ppt

Biologicals in Crohns disease

Dr G Loganathan MD, DM GE

Adjunct Professor – TN Dr MGR MU

GL Hospital, Salem


Biologicals – Definition

• Biological products, or biologics, are medical products.

• Many biologics are made from a variety of natural sources (human, animal or microorganism). Like drugs, some biologics are intended to treat diseases and medical conditions. Other biologics are used to prevent or diagnose diseases.

Examples of biological products include

• vaccines

• blood and blood products for transfusion and/or manufacturing into other products

• allergenic extracts, which are used for both diagnosis and treatment (for example, allergy shots)

• human cells and tissues used for transplantation (for example, tendons, ligaments and bone)

• gene therapies, cellular therapies

• tests to screen potential blood donors for infectious agents such as HIV3/22/2015

ISGTNCON2015

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http://www.fda.gov/BiologicsBloodVaccines/UCM2018586

How does the monoclonal antibody work? –

Replace cancer cell with inflammed colonocyte

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How does the monoclonal antibody work? –Replace cancer cell with inflammed colonocyte

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How does the monoclonal antibody work? –Replace cancer cell with inflammed colonocyte

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Biologicals in Crohn’s Disease

1. When to use ?

2. How to use ?

3. How long to use ?

4. What dose to use

5. On whom to use?

6. Is it safe to use?

7. Is it safe to use in special situations? – Pregnancy, Elderly, TB!!!

8. Indian Recommendations – Do we have one?

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NICE Guidance for use of Infliximab & Adalimumab

1. Crohns Disease - Severe active in adults

• Failed conventional therapy – Immunosuppressives and steroids

• Intolerant to conventional therapy

• Contra Indications to conventional therapy

• Administered as a planned course of treatment till treatment failure / 12 months after start whichever is shorter

• Reassess after that period to decide on future course

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2. Crohns disease – Active Fistulizing

• Failed conventional therapy – Immunosuppressives, antibiotics and drainage





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Crohns disease – Severe Active - 6 – 17 yrs of age

• Failed conventional therapy – Immunosuppressives, nutrition and steroids





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ISG Consensus Statement Indian J Gastroenterol DOI 10.1007/s12664-015-0539-6

No Statement Level of

Evidence

Grade of

recommendation

41 Infliximab and other anti TNF factor antibodies are

useful in induction of remission in moderate to

severe CD

1 – Evidence

obtained from

atleast one RCT

A – There is good

evidence to

support the

statement


useful in maintanenance remission in moderate to

severe CD in patients who responded to induction

regimen

1 – Evidence

obtained from

atleast one RCT

A – There is good

evidence to

support the

statement


useful in induction of remission in fistulizing CD

1 – Evidence

obtained from

atleast one RCT

B – There is fair

evidence to

support the

statement3/22/2015ISGTNCON2015

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Biologicals in Crohns disease – Indication 1

Crohns Disease - Severe Active - Definition

• General health – Very Poor

• Symptoms - Weight loss, Fever, Severe abdominal pain (one or more)

• Bowel movement - 3-4 times / day of diarrhoeal stools

• CDAI > 300

• Harvey – Bradshaw score of 8 to 9 and above

• Assess physical, sensory, learning disabilities and communication difficulties

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Biologicals in Crohn’s Disease – Indication 2

Fistulizing Disease

• Peri Anal Fistulating disease

• Non Peri Anal Fistulating Disease

• Abdominal Enterocutaneous Fistula – 10% in ACCENT STUDY

• Entero – Gynaecological Fistula

• Low Anal – Introital – Asymptomatic – Sx

• Recto Vaginal Fsitula – Sx

• Intestinal small bowel / Sigmoid – Gyanecological Fistula – Sx

• Entero-Vesical Fistula – Sx

SIMPLE / COMPLICATED / NUISANCE FISTULAS 3/22/2015

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1. Proved Drugs – By Infusion

