Management of CDBiological Agents

Associate Professor Rupert WL LeongDirector of Endoscopy, Concord Hospital

University of New South Wales, Sydney Australia

APDW IBD-Working Party Crohns Disease Consensus Statements 2011

Quality of Evidence

• Major publication(s)• Cochrane/ systematic reviews• Current guidelines/ recommendations

– BSG Guidelines 2004– AGA Position Statement 2006– ECCO Consensus 2 2010

• Asia-Pacific studies• Quality of evidence – mostly Western

– assumption: similar efficacy– note pharmacogenomics eg thiopurines– infectious diseases

Management Statement 12

Statement rationale: biological agents - indications

•There are no data that internal fidtulae respond to biologis - these need surgical treatment•Numbering would help.•Surgery adjustment to anti-TNF"Too many substatements here too....may be we should vot for substetements example:

""Biologial agenst should be cosindiered:

a. failure of 2nd line medical treatment

b. presence of fistulizing diesases (and a quailifying stteemtn about fibritic strictures...not been responsive)

• Maintenance of Remission

EIM

3 months

Pyoderma gangrenosum

Hewitt et al Austral J Derm 2007Etanercept can precipitate uveitis

Management Statement 12

• conventional steroids

• with or without immunomodulators

• maintenance of remission

• EIM

• fistulas

• strictures

toThe indications for anti-TNF biological agents include failure of conventional therapy in luminal disease [I-A], as well as fistulizing CD [I-A] and some extra-intestinal manifestations [II-3,B] of CD.

Perianal fistulizing CD in addition to appropriate surgical management.

Text: Anti-TNF therapy may have limited efficacy in the treatment of internal fistulas. Fixed fibrotic strictures do not respond well to anti-TNF.

Management 13

Statement rationale: monotherapy or combined

• I would not use the word synergism here. It implies a phaarmacologic interaction. Also, the benefits of combined treatment are only present for infliximab in very specific ircumstances. The COMMIT study showed no benefit from infliximab plus methotrexate

• The statement of efficacy should be clarified completely, then state reversed event.• "substatements: (voting separately_• Combined therapy with infliximab and azathioprine, is useful• Combined therapy is safe"

13

Median serum trough IFX

IFX + AZA

IFX + placebo

Immunomodulator Withdrawal

• withdrawal of IM at 6 mth– maintenance infliximab q2mth

Van Assche Gastroenterol 2008

Rescue anti-TNF Cease anti-TNF

Azathioprine/ 6MP Withdrawal

Van Assche Gastroenterol 2008

CRP: favours continuing immunomodulator

infliximab trough level: favours continuing immunomodulator

Hepatosplenic T Cell Lymphoma

Mackey J Pediatr Gastroenterol Nutr 2007

Hepatosplenic T Cell Lymphoma

Little data from Asia

Hepatosplenic T Cell Lymphoma

• ?increased recognition following concern regarding anti-TNF causing lymphoma

• ?anti-TNF reduces threshold of developing HSTCL with thiopurines & Crohn’s disease

• ?independent to anti-TNF

MTX

• no synergism with IFX (COMMIT)– CD active disease induced with steroids

and IFX– 50 week steroid-free remission– IFX + placebo: 56% – IFX + MTX: 57% (ns)– abstract

Management 13

• infliximab and thiopurine

• HSTCL

Combined infliximab and thiopurine is more effective than either alone in thiopurine-naïve patients. [I-A]

The risk-benefit balance including lymphoma-risk and opportunistic infections need to be considered. [II-3, B]

MTX in text no data with ADA

Management 14

Statement rationale: dosing, other biologics

• 80mg SC then 2 weekly thereafter. • 8-weekly?• "Should be 2 weekly therefore for Adalimumabs.• Certouzumis should be mentioned as well "• About adalimab, "then 8-weekly" is wrong. It should be corrected to "40mg sc bi-weekly".• Certoluzimab and natalizumab have been adopted by US FDA• Adalimumab need 2 weekly• Infiximab and adalimumab are the only 2 clically useful biological agents (doses given inthe

paragraph belw as qualifying statements...not for voting!

