Vaccinations in patients with immune mediated inflammatory ... · Vaccinations in patients with immune mediated inflammatory diseases ... used as “correlate” and/or “surrogate”

Jean-François Rahier , MD

CHU UCL Mont- Godinne, Belgium

Vaccinations in patients with immune mediated inflammatory diseases

“Safety means first aid to the uninjured”

unknown author

10472 situations !!

Immune mediated inflammatory diseases in GI

Ulcerative Colitis

Crohn’s disease

Immunomodulatory drugs commonly used in gastro

Corticosteroids

Methotrexate (MTX)

Azathioprine (AZA) and analogues

Anti Tumor Necrosis Factor α agents (infliximab (IFX),

adalimumab (ADA), certolizumab)

Cyclosporine

Potential triggers of autoimmunity

• Viral infection (Epstein Barr virus, Human Herpes virus-6,

HIV, Human Parvovirus B19…)

• Bacterial infection (Campylobacter jejuni, Yersinia

enterocolitica, Streptococcal group A, H Pylori …)

• Parasitic infection (malaria, schistosomiasis, leishmaniasis…)

• Vaccines

• Silicone implants

• Occupational and chemical exposures

Molina V et al., Autoimmunity 2005

Vaccination and auto immune diseases

Reality or fairy tales ?

IMID (Dermatology) following vaccination... Reality or fairy

tales ?

• Extremely rare cases of psoriasis following BCG vaccination

• No induction of psoriasis by other vaccines in large database !

• Köbner phenomenon !

R Koca et al., J Trop Ped 2004

K Takayama et al., Acta Derm Venereol 2008

BCG vaccination:

IMID (Gastroenterology) following vaccination... Reality or

fairy tales ?

- Controversial statement: Measles-vaccination may play a role in

the development of IBD

NP Thompson et al., Lancet 1995

No association Measles, mumps and rubella

(infection/vaccination) and onset of IBD

M Feeney et al., Lancet 1997

RL Davis et al., Arch Pediatr Adolesc Med 2001

C Bernstein et al., Inflamm Bowel Dis 2007

-

Measles vaccination:

IMID (Rheumatology) following vaccination... Reality or fairy

tales ?

• Arthritis and MMR: increased risk of joint symptoms in

immunized children BUT risk of frank arthritis less than after

wild rubella infection!

• RA : transient rise in rheumatoid factor or some form of

arthritis in patient immunized with variety of viruses (tetanus,

thyphoid, parathyphoid, mumps, diphtheria, polio, smallpox )

BUT

• Incidence of RA among vaccinated population not higher than

in non vaccinated population !

CM Benjamin et al., BMJ 1992; K Aho et al., Acta Path Microbiol Scand 1962;RN

Peeler et al,. Ann Intern Med 1956;LT Kurland et al., May Clin Proc 1984

MMR, tetanus, thyphoid, parathyphoid, mumps, diphtheria,

polio, smallpox, HBV

IMID following vaccination... Reality or fairy tales ?

• There are subjects who, subsequent to vaccination have developed

diseases that they may not have developed if not vaccinated

• We are not able to identify those subjects and not all who have the

genetic predisposition end up with post vaccine autoimmune

illness

• ?? Would those subjects who acquired autoimmune illnesses after

immunization, have acquired those illnesses had they been

exposed to the natural infection?

Y Shoenfeld et al., J Autoimmunity 2000

Which vaccines for adults ?

Increased severity of infection in

immunocompromised patients ?

Routine:

Tetanus No

Diphtheria No

Pertussis No

Polyomyelitis No

Measles Yes

Canada Communicable Disease Report (CCDR RMTC). Advisory Committee Statement (ACS) - Committee to Advise on Tropical Medicine and Travel (CATMAT) The Immunocompromised Traveler. 04/2007



In selected groups:

Invasive Pneumococcal Disease Yes

Influenza Yes

Others:

Human Papilloma virus Yes

Varicella /Zoster Yes

Hepatitis B Yes

Increased severity of infection

in IC patients ?



Travel related

vaccine:

Hepatitis A No

Typhoid fever ?

Yellow fever ?

Japanese encephalitis No

Meningococcal meningitis ?

Tick born encephalitis ?

Rage No

(TBC/BCG) Yes

Cholera ?

Increased severity of infection

in IC patients ?

Live and inactivated vaccines

Do we need vaccines in IMID patients ? - HBV

- Prevalence of HBV in IBD population = general population

BUT consequences are different !

- Numerous reports of HBV infections in IBD patients

- Risk of reactivation and hepatic failure in chronic HBV

carriers

- Treatment for HBV – unfriendly for IBD

Esteve M et al, Gut 2004; Loras C et al, Am J Gastroenterol 2009; Chevaux JB et al,

Inflamm Bowel Dis 2009

Do we need vaccines in IBD? - VZV

- Immunosuppression increases the risk of dissemination and

complications such as pneumonia, hepatitis, encephalitis, or

haemorrhagic disorders

- Fatal cases of primary varicella infection in young IBD

patients

Arvin AM, Clin Microbiol Rev 1996; Hambleton S, Clin Microbiol Rev 2005; Deutsch DE, J Pediatr Gastroenterol Nutr 1995; Leung VS, Am J Gastroenterol 2004; Vergara M,Gastroenterol Hepatol 2001

Do we need vaccines in IBD? - HPV

- Higher incidence of abnormal Pap smears in women with IBD

- Increased risk in patients treated with immunomodulators

Kane S et al, Am J Gastroenterol 2008; Bhatia J et al, World J Gastroenterol 2006; Zabana Y

et al, Inflamm Bowel Dis 2009; Lees CW et al, Inflamm Bowel Dis 2009

Recommended vaccine in IMID patients ?

Rahier JF et al, J Crohn Colitis 2009


Van Assen S et al, Ann Rheum Dis 2011


Basic vaccines:

Tetanus (every 10 yrs)

Diphtheria (every 10 yrs)

Pertussis (1x)

Polio (1x)

HP Brezinschek et al., Curr Opin Rheumatol 2008 ; B Sands et al., Inflamm Bowel Dis

2004; JF Rahier et al., JCC 2009 ; M Lebwohl et al., J Am Acad Dermatol 2008; British

Society for Rheumatology 2002, Van Assen Ann Rheum Dis 2011

http://rheumatology.org.uk/guidelines/guidelines_other/vaccinations/view

Superior Health Council www.health.fgov.be/CSS_HGR

CDC http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5515a1.htm



http://www.health.fgov.be/CSS_HGR

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5515a1.htm


IMID Patients

Vaccine Impact

disease

in IC

patients ?

Belgian

Superior

Health

Council

CDC RA

Association

European

Crohn &

Colitis

Org.

Am.

Psoriasis

Found.

Influenza Increased

mortality

YES YES YES YES YES

Pneumo Increased

mortality

subgroups YES YES YES











4. Recommended vaccine in IMID patients ?







IMID Patients

Vaccine Impact

disease

in IC

patients ?

Belgian

Superior

Health

Council

CDC RA

Association

European

Crohn &

Colitis

Org.

Am.

Psoriasis

Found.

HPV Increased

morbidity

(yes )

Selected

YES

Varicella

/Zoster

Increased

mortality

YES YES YES

HBV Increased

morbidity

subgroups Sub

groups

(yes)

At risk

YES





Safety of a vaccine

in terms of

• Adverse events

• Risk for flare up of the IMID

• Risk for infection by the vaccine itself (live vaccines)

Safety of a vaccine – adverse events

When evaluating the safety of a vaccine ,

consider “safety” of the disease !

Idiopathic thrombocytopenia following MMR vaccination: 1/

30000 vaccinated children. Risk of thrombocytopenia after

natural rubella or measles infection is 1/3000 and 1/6000

respectively!

DC Wraith et al,. Lancet 2003;362:1659-66

When evaluating the safety of a vaccine , consider “safety” of the disease !

Rahier JF et al, APT 2010

1918 – Spanish flu A/H1N1

40 millions deaths

WHO 2010:17000 H1N1 related deaths

88%






Prepare and prevent, don't repair and repent.

Effect of vaccination (non-live vaccines) on IMID disease activity

Rahier JF, Rheumatology 2010; Brezinschek HP, Curr Opin Rheumatol 2008; Melmed

GY, Am J Gastroenterol 2010; Mamula P, CGH 2007; Lu Y, Am J Gastroenterol

2009, Chaparro M , P172 ECCO 2010 ; Rahier JF , Gut 2011

Safety of a vaccine – adverse events

Vaccination in patients with AIIRD should ideally be administered during stable disease (EL 5 RG D)

Efficacy of a vaccine

1/ demonstration of field efficacy

preferably trough well-conducted and well-controlled vaccine

efficacy trials; different possible end points (infection, disease,

hospitalization, death); in different settings and populations

not always possible or feasible…

SA Plotkin, CID 2008


2/ immunological markers (adaptive immune system)

used as “correlate” and/or “surrogate” of protection (against infection and/or disease)

MOST OFTEN :

demonstration of B cell–generated antibodies

- seroconversion & geometric mean titers / peak titers

- quality (e.g. avidity; bactericidal / opsonic / neutralizing antibodies; etc)

- rapidity of decline of titers or long term persistence

ALSO : effector T cells / memory B & T cells

SA Plotkin, CID 2008


- No vaccine is completely effective

- Heterogeneous studies( disease and combination of therapies)

Brezinschek HP, Curr Opin Rheumatol 2008

Efficacy of the influenza vaccine in the IMID patient

¹ I Fomin et al., Ann Rheum Dis 2006; ² A Chalmers et al., J Rheumatol 1994; ³ LBS Gelinck et

al,.Ann Rheum Dis 2008 ; ⁴ A Holvast et al., Ann Rheum Dis 2006;⁵ F Del Porto et al.,

Vaccine 2006 ;⁶ MC Kapetanovic et al., Rheumatology 2007;⁷ JL Kaine et al., J Rheumatol

2007 ; *P Mamula et al,. Clin Gastroenterol Hepatol 2007

Drug MTX AZA CS Ciclo

Antibody

Response

NE (1,2,5,6) NE (2,5,*)

D (4)

NE (2,5) NE (5)

Drug ADA AZA +

IFX

IFX Etanercept

Antibody

Response

NE (7) D (*) NE (1) NE (1)

Antibody

Response

D (3,6) D (3,6) D (3,6)

NE no effect; I increased; D decreased

Influenza vaccine

- Decreased response in patients with IM+biologicals compared

to IM alone or IBD without IM: similar to controls ( healthy )

- The proportion of seroprotected patients and geometric mean

titers at post-vaccination were similar between NIS and IS

groups for all three strains

Mamula P CGH 2007; Lu Y Am J Gastro 2009; Debruyn JC , IBD 2011;

Efficacy of a vaccine in IBD

No vaccine is completely effective

Cullen G, Gut 2011


Melmed GY Am J Gastro 2010 ; Fiorino G, IBD 2011

Pneumococcal polysaccharide

Patients IBD IM+biologicals IBD no

IM

Healthy

controls

Vaccine response 40% 80% 85%

AZA: 79%

Biologics: 58%

Combination: 63%

88%



HBV vaccine

- various regimens (0, 1 and 2 months- 0,1 6)

- various cut-off point for adequate immunity (>10 mUI/ml or 100 mUI/ml)

- 211 IBD

- Response rate lower for patients on anti-TNF

- Overall , response rate in 60% patients

Chaparro M , P172 ECCO 2010 Prague

HPV vaccine (Gardasil ®; HPV6-11-16-18)

17/34 (50%) on immunomodulator therapy and 17/34 on anti-TNF therapy; majority of subjects had inactive disease throughout the study No serious adverse events Immune response to each serotype in the vaccine was strong and comparable to healthy controls

Lu, DDW 2011


Efficacy of vaccines in IMID patients

Rahier JF, Rheumatology 2010;

Efficacy of a vaccine IMID - summary

Heterogeneous results:

- Disease itself and treatment may impair response to vaccine

- Some anti TNF agents may impair the immune response for influenza vaccine and probably HBV vaccine

- MTX seems to impair responsiveness for pneumococcal vaccine

Brezinschek HP, Curr Opin Rheumatol 2008; Rahier JF JCC 2009; Van Assen S Ann

Rheum Dis 2011

Immunization is an unimpeachable measure to defend

against major causes for increased morbidity and mortality

Safety of the YF & other live vaccines

• Corticostéroïdes

• Méthotrexate

• Léflunomide

• Azathioprine & 6-mercaptopurine

• Cyclosporine A

• Cyclophosphamide

• Tacrolimus, Everolimus, Sirolimus, Temsirolimus

• Mycophenolat mofetil

• Anti Tumor Necrosis Factor α agents, Adalimumab (Humira®), certolizumab (Cimzia®),etanercept (Enbrel®), golimumab (Simponi®) en infliximab (Remicade®)

• Autres anticorps monoclonaux et biologiques: Rituximab (Mabthera®), Abatacept (Orencia®), Tocilizumab (Roactemra®), Basiliximab (Simulect®), Natalizumab (Tysabri®) et autres en cours de développement: Muromonab-CD3, …

• Antitumoraux: agents alkylants, antimétabolites, antibiotiques antitumoraux, inhibiteurs de la topo-isomérase, inhibiteurs des microtubules et antitumoraux divers

Safety of the YF & other live vaccines

• Severely immunosuppressed travelers strongly discouraged from

travel to destinations with true risk of yellow fever. If travel is

unavoidable and the vaccine is not given, travelers should be

instructed in methods to avoid mosquito bites and should be provided

a vaccination waiver letter.

• Patients with limited immune deficits (chronic hepatic disease

(cirrhosis and alcoholism), diabetes, and nutritional deficiencies,

interferon for hepatitis C infection) or asymptomatic HIV should be

offered the choice of vaccination and monitored closely for possible

adverse effects

CDC Travelers' Health - Yellow Book

http://wwwn.cdc.gov/travel/yellowBookCh9-Immunocompromised.aspx

Safety of Zoster vaccine

Therapy with low-doses immunomodulatory drugs for treatment of

rheumatoid arthritis, psoriasis, polymyositis, sarcoidosis, inflammatory

bowel disease, and other conditions including :

• methotrexate (<0.4 mg/Kg/week),

• azathioprine (<3.0 mg/Kg/day), or

• 6mercaptopurine (<1.5 mg/Kg/day)

are not considered sufficiently immunosuppressive to create vaccine

safety concerns and are not contraindications for administration of

zoster vaccine. … with antiviral therapy should complications ensue.

Prevention of Herpes Zoster ; Recommendations of the Advisory Committee on Immunization

Practices (ACIP); Recommendations and Reports June 6, 2008 / Vol. 57 / RR-5 Morbidity

and Mortality Weekly Report www.cdc.gov/mmwr

9. Vaccination of House hold Contacts of Persons with Altered

Immunocompetence

• Household and other close contacts of persons with altered immunocompetence : all age-appropriate vaccines, with the exception of live OPV and smallpox vaccine.

• MMR, varicella, and rotavirus vaccines should be administered when indicated. MMR vaccine viruses are not transmitted to contacts, and transmission of varicella vaccine is rare.

• To minimize potential rotavirus transmission, hand hygiene measures after contact with feces of a rotavirus-vaccinated infant for at least 1 week.

• Annual influenza vaccination.

General Recommendations on Immunization. Recommendations of the Advisory Committee

on Immunization Practices (ACIP)Morbidity and Mortality Weekly Report

Recommendations and Reports December 1, 2006 / Vol. 55 / No. RR-15

Centers for Disease Control and Prevention www.cdc.gov/mmwr

10. Timing of vaccination

Best before the start of immunomodulator therapy :

• Better immunogenicity (i.e MTX)

• No contraindication in case of live vaccines

• Patient today = traveler tomorrow

For live vaccine, if possible to interrupt temporarily the IMs

• How long to wait before vaccine administration : 3 months (except for

corticosteroids : 1 month)

• How long to wait to restart drug after the vaccination : 3-4 weeks

HP Brezinschek et al., Curr Opin Rheumatol 2008;20:295-299

Van assen S et al, Ann Rheum Dis 2011; JF Rahier et al., JCC 2009

British Society for Rheumatology 2002,


M Lebwohl et al., J Am Acad Dermatol 2008;58 (1):94-105


Vaccination in practice in IMID

• Best before introduction of immunomodulator therapy.

• Immunization status of patients with IMID patients should be

checked and vaccination considered for routinely administrated

vaccines: tetanus, diphteria, poliomyelitis, pertussis.

• Immunization for specific vaccines must be considered in every

patient following national or international guidelines

• Vaccines for patients on immunomodulators traveling in

developing countries or frequently traveling around the world

should be discussed with an appropriate specialist.

Documents

Vaccinations in patients with immune mediated inflammatory ... · Vaccinations in patients with immune mediated inflammatory diseases ... used as “correlate” and/or “surrogate”