Infliximab FDA Approved / Natalizumab – Gut Specific / Vedolizumab

2. Proved Drugs – By Subcutaneous route

1. Adalimumab – FDA Approved,

2. Golimumab1. 200 mg – 0,2 and then 100 mg / every 4 weeks

3. Certolizumab pegol – FDA approved1. Pegylated anti TNF alpha antibody2. 0, 2, 4 and then every 4 weeks

CCFA 3/22/2015ISGTNCON2015

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Biologicals in Crohns diseaseNo Infliximab Adalimumab

1 Anti TNF – alpha – monoclonal antibody Anti TNF – alpha – monoclonal antibody

2 Chimeric – 75% IgG & 25% murine component for

binding TNF alpha

Humanised anti TNF antibody

3 Route – Intravenous infusion only Sub cutaneous injection only

4 FDA Approved FDA approved

5 Success Rate:

Induction -5 mg / kg / week

• 81% at 4 wks over 17%

• 48% at 12 weeks

Maintenance:5 mg/Kg,10 mg/Kg/8 wks

• 39% over 21% with 5 mg / Kg (p=0.003)

• 45% over 21% with 10 mg / Kg (p=0.0002)

Success Rate

Induction: CLASSIC I (160/80, 80/40 mg)

• 30% over 12% with placebo (p=0.004)

• 35.5% in 160/80 mg group at 4 weeks

• GAIN study:21.4% over 7.2% (p=0.0006)

Maintanence

• Conclusively demonstrated in CLASSIC II and

CHARM study

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Biologicals in Crohns diseaseNo Infliximab Adalimumab

6 Fistulating CD

• 50% reduction over 12 weeks reviewed weekly

• 68% with 5 mg/Kg and 56% with 10 mg/Kg groups

• Response was not sustained

ACCENT II

• 3 Induction Infusions 5 mg/Kg at 0,2,6 weeks

• 69% responded

Randomised to Maint. with 5 mg/Kg/8 wks VS Placebo

• 43% over 23% at 12 months with active re-trt

• Complete closure in 36% over 19% with active re-trt

Median Time to RESPONSE – 2 weeks

Median Time To CLOSURE - 3 Months

No difference between 5 mg/Kg and 10 mg / Kg dose

CHARM Study

Fistula Closure: 33% over

13% at week 56 (p=0.016)

7 • Auto Antibodies - Present Auto – Antibodies – Absent

but less commonly present

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No Infliximab Adalimumab

8 A Induction Induction

5 mg / Kg at 0,2,6 weeks 80 / 40 mg – Successive weeks 0,2 weeks

8 B Maintenance if there is response Maintenance if there is response

5 MG / Kg / 8 weeks till 12 months or failure 40 mg / Alternate week till 12 months or failure

8 C Non Responders to Induction regimen Non Responders to induction regimen

Surgery / Alternate treatment / Higher dose Surgery / Alternate treatment / Higher Dose

8 D Non responders to Maintanence Non Responders to Maintanence

• Decrease interval to not less than 4 weeks

• Increase dose

• Reactive treatment

Escalate treatment to weekly dose

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Biologicals in CD – Special PrecautionsNo Variable List

1 Contraindications Demyelinating illness / Optic Neuritis in person

Demyelinating illness / Optic Neuritis – IN FAMILY - Caution /

Avoid

2 Pregnancy Weigh against risk / VACTREL Abnormality

3 > 65 yrs With caution / CXR every 6 to 12 months

4 Malignancy Caution with H/O Malignancy in patient

5 Heart CAD, CCF – Avoid use of drug

6 In Fistulating CD Ensure all abscess are draining well

7 Steroid Pre Dosing not necessary

8 Re Treatment Significant Drug Holiday - 12 months - for Infliximab

High vigilance for acute and chronic infusion reactions

9 Initial dose Infliximab infusion over 2 hours and subsequently over 1 hour3/22/2015ISGTNCON2015

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BIOLOGICALS

Symptoms

Biological Markers

GI Endoscopy

Investigations

Risk and Benefits

Cost

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Adverse Effects

Similar profile of adverse events for all anti TNF therapies

• Increased risk of intracellular pathogens – TB & Other opportunistic infections increase from 3 fold to 15 fold – Tourner et al

