The document discusses the use of biologicals such as infliximab and adalimumab in treating Crohn's disease. It provides details on their indications, administration protocols, effectiveness, safety considerations like risks of tuberculosis and autoimmune reactions, and constraints to their use like cost and lack of insurance coverage. Special precautions are needed with biologicals regarding vaccinations, screening for latent infections, and monitoring for adverse effects. Overall, biologicals are effective for inducing and maintaining remission in severe Crohn's disease and fistulizing disease when conventional treatments have failed or are not tolerated.

1. Biologicals in Crohns disease
Dr G Loganathan MD, DM GE
Adjunct Professor – TN Dr MGR MU
GL Hospital, Salem

2. Biologicals in Crohns disease
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 HIV
3/22/2015
ISGTNCON2015
2

3. How does the monoclonal antibody work? –
Replace cancer cell with inflammed colonocyte
3/22/2015ISGTNCON2015
3

4. How does the monoclonal antibody work? –
Replace cancer cell with inflammed colonocyte
3/22/2015ISGTNCON2015
4

5. How does the monoclonal antibody work? –
Replace cancer cell with inflammed colonocyte
3/22/2015ISGTNCON2015
5

6. 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?
3/22/2015ISGTNCON2015
6

7. 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
3/22/2015ISGTNCON2015
7

8. NICE Guidance
for use of Infliximab & Adalimumab
2. Crohns disease – Active Fistulizing
• Failed conventional therapy – Immunosuppressives, antibiotics
and drainage
• 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
3/22/2015ISGTNCON2015
8

9. NICE Guidance
for use of Infliximab & Adalimumab
Crohns disease – Severe Active - 6 – 17 yrs of age
• Failed conventional therapy – Immunosuppressives, nutrition 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
3/22/2015ISGTNCON2015
9

10. 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
42 Infliximab and other anti TNF factor antibodies are
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
43 Infliximab and other anti TNF factor antibodies are
useful in induction of remission in fistulizing CD
1 – Evidence
obtained from
atleast one RCT
B – There is fair
evidence to
support the
statement 3/22/2015ISGTNCON2015
10

11. 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
3/22/2015ISGTNCON2015
11

12. 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
ISGTNCON2015
12

13. 3/22/2015ISGTNCON2015
13

14. Biologicals in Crohn’s Disease
3/22/2015ISGTNCON2015
14

15. Biologicals in Crohn’s Disease
1. Proved Drugs – By Infusion
Infliximab FDA Approved / Natalizumab – Gut Specific / Vedolizumab
2. Proved Drugs – By Subcutaneous route
1. Adalimumab – FDA Approved,
2. Golimumab
1. 200 mg – 0,2 and then 100 mg / every 4 weeks
3. Certolizumab pegol – FDA approved
1. Pegylated anti TNF alpha antibody
2. 0, 2, 4 and then every 4 weeks
CCFA 3/22/2015ISGTNCON2015
15

16. Biologicals in Crohns disease
No 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
3/22/2015ISGTNCON2015
16

17. Biologicals in Crohns disease
No 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
3/22/2015ISGTNCON2015
17

18. Biologicals in Crohns disease
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
3/22/2015ISGTNCON2015
18

19. Biologicals in CD – Special Precautions
No 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 hour
3/22/2015ISGTNCON2015
19

20. Biologicals in Crohns disease
BIOLOGICALS
Symptoms
Biological
Markers
GI Endoscopy
Investigations
Risk and
Benefits
Cost
3/22/2015ISGTNCON2015
20

21. Biologicals in Crohns disease
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
3/22/2015ISGTNCON2015
21

22. Anti TNF – Alpha and TB
Clinical
examination
•History, Chest Skiagram, Tuberculein
test
•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
3/22/2015
ISGTNCON2015
22

23. Anti TNF – Alpha and TB
Evidence of
past TB
•Trt Completed - Monitor
•Trt Not Completed – Chemoprophy
with 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
www.thoraxjnl.com3/22/2015ISGTNCON2015
23

24. Anti TNF – Alpha and TB
3/22/2015ISGTNCON2015
24

25. Anti TNF – Alpha and TB
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
3/22/2015
ISGTNCON2015
25

26. Anti TNF – Alpha and TB
Symptoms of
TB after anti
TNF alpha
• Continue TB drugs
along with anti TNF
alpha
3/22/2015ISGTNCON2015
26

27. 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
3/22/2015ISGTNCON2015
27

28. Biologicals in Crohn’s Disease
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 RESPONSE
3/22/2015
ISGTNCON2015
28

29. Biologicals in Crohn’s Disease
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
3/22/2015ISGTNCON2015
29

30. Biologicals in Crohn’s Disease
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 3/22/2015
ISGTNCON2015
30
VACTERL Anomaly

31. Biologicals in Crohn’s Disease
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
3/22/2015ISGTNCON2015
31

32. Biologicals in Crohns disease
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
3/22/2015ISGTNCON2015
32

33. Biologicals in Crohn’s Disease
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
3/22/2015ISGTNCON2015
33

34. Biologicals in CD
Thanks to
THE ORGANIZING COMMITTEE ISGTNCON 2015
3/22/2015ISGTNCON2015
34