenterol Hepatol 2012;10:1079

9/17/2013 13 Case‐ Patient decides to spend junior year in college in Botswana, and asks…

• Can I switch to adalimumab? I don’t think I

can find an infusion center in Botswana.

• What is my likelihood of doing well?
• Can I ever go back to infliximab when I come

home?

SWITCH study

Van Assche et al. Gut 2012;61:229

Overview of Outcomes Following Elective Switch From Infliximab to Adalimumab

Stable Early term Dose escal

53%

19% 28% Stable Early term Dose escal 84% 14% 2% Group A. Adalimumab Group B. Infliximab

Van Assche et al. Gut 2012;61:229

9/17/2013 14

Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday

Filip J. Baert et al. DDW 2013, Abstract 492

128 patients in whom IFX had been stopped because of LOR, remission, pregnancy. Or Infusion reaction. Mean duration off 15 months. Bottom line: IFX successful re‐start in 85% at week 14, 70% at year 1, 61% at last f/u. Infusion reaction in 25/128 (19.5%), 16/128 had to stop IFX. Predictors of course: Reason for stopping first course (remission better), concomitant IM at re‐start (better), TL (higher better) and absence of ATI (better) were predictors of response and absence of infusion reaction.

Case

• Patient does well in Botswana on adalimumab

and returns to U.S. to finish college. Graduates and goes to his job on Wall Street.

• Decides to go back on infliximab and does well

for the next four years and is thinking about stopping all his medications

• He wants your advice on what to do.

You suggest (Vote):

• A. Do not ever stop your Crohn’s disease

medication

• B. Perform a fecal calprotectin and CRP and if

it is normal safe to stop

• C. Do a prophylactic ileocecal resection
• D. Repeat colonoscopy and MRE and if normal

it is safe to stop

9/17/2013 15 Can I Ever Stop Anti‐TNFα Therapy?

• Louis et al. Maintenance of remission among patients with

Crohn’s disease on anti‐metabolite therapy after infliximab is

• stopped. Gastroenterology 2012;142:63
• 115 GETAID patients with luminal disease, at least 1 year of

anti‐TNF + IM, stable, CS free remission for at least 6 months. IM maintained throughout observation period, median 28

• months. Median disease duration at withdrawal 7.8 yrs
• Prognostic factors examined included: gender, hx of previous

resection, white blood count >6.0 x 109, hemoglobin ≤14.5, CRP≥5, fecal calprotectin ≥300 ug/g.

Risk of Relapse Upon Stopping Anti‐ TNFα Therapy and Continuing IM

Louis et al. Gastroenterology 2012;142:63

50% at 1‐2 years

Factors Associated With Relapse

Louis et al. Gastroenterology 2012;142:63

9/17/2013 16

Case

• Patient decides he wants no further

intervention and begins holistic approach with worms, herbs

• Two years later comes into ED with bilious
• vomiting. CT scan shows diseased terminal

ileum/right colon and abscess. IR drained, treated with antibiotics and 4 weeks later has ileocecectomy

• Patient says he wants to be treated again.

Case: Post‐operatively I would treat with: (Vote)

• A. Pentasa
• B. Azathioprine
• C. Methotrexate
• D. Infliximab + IM
• E. Adalimumab + IM

Post Operative Prophylaxis with Infliximab

Regueiro et al. Gastroenterology 2009;136:441

9/17/2013 17

Treatment Paradigms in Symptomatic Patients that Lose Response to IFX

ATI− ATI+ IFX < threshold Consider increasing the IFX exposure (dose or duration)

Consider switching within class If titer low and no serious infusion reaction consider increasing dose and using concomitant IM

IFX ≥ threshold Check for active disease, ? functional symptoms, check for stricture Consider switching out of class with signs of active disease Consider switching within

• r out of class

???????????

Loss of Response Paradigm

Ordas et al. Clin Gastroenterol Hepatol 2012;10:1079