• Death due to pseudomonas Pneumonia / fungal septicaemia post – op – Scottish

• Autoimmunity

• Infusion Reactions

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Anti TNF – Alpha and TB

Clinical examination

•History, Chest Skiagram, Tuberculeintest

•Thorough examination, Specialist consultation if TB is suspected to exclude ACTIVE TB

Active TB•Standard TB treatment

•Minimum 2 months of full TB drugs before anti TNF alpha

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Evidence of past TB

•Trt Completed - Monitor

•Trt Not Completed – Chemoprophywith INH for 6/12

Normal CXR

•Not on Immunosuppression –Tuberculin Test

•On Immunosuppression – Individual risk assessment

A close association between gastroenterologist and infection specialist is mandatory

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Latent TB Diagnosis

•Tuberculin – High false negative rate

•T cell IFN gamma assay

•More specific and sensitive, reliable

•Results not affected by BCG vaccine, immunosuppression

•Result affected by current anti TNF therapy

Latent TB Treatment

•12 weeks of TB drugs pre anti TNF alpha treatment

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Symptoms of TB after anti

TNF alpha

• Continue TB drugs along with anti TNF alpha

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Anti TNF – Alpha and Hepatitis Virus B and C

Hepatitis B

• Pre Tx Screen – Must

• Vaccination in Non Immune High Risk Patient

• Reactivation while on anti TNF alpha reported

Hepatitis C • No effect on course of hepatitis C

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Auto Immune reactions

• Antibodies to INFLIXIMAB – ATI

• Acute Infusion and delayed serum sickness like reaction

• Management

• Slowing of infusion

• Trt with anti histamines, steroids

ACCENT 1 Study

On ATI

• ATI

• 7 and 10% with systemic treatment

• Incidence 30% through 72 weeks

• Associated with increased incidence of infusion reaction

• Associated with LOSS OF RESPONSE3/22/2015

ISGTNCON2015

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ADALIMUMAB •Humanised antibody

•Antibodies to ADA do happen

Serum Levels

•Drug levels not measurable

•Antibodies levels not measurable

•Antibodies result in low trough levels

•Low trough levels associated with low response

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Malignancies

• Lymphomas – NHL, Rare hepato-splenic T Cell lymphoma

• Leukemia

• Solid organ cancer

• Breast cancer – Invasive

• Lung cancer – Mayo, Edinburgh

CNS

• Optic Neuritis

• Seizures

• Demyelination including multiple sclerosis

Pregnancy 3/22/2015ISGTNCON2015

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VACTERL Anomaly


Constraints

• Remissions with drugs Majority

• Spontaneous remission without drugs Good Number

• Severity Scoring Not Done

• Cost affordability Less number

• Insurance Coverage Not Clear

• Education/structurising adverse effects monitoring Task Force

• Awareness of disease VVVV Less

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Policy on Vaccinations

• Avoid LIVE vaccines – Oral polio, MMR, Typhoid, Varicella, BCG

• Influenza - Annually

• Pneumococcal – every three years

• HPV in young females

• Hepatitis B vaccination prior to immunosuppression / steroids

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Take Home Message

Anti TNF alpha antibodies are very effective in

• Inducing remission in refractory severe active / Fistulating disease

• Achieving maintenance in significant patient population

• Awareness, Cost, Complications are CONSTRAINT

• Vaccinations are of paramount importance

Propose Development of TEACHING MODULE based on TASK FORCE guidelines for FAMILY & CONSULTANT PHYSICIANS

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Biologicals in CD

Thanks to

THE ORGANIZING COMMITTEE ISGTNCON 2015

3/22/2015ISGTNCON2015

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ppt

Healthcare

planned course of treatment

treatment failure

use of infliximab adalimumab1

use of infliximab adalimumab2

crohns disease biologicals

crohns disease severe

crohns diseasewhen

blood products