James Markowitz, MD
Professor of Pediatrics
Hofstra North Shore – LIJ School of Medicine
Division of Pediatric Gastroenterology
Cohen Children’s Medical Center of NY
New Hyde Park, NY

• Janssen Pharmaceuticals – Consultant
• Abbvie – Consultant
• UCB – Consultant
• Soligenix – Consultant

When Do We Stop Anti-TNF Therapy?
• When it stops working
• When it is working but associated with toxicity
• When it is still working

When Do We Stop Anti-TNF Therapy?
WHEN IT IS WORKING BUT
ASSOCIATED WITH TOXICITY

Toxicities Requiring Discontinuation of
Anti-TNF Rx (Probable Class Effect)
• Severe psoriasis
• Autoimmune disease
– Autoimmune hepatitis
– Agranulocytosis
• ?Opportunistic infection
– Histoplasmosis
– Coccidiomycosis
– Blastomycosis
Sherlock ME, et al. JPGN 2013;56: 512–518
Doyle A, et al. J Crohn's Colitis 2011;5:253–5
Sebastian S, et al. J Crohn's Colitis 2012;6:713–6
Ordonez ME, et al. IBD 2013;19:2490–2500
•
• Lymphoma
• Demyelinating disease
– Multiple sclerosis
– Chronic inflammatory demyelinating polyneuropathy
– Guillain Barre
Interstitial pneumonitis
Cassaday RD, et al. Clin Lymphoma Myeloma Leuk.
2011;11:289–292
Flynn AD, et al. IBD 2013;19(5):E69-70
Deepak P, et al. Aliment Pharm Ther 2013;38:388–96
Seror R, et al. Rheum 2013; 52(5): 868-74
Villeneuve E, et al. J Rheum 2006;33(6):1-5

When Do We Stop Anti-TNF Therapy?
WHEN IT IS STILL WORKING

• Significant cost
• Side effect profile

• Before starting anti-TNF Rx, many express concern regarding possible long term effects
• In UK, National Institute for Health and Clinical
Excellence (NICE) recommends use of anti-TNF until it fails, or for 12 months
– At 12 months, reassess for ongoing need of Rx
• 21 adults with CD on anti-TNF ≥12 months
– 8 (38%) agreed to reassessment: afraid of lymphoma, infections, demyelinating disease
– 13 (62%) refused: afraid of possible relapse, lost wages, possible need for surgery if disease relapsed
Blackmore L, Harris A. Clin Med 2012;12(3):235-8

High Rate of Relapse Following
Infliximab Withdrawal
• 48 adults on maintenance IFX
– CS free clinical remission
– 67% on AZA/6MP/MTX
– Median # infusions:
8 (2-51)
– Median duration IFX:
15.6 mos (1-67.3)
• No clinical predictors for long term remission identified
50% relapse at 15 months
35% long term remission
Waugh AWG, et al, Aliment Pharmacol Ther 2010;32:1129-34

Risk of Relapse Upon Stopping Anti-TNFα
Therapy and Continuing IM
• 115 GETAID patients with luminal disease
– ≥ 1 yr 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 of IFX = 7.8 yrs
39% relapse by 1 yr
~50% by 2 yrs
Louis E, et al. Gastroenterology 2012;142:63-70

Louis et al. Gastroenterology 2012;142:63

Increasing Number of Risk Factors are
Associated with Greater Likelihood of Relapse
Louis et al. Gastroenterology 2012;142:63

Predicting the Likelihood of Relapse after Discontinuing Anti-TNF Therapy
WBC < 6x10 9 /L hsCRP < 5 mg/L
Calprotectin <300 µg/g
Hemoglobin >145 g/dl
Louis et al. Gastroenterology 2012;142:63

• In Hungary, anti-TNF must be stopped after 1 yr of Rx
– Can be restarted for relapse
• 121 CD adults discontinued anti-TNF
– 87 IFX, 34 ADA
– 85% concomitant 6MP/AZA
• 45% resume anti-TNF by 1 yr
– Median time to resumption:
6 months (IQR: 3.75-12 mos)

Objective: To rate the appropriateness of stopping anti-TNF therapy in CD patients in remission
Methods: RAND/UCLA Appropriateness Method
• Withdrawing anti-TNF monotherapy:
– After 2 yrs of clinical and endoscopic remission
– After 4 yrs of clinical remission
• Withdrawing anti-TNF from combo Rx:
– After 2 yrs of clinical remission
Pittet V, et al. J Crohns Colitis 2013;7:820-6

Clarke K, Reguerio M. IBD 2012;18:174-9

When should we stop anti-TNF therapy?
OK to Consider Stopping Anti-TNF
• Deep remission
– Clinical
– Biologic
• No recent need for dose escalation
• ?Low/absent trough levels
• Longer duration of remission
(2-4 yrs ??)
• Normal growth; Tanner IV-V
• Willing to consider alternative maintenance Rx

How Common is a Deep Remission in Patients
Treated with anti-TNF Rx?
• 252 pts with IBD (Finland)
– 183 CD, 62 UC, 7 IBD-U
– 177 IFX, 75 ADA
– Minimum duration 11 mos
• Concomitant IM
– CD 69%, UC 82%, IBD-U 86%
• Reassessed clinically and with ileocolonoscopy and Bx
• Deep remission
– No clinical symptoms AND
– No endoscopic activity
• SES-CD = 0-2
• Mayo endo subscore 0-1
•
Results
• 168 (67%) clinical remission
– 64% CD, 75% UC
122 (48%) deep remission
– 43% CD, 62% UC
– 99/122 (81%) also with histologically inactive
Molander P, et al. J Crohn's Colitis 2013;7:730–735

When should we stop anti-TNF therapy?
OK to Consider Stopping Anti-TNF
• Deep remission
– Clinical
– Biologic
• No recent need for dose escalation
• ?Low/absent trough levels
• Longer duration of remission
(2-4 yrs ??)
• Normal growth; Tanner IV-V
• Willing to consider alternative maintenance Rx
Continue Anti-TNF
• Active disease
– Clinical
– Biologic
• ↑CRP, ↑calprotectin
• No mucosal healing
• Recent dose escalation
• Short duration remission
• Ongoing growth impairment, delayed puberty

How do we treat after stopping anti-TNF Rx?
• To maintain remission
– Immune modifiers
• 6MP, Azathioprine, Methotrexate
– Enteral feeds
– Nothing???

How do we treat after stopping anti-TNF Rx?
• If the patient relapses
– Restart anti-TNF
– Alternative biologic with a different mechanism of action
• IL-12/23 inhibitor
• Anti-adhesion molecule Rx

Trough Levels and Antidrug Antibodies Predict Safety and
Success of Restarting Infliximab After a Long Drug Holiday
Baert FJ, 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 IFX = 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.

How do we treat after stopping anti-TNF Rx?
• If the patient relapses
– Restart anti-TNF
– Alternative biologic with a different mechanism of action
• IL-12/23 inhibitor
• Anti-adhesion molecule Rx