Infliximab(Remicade)

Certolizumab(Cimzia)

Adalimumab(Humira)

Schreiber et al NEJM 2007Hanauer et al Lancet 2002 Colombel et al Gastroenterol 2007

%

Biologics

• 4 commercially available:– infliximab (Remicade) – adalimumab (Humira) – certolizumab (Cimzia) – further phase 3 – natalizumab (Tysabri) – limited use

• others under trial– vedolizumab – ustekinumab (Stelara) etc – small molecule: CCR9 receptor blocker

• induction: – ineffective: etanercept, CDP571 – ?certolizumab

• maintenance

Natalizumab

• leukocyte trafficking – blocks migration of

lymphocytes to inflamed tissue– monotherapy– reactivation of JC virus in brain– monitor for neuro Sx– 7 cases– plasma exchange

vessel wall vessel wall vascular vascular cell adhesion cell adhesion

molecule (VCAM)molecule (VCAM)

progressive multifocal leukoencephalopathy (PML)progressive multifocal leukoencephalopathy (PML)Adelman NEJM 2005, Yousry NEJM 2006Adelman NEJM 2005, Yousry NEJM 2006

lymphocytelymphocytealpha-4 integrinalpha-4 integrin

alpha-4-beta-7 integrin inhibitor (Vedolizumab)

• monoclonal Ab– targets only a4b7 integrin:– GI tract-specific

– ligand = MAdCAM (mucosal addressin cell adhesion molecule) – expressed on intestinal vascular endothelium

– increased expression in inflamed gut

Management 14

• IFX

• ADA

• other biologics

2

Infliximab etc

[I-A]Remove other biologics

Management 15

• Screening and treatment for active/ latent TB and any form of sepsis should be carried out prior to commencing anti-TNF treatment.

• Tuberculin skin tests rather than IGRA may still be acceptable due to cost constraints• IGRA is not available in some countries like us• TB culture/PCR not done under to high supervision • "This shoud be the stetemtn.....""Active and latent tuberculosis and other infectious

colitides must be excluded prior to treatment with anti-TNF therapy""• Others as clarifying statements"• Should we say that when ever IGRA is not available, an alternative may be the

mantoux test?

Tuberculosis

TB reporting rate per 1,000 patients

Tuberculosis

• PPD not helpful: BCG, immunosuppressed

– individual risk assessment:Case Annual

disease/ 100,000

Anti-TNF effect (x5)

Risk of prophylaxis (/100,000)

Risk/ benefit

White, 55-74, UK born 7 35 278 Observe

Indian subcontinent >35; UK 3 years

593 2965 278 Prophylaxis

Black African, 35-54 168 840 278 Prophylaxis

Other ethnic, >35; UK >5 years

39 195 278 Observe

• serious infections:– randomised studies: no increase in infections

• Exposure history, examination

• IGRA

• CXR

• mucosal biopsies: TB culture, PCR

Opportunistic Infections

• Japan: RA date; n = 646 anti-TNF vs 498 on DMARDs

Revised Management 15

• Screening and treatment for active/ latent TB and any form of sepsis should be carried out prior to commencing anti-TNF treatment.[II-3,B]

Management 16

Statement rationale: HBV screening

• Cost may be an issue in developing countries. Which vaccine souhld be carried out also not established. (the adult vaccine schedule is very extensive). Live vaccines (eg varicella) BEFORE treatment may not be feasible in patients requiring prompt treatment.

• Prior to immunomoderator, stewia, and biologics. • Whether anti-viral prophylaxis with immunomodulator?• this is mainly for rheumatological diseases....makes sense to

reccommend but I dont know the incidence of reactivation• Is there any evidence for screening for Hepatitis C although

there is no vaccine or single effective anti-viral therapy?

• HBV Screening

alive

alivedied

subfulminantsubfulminant

hepatitisTx LAMTx LAM

Tx LAM

died

Tx LAM

Tx LAM

Tx LAM

HBV

• majority HBsAg+patients

• some HBsAg−, anti-HBc Ab +

• variable manifestations

• TNF-α central mediator of anti-HBV responses

• reactivation (increased viral loads with or without increased transaminases) – some fatal hepatitis

HBV Strategies

• 1. monitor HBV, ALT: reactivation not in everyone

• 2. prophylactic LAM/ anti-viral therapy: reactivation unpredictable and risk of death– prophylaxis for 3-6 mths after cessation

of anti-TNF

HCV

• TNF-α in HCV infection differ to HBV– serum TNF levels predict failure of

interferon therapy– liver inflammation perpetuated– favourable short-term safety profile

• longer term safety remains to be proven

• ECCO: screening not routine

ECCO 2009

Management 16

• ?which HBV serologies

• ?HCV, VZV, HIV

• ?prophylaxis

Screening for HBV is recommended prior to initiation of immunosuppressive agents.

Anti-viral prophylaxis should be considered in HBV-positive individuals receiving biological agents or steroids.

Patients with HBV on immunomodulator therapy requires monitoring for HBV reactivation and commencement of anti-viral therapy for reactivation.

Patients should be up-to-date with specific vaccinations.

Live virus vaccinations are to be avoided for at least 3 weeks prior to commencement of biological agents and 3 months after the last dose of biological agents

Management 17

Statement rationale: contraindications

• nil comments

• TNFα elevated in CCF– contraindicated

• demyelination:– case reports– improvement on discontinuation

Pregnancy Outcomes

Vinet E, et al. Biologic Therapy and Pregnancy Outcomes in Women With Rheumatic Diseases. Arthritis & Rheumatism 2009. 61;5:587-92

Infliximab

Vinet E, et al. Biologic Therapy and Pregnancy Outcomes in Women With Rheumatic Diseases. Arthritis & Rheumatism 2009. 61;5:587-92

Infliximab Birth Anomalies

• trisomy 18

• intestinal malrotation, tetralogy of Fallot

Management 17

• CCF

• demyelination

• pregnancy

Contra-indications for anti-TNF therapy include congestive cardiac failure (NYHA Class III and IV) and demyelination disorders.

There is little data on the use of anti-TNF agents during pregnancy but it appearsto be safe.

Management 18

Statement rationale: stopping anti-TNF where cost prohibitive

• May reserve the choice for switching back to AZA due to finacial constrain in some countries

• 3-6 month of treatment with anti-TNF for maintenance is too short.

• Should clarify how to select patients

• Must vote for substatements

Stopping IFX • STORI trial

– when to stop IFX? • no inflammation on colonoscopy• normal CRP

Activity

Episodic vs Scheduled Maintenance

0 2 6 14 22 30 38 46 54

Maintenance Dosing

0 2 0 0 2 0 0

Episodic Dosing

Activity

Episodic vs Scheduled Maintenance

• scheduled IFX improves mucosal healing (lower CDEIS)

Rutgeerts et al GI Endoscopy 2006

P =0.066

P =0.053

% im

prov

emen

t

Infliximab

Management 18

• duration of anti-TNF

• monitoring

• scheduled maintenance In patients who enter clinical remission, anti-TNF may be given indefinitely

Ongoing monitoring of clinical efficacy and complications is recommended at least 3-6monthly.

Cessation of anti-TNF may be an option

Scheduled maintenance therapy is recommended rather than episodic therapy.

Management 19

Statement rationale: anti-TNF Ab, titres, cancers, sepsis

• We should watch out all of the infectious signs clinically during anti-TNF treatment.

• "Should subdivide statements - use of antibody/drugs and level vs sediffuts of anti-TNF"

• Only data come from Western countries. No evidence in Asian population. It should be described in statement.

• study of the prevalence of AB to anti-TNF should be done in this region• Too many parts in this statement. First statement too stretchy. Last statement

too non-specific. • several diifrernt statements here.

IFX Titres

66

mucosal healing associated with high IFX trough levels

IFX Titres

• IFX trough levels:– strongly correlate with the degree of

mucosal healing• complete healing: median 6.05 (0.67 – 10.33)• partial healing: median 3.29 (0.35 – 7.76)• no healing: median 0.85 (0.35 – 6.62)

– IFX trough levels: useful in optimizing therapy – allow dose adjustment

Cancers

• RCT malignancies: not increased

Cancer with Anti-TNF

• Clinical trials: lymphoma risk– OR 3.2 (95% CI: 1.5 – 6.9) vs general population– OR 1.7 (95% CI: 0.5 – 7.1) vs IBD on IM

• Spanish BIOBADASER national RA drug registry (1540 patients)

– anti-TNF: 60 per 10,000 pt-yr (95% CI: 47 -75)

– control RA: 129 per 10,000 pt-yr (95% CI: 90 – 186)

Gómez-Reino JJ, Arthritis Rheum, 2003

Cancer with Anti-TNF

• Swedish RA registry: 1998 – 2006 (6366 patients)

– NO increased cancer risk with anti-TNF – RR 0.99 (95% CI: 079 – 1.24) vs non-anti-

TNF– RR 1.14 (95% CI: 1.00 – 1.30) vs non-RA

Askling et al. Arthritis Rheum 2009;60:3180-3189

Anti-TNF• Older meta-analysis of RA studies:

– pooled OR for malignancy 3.3 (95% CI: 1.2 – 9.1)

– dose-response effect– NNH: 154 (95% CI: 91 – 500)

• Cancer risk: highest in first 2 – 4 months of treatment

• ? pre-clinical tumours becoming clinically manifest rather than new cancers

Bongartz T, et al. JAMA. 2006;295:2275-2285.

• FDA warning:– cancer risk increased with anti-TNFs

Sepsis Symptoms

Management 19

• titres

• antibodies

• sepsis symptoms

• cancers, lymphomas Few data are available at present on the use of anti-TNF antibody titres and anti-bodies to anti-TNF agents to optimise treatment or to explain primary non-response or secondary loss of response to anti-TNF agents.

Patients maintained on anti-TNF agents should be aware of new TB exposure and need to present for urgent medical attention for unexplained sepsis symptoms.

Cancers especially lymphomas are increased with anti-TNF treatments.

Management 20

Statement rationale: non-response, loss of response anti-TNF

• Re-evaluation shold be the priority over changing treatment

• Statement in teal

• "vote for ""Primary non-response to anti-TNF usually requires change of treatment or re-evaulation of symptoms""

• the rest qualifying or clarifying statements"

Dietary Intolerances, IBS

Management 20

• exclude non-inflammatory cause of symptom

• secondary loss of response

Primary non-response to anti-TNF usually requires changes of treatment or re-evaluation of symptoms. Exclude symptoms from other causes, such as stricture in the setting of Crohn’s disease, concurrent irritable bowel syndrome, or dietary intolerances.

Repeat radiological imaging, inflammatory biomarkers (CRP, faecal calprotectin), or ileocolonoscopy may be helpful.

Management 21

Statement rationale: managing loss of response

• nil

Switch IFX to ADA

Loftus et al, Gastroenterology 2007; 132 (4 Suppl. 2): A-508 (#T1288)

• IFX Failures (lost response, adverse reactions) moderate-to-severely active CD• randomised placebo or adalimumab 160/80 mg SC (n=159)• IBDQ total score and 4 IBDQ dimensional scores were assessed at baseline and week 4

Management 21

• dose increase

• dose interval decrease

• temporary steroids

• immunomodulators

• surgery

Secondary loss of response to anti-TNF treatments may require either increase of dose of anti-TNF, decreasing dose-interval, temporary steroids, and commencement, change or increase of immunomodulation.

Change in medical mangement or surgical management may be required.

Management 22

Statement rationale: pediatric IBD

• ?Leave out paediatrics

• I think more safety data is necessary for pediatric patients

• Is there a age limit?

Pediatric CD Mx

Pediatric CD Mx

6MP

6MP

Management 22

• ?delete pediatric

• ?mention immunomodulators and enteral nutrition

Long-term steroids should be avoided in the pediatric CD population. Exclusive enteral nutrition can used to induce remission and thiopurines are effective in the maintenance or remission.

Infliximab is indicated in the management of refractory CD.

** Review by pediatric gastroenterologist – Don Cameron, Andrew Day

Management 23

Statement rationale: surgery (covered elsewhere)post-operative recurrence

• Balloon dilatation may be a less invasive option. • Role of disfunctioning ilwsiy • About post operative anti-TNF therapy, there is a

few papers now. So, we should tone down.• No mention of endoscopic dilatation. • Many statemtns here again

Anti-TNF in Postop CD

• IFX or placebo: within 4 weeks of surgery

• q8wk for 1 year• endoscopic recurrence at 1yr

– IFX: 1/11 (9%)– placebo: 11/13 (85%, P = 0.0006)

• clinical remission – IFX: 8/10 (80%) – placebo: 7/13 (54%, P = 0.38)

Endoscopic dilatation

Management 23

endoscopic dilatation

For localised disease with recurrent obstruction: resection of the diseased segment and end-to end anastomosis should be performed. Structuloplasty is a safe alternative to resection in jejuno-ileal CD, including ileocolonic recurrence, with similar short-term and long-term results.

Endoscopic dilatation of accessible short strictures is an option in specialised centres.

Anti-TNF therapy may reduce disease recurrence following CD resectional surgery.

Management 24

Statement rationale: MAP therapy controversial

• nil

Anti-MAP Trials

Management 24

• MAP therapy

• ?antibiotic therapy in maintenance

At present, there is no definite role of anti-mycobacterial avium para-tuberculosis therapy in the treatment of patients with CD.

Management 25

Statement rationale: other aspects of treatment

• what is the focus here?

Drugs in Treating IBD

FDA Class Drug

A

B Adalimumab, Infliximab, 5-ASA, metronidazole

C Alendronate, Budesonide, Ciprofloxacin, Corticosteroids, Ciclosporin, Tacrolimus

D AZA, 6MP

X MTX, Thalidomide

Osteoporosis

Management 25

• fertility

• pregnancy

• breast feeding

• nutrition

• osteoporosis

Fertility, pregnancy, breast feeding, nutrition and osteoporosis are important considerations in the management of CD.

Management 26

Statement rationale: colonic dysplasia surveillance in CD

• Should put 8-10 years instead (more flexible)• "For UC<extensive type: 7-8 years• <Left side colm type: 10-12 years "• after 7 years.• CRC risk independent of CD should be a

condition

CRC Risk in CD• Ekbom: n=1,655

– CD CRC RR 2.5 (95% CI: 1.3–4.3)– Crohn’s colitis RR 5.6 (95% CI: 2.1-12.2)

• Jess (Denmark)– SMR 1.65 (95% CI 0.2-5.92)– 20% colectomy, 5-ASA

• meta-analysis 12 studies– CRC RR 2.5 (95% CI 1.3-4.7)– colonic CD RR: 4.5 (95% CI 1.3-14.9)

• CRC risk CD = UC

Surveillance in Australia Gastroenterologist

(n = 60)

Colorectal surgeon

(n = 35)

P

Ulcerative Pancolitis 93% 66% 0.99

Left sided Ulcerative colitis 80% 69% 0.042

Ulcerative Proctitis 15% 40% 0.00

Terminal Ileal Crohn's Disease 7% 20% 0.03

Colonic or ileo-colonic Crohn's 80% 69% 0.10

Perianal Crohn's 13% 11% 0.11

Primary Sclerosing Cholangitis 88% 54% 0.02

Management 26

• surveillance in CD

8-10 years

Colonoscopy surveillance for dysplasia can be recommended for patients with extensive Crohn’s colitis (more the one-third involvement of the colon) after 8-10 years (II-2, B)