When Should We Stop Anti-TNF Therapy and How Do We Then

Treat the Patient?

James Markowitz, MDProfessor of Pediatrics

Hofstra North Shore – LIJ School of MedicineDivision of Pediatric GastroenterologyCohen Children’s Medical Center of NY

New Hyde Park, NY

Disclosures

• 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 IT IS WORKING BUT ASSOCIATED WITH TOXICITY

When Do We Stop Anti-TNF Therapy?

Toxicities Requiring Discontinuation of Anti-TNF Rx (Probable Class Effect)

• Severe psoriasis• Autoimmune disease– Autoimmune hepatitis– Agranulocytosis

• ?Opportunistic infection– Histoplasmosis– Coccidiomycosis– Blastomycosis

• Lymphoma• Demyelinating disease– Multiple sclerosis– Chronic inflammatory

demyelinating polyneuropathy

– Guillain Barre

• Interstitial pneumonitis

Sherlock ME, et al. JPGN 2013;56: 512–518Doyle A, et al. J Crohn's Colitis 2011;5:253–5Sebastian S, et al. J Crohn's Colitis 2012;6:713–6Ordonez ME, et al. IBD 2013;19:2490–2500

Cassaday RD, et al. Clin Lymphoma Myeloma Leuk. 2011;11:289–292

Flynn AD, et al. IBD 2013;19(5):E69-70Deepak P, et al. Aliment Pharm Ther 2013;38:388–96Seror R, et al. Rheum 2013; 52(5): 868-74Villeneuve E, et al. J Rheum 2006;33(6):1-5

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

Why Stop?

• Significant cost• Side effect profile

Do Patients Want to Stop?• 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

Waugh AWG, et al, Aliment Pharmacol Ther 2010;32:1129-34

50% relapse at 15 months

35% long term remission

• 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

Louis E, et al. Gastroenterology 2012;142:63-70

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

39% relapse by 1 yr~50% by 2 yrs

Factors Associated With Relapse

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 < 6x109/LhsCRP < 5 mg/LCalprotectin <300 µg/gHemoglobin >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)

EPACT-II Update Objective: To rate the appropriateness of stopping anti-TNF therapy in CD patients in remissionMethods: 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

“If It Ain’t Broke, Don’t Fix It”

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?

Continue Anti-TNF

• Active disease– Clinical– Biologic

• ↑CRP, ↑calprotectin• No mucosal healing

• Recent dose escalation• Short duration remission• Ongoing growth impairment,

delayed puberty

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 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, orinfusion 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 ofresponse 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