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Content. IMID and immunomodulatory drugs Which vaccines for adults ? Live and inactivated vaccinesWhich vaccines are recommended in IMID/immunocompromised patients ?Potential triggers of autoimmunityVaccination and auto immune diseases. Reality or fairy tales ?Efficacy and safety of a vaccineRisk/benefit ratio of vaccinations in patients with IMIDHouse hold contactTiming vaccinationConclusion and take home messages.
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1. Vaccinations in patients with immune mediated inflammatory diseases JF Rahier
Cliniques Universitaires UCL Mont Godinne
A Van Gompel
Tropical Institute Antwerpen
2. Numeroter les slides correspondants ? Numeroter les slides correspondants ?
3. Immune mediated inflammatory diseases in GI, Rheumatology and Dermatology Ulcerative Colitis, Crohn’s disease
Rheumatoid arthritis, Systemic lupus erythematosus, Psoriatic arthritis, Ankylosing spondylitis (connective tissue diseases, vasculitis)
Psoriasis
Many other causes of secondary immune dysfunction / deficiency exist: post-transplant situations (solid ; bone marrow or stem cell), thymectomy and thymoma, malignity, limited immune deficit (asplenia/hyposplenism, renal failure, diabetes, malnutrition,…), …
4. 1. Immunomodulatory drugs commonly used Corticosteroids (high dose = > 20 mg/day of prednisone or equivalent for =2 weeks)
Methotrexate
Azathioprine and analogues
Anti Tumor Necrosis Factor a agents (infliximab, adalimumab, etanercept, certolizumab)
Leflunomide
Cyclosporine
Others: Interferon, cyclophosphamide, anti CD20 (rituximab), anti T cell costimulation (CYLA4/abatacept), anti IL6 receptor (tocilizumab), efalizumab…
NB: Not immunocompromising : non-steroidal anti-inflammatory drugs & sulphasalazine & hydroxychloroquine
5. 2. Which vaccines for adults ? Tetanus ? No
Diphtheria ? No
Pertussis ? No
Polyomyelitis ? No
Measles ? Yes
6. 2. Which vaccines for adults ? Invasive Pneumococcal Disease ? Yes
Influenza ? Yes Human Papilloma virus ? Yes
Varicella /Zoster ? Yes
Hepatitis B ? Yes
7. 2. Which vaccines for adults ? Hepatitis A ? No
Typhoid fever ? No ?
Yellow fever ? No ?
Japanese encephalitis ? No
Meningococcal meningitis ? No ?
Tick born encephalitis ? No ?
Rage ? No
(TBC/BCG) ? Yes
Cholera ? No ?
8. 3. Live and inactivated vaccines Tetanus ? No
Diphtheria ? No
Pertussis ? No
Polyomyelitis ? No
Measles ? Yes
9. 3. Live and inactivated vaccines Invasive Pneumococcal Disease ? Yes
Influenza ? Yes Human Papilloma virus ? Yes
Varicella /Zoster ? Yes
Hepatitis B ? Yes
10. 3. Live and inactivated vaccines Hepatitis A ? No
Typhoid fever ? No ?
Yellow fever ? No ?
Japanese encephalitis ? No
Meningococcal meningitis ? No ?
Tick born encephalitis ? No ?
Rage ? No
(TBC/BCG) ? Yes
Cholera ? No ?
11. 4. Which vaccines are recommended in IMID/ IC patients ? Basic vaccines:
Tetanus (every 10 yrs)
Diphtheria (every 10 yrs)
Pertussis (1x)
13. 4. Which vaccines are recommended in IMID/ IC patients ?
14. 5. 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
Gender related difference
15. 6. Vaccination and auto immune diseases. Reality or fairy tales ? 1976: Guillain-Barré syndrome following swine flu vaccine. No significant increase with subsequent influenza vaccine
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!
HBV and multiple sclerosis: cases 1991-1999. During this period, 25 million people received vaccine in France (40% country population)
10 new studies: no association
2 large scale studies: no association
16.
Extremely rare cases of psoriasis following BCG vaccination
No induction of psoriasis by other vaccines in large database !
Köbner phenomenon ! 6. Vaccination and auto immune diseases. Reality or fairy tales ?
17. 6. 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 IBD
M Feeney et al., Lancet 1997
RL Davis et al., Arch Pediatr Adolesc Med 2001
C Bernstein et al., Inflamm Bowel Dis 2007
Association BCG vaccination and Crohn’s disease
S Baron et al., Gut 2005
Insufficient evidence to conclude on CD
MC Rousseau et al,. Pediatr Allergy Immunol 2008
18. 6. 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 !
19. 6. IMID (Rheumatology) following vaccination... Reality or fairy tales ? Few cases mainly in patients with HLA-DR4 and HLA class II genes associated with RA
BUT
Large case control study : no association
The Committee concluded “no convincing evidence to support an association between hepatitis B vaccination and rheumatoid arthritis”.
20. 6. IMID following vaccination... Reality or fairy tales ? For the general population, vaccines are safe and a beneficial procedure that prevents disease with high morbidity and mortality
There are subjects who, subsequent to vaccination have developed diseases that they may not have developed had they not been 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 infection?
21. 7. Is efficacy and/or safety of vaccines influenced by the IMID itself or by the underlying immunocompromised status ? The physiopathology for these diseases is different
IBD : NO (defective innate immunity ?)
Psoriasis: NO
RA & co : YES (according to disease activity?)
22. 7. Definition of efficacy of a vaccine Demonstration of field efficacy
preferably trough well-conducted and well-controlled vaccine efficacy trials; differentpossible end points (infection, disease, hospitalization, death); in different settings and populations
not always possible or feasible…
23. 7. Definition of efficacy of a vaccine 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
Immunological surrogates of protection for vaccines ?
Relationship between specific immune responses and protection ?
24. 7. Definition of safety of a vaccine In terms of:
risk for flare up of the IMID
risk for infection by the vaccine itself (live vaccines)
25. 8. Risk/benefit ratio of vaccination in patients with IMID Hepatitis B vaccine
Pneumococcal vaccine
Influenza vaccine
MMR vaccine
Yellow fever & other live vaccines – Zoster vaccine
26. Efficacy of the hepatitis B vaccine in the IMID patient Humoral response to Hepatitis B vaccination is expected to be = 85 % in young healthy adults
68 % in RA patients (1)
93% in SLE patients (4)
27. Efficacy of the hepatitis B vaccine in the IMID patient
28. Safety of the hepatitis B vaccine in the IMID patient RA: No significant worsening in clinical or laboratory measure of disease
JIA: No significant worsening in clinical or laboratory measure of disease
SLE: No change in SLEDAI
29. Efficacy of the pneumococcal vaccine in the IMID Patient % of patients with ADA achieving a vaccine response compared to placebo: similar (1)
% of RA patients achieving a vaccine response compared to controls: similar (2)
Low or no response rate in 33% of RA and 20% SLE patients compared to controls (4)
30. Efficacy of the pneumococcal vaccine in the IMID Patient
31. Safety of the pneumococcal vaccine in the IMID patient No deterioration in any clinical or laboratory measure of disease activity (RA and SLE patients)
Lupus disease activity unaffected by immunization
No alteration of the underlying disease (SLE)
32. Efficacy of the influenza vaccine in the IMID patient Lower response rate in RA patients compared to controls ¹
Similar response rate in RA compared to controls²
Lower response rate in RA patients treated with anti TNF³
Lower response rate in SLE patients than in controls4
Response rate in SLE and RA similar than controls 5
Similar rate response in RA (ADA vs placebo)7
Lower response rate in IBD (IBD vs control) *
33. Efficacy of the influenza vaccine in the IMID patient
34. Safety of the influenza vaccine in the IMID patient Indices of disease activity unchanged in RA patients
I Fomin et al., Ann Rheum Dis 2006
F Del Porto et al., Vaccine 2006
Similar adverse reaction in RA and control patients
A Chalmers et al., J Rheumatol 1994
LBS Gelinck et al,.Ann Rheum Dis 2008
No change in disease activity in SLE patients
A Holvast et al., Ann Rheum Dis 2006
F Del Porto et al., Vaccine 2006
No change in disease activity
P Mamula et al,. Clin Gastroenterol Hepatol 2007
35. Efficacy of the MMR vaccine in the IMID patient
36. Safety of the MMR vaccine in the IMID patient
No increase in disease activity or medication use in JIA patients
MW Heijstek et al., Ann Rheum Dis 2007
No increase in disease activity, use of medication within 6 months after MMR revaccination
S Borte et al., Rheumatology 2009
37. Safety of the YF & other live vaccines Severe Immunocompromise (Non-HIV)
high-dose corticosteroids, (>2 mg/kg of body weight or 20 mg/day of prednisone or equivalent when administered for =2 weeks )
alkylating agents (e.g., cyclophosphamide),
antimetabolites (e.g., azathioprine, 6-mercaptopurine),
transplant-related immunosuppressive drugs (e.g., cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil),
mitoxantrone
cancer chemotherapeutic agents (excluding tamoxifen)
methotrexate, including low-dose weekly regimens, (not considered by all rheumatologists as severely immunocompromising; Leflunomide is considered by most rheumatologists as immunocompromising)
Tumor necrosis factor (TNF)-blocking agents
38. 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 (serologic testing 1 month post-vaccination (not routinely available in Belgium))
39. 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.
40. 8. Risk/benefit ratio of vaccination in patients with IMID: General statements Influenza, pneumococcal and HBV vaccines are safe and generally immunogenic in patients with autoimmune rheumatic diseases
Some anti TNF agents may impair the immune response for influenza vaccine
MTX seems to impair responsiveness for pneumococcal vaccine
Immunization = unimpeachable measure to defend the major causes for increased morbidity and mortality
41. 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.
42. 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
43. 11. Conclusion and take home message Vaccines are best given before introduction of immunomodulator therapy.
As in the general population, the immunization status of patients with IMID should be checked and vaccination considered for routinely administered vaccines: Tetanus, Diphtheria, Pertussis.
In addition, every patient IMID should be considered for the following vaccines according to specific guidelines:
VZV varicella/zoster vaccine, Human papilloma virus, Influenza, Pneumococcal polysaccharide vaccine, Hepatitis B vaccine
Vaccines for patients on immunomodulators traveling in developing countries or frequently traveling around the world should be discussed with an appropriate specialist.
44. References Canada Communicable Disease Report (CCDR RMTC). Advisory Committee Statement (ACS) - Committee to Advise on Tropical Medicine and Travel (CATMAT) The Immunocompromised Traveller. 04/2007
HP Brezinschek et al., Curr Opin Rheumatol 2008;20:295-299
B Sands et al., Inflamm Bowel Dis 2004;10:677-692
JF Rahier et al., JCC 2009(in press)
British Society for Rheumatology 2002, 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
M Lebwohl et al., J Am Acad Dermatol 2008;58 (1):94-105
Molina V et al., Autoimmunity 2005 ;38(3) :235-245
DC Wraith et al,. Lancet 2003;362:1659-66
R Koca et al., J Trop Ped 2004;50(3) :178-9
K Takayama et al., Acta Derm Venereol 2008; 88(6):621-2
NP Thompson et al., Lancet 1995 ;345 (8957) :1071-4
M Feeney et al., Lancet 1997;350 (9080):764-6
RL Davis et al., Arch Pediatr Adolesc Med 2001;155 (3):354-9
C Bernstein et al., Inflamm Bowel Dis 2007;13 5(6):759-762
S Baron et al., Gut 2005;54:357-63
45. References MC Rousseau et al,. Pediatr Allergy Immunol 2008;19:438-448
CM Benjamin et al., BMJ 1992;304:1075-77
K Aho et al., Acta Path Microbiol Scand 1962;56:478-9
RN Peeler et al,. Ann Intern Med 1956;63:44-57
LT Kurland et al., May Clin Proc 1984;59:816-821
K Gross et al., Scand J Rheumatol 1995; 24:50-52
JE Pope et al., J Rheumatol 1998;25:1687-1693
Vaccination anti hépatite B , mise a jour des données et des études de pharmacovigilance 02/2000 http://www.afssaps.fr/var/afssaps_site/storage/original/application/b460abed4a9a61d8dad78d4364033354.pdf
WHO - Global Advisory Committee on Vaccine Safety (GACVS) (June 2006)
http://www.who.int/vaccine_safety/topics/hepatitisb/hep_B_and_rheumatoid_arthritis/en
Y Shoenfeld et al., J Autoimmunity 2000;14:1-10
MF Doran et al. Arthritis Rheum2002;46;2287-2293
SA Plotkin Correlates of Vaccine-induced immunity CID 2008;47:401-9
O Elkayam et al,. Ann Rheum Dis 2002;61:623-25
O Kasapçocur et al., Ann Rheum Dis 2004 ; 63(9) :1128-30
R Ravikumar et al., Arthritis Rheum 2006 ;56 (Suppl 9) :S366
K Kuruma et al., Lupus 2007 ;16 :350-354
46. References L Kaine et al., J Rheumatol 2007;34:272-279 (RA patients ADA vs placebo)
MC Kapetanovic et al., Rheumatology 2006 ;45 :106-111 ( RA and controls patients)
PJ Mease et al., J Rheumatol 2004;31:1356-61 (Psoriatic arthritis etanercept vs placebo)
O Elkayam et al., CID 2002;34:147-153 (RA, SLE and controls)
S Visvanathan et al., J Rheumatol 2007; 34:952-957 (RA patients IFX, MTX, placebo)
DF Battafarano et al., Arthritis Rheum 1998 ;41 :1828-34
E McDonald et al., J Rheumatol 1984;11:306-8
I Fomin et al., Ann Rheum Dis 2006;65:191-194 (RA patients and controls)
A Chalmers et al., J Rheumatol 1994;21:1203-6 (RA patients and controls)
LBS Gelinck et al,.Ann Rheum Dis 2008 ;67 :713-716 ( RA and controls)
A Holvast et al., Ann Rheum Dis 2006 ;65 :913-918 (SLE and controls)
F Del Porto et al., Vaccine 2006 ;24 :3217-3223 (SLE,RA and controls)
MC Kapetanovic et al., Rheumatology 2007;46 (4):608-11 (RA and controls)
JL Kaine et al., J Rheumatol 2007;34:272-9 (RA Ada vs placebo)
P Mamula et al,. Clin Gastroenterol Hepatol 2007 ; 5 :851-6 (IBD and controls)
S Borte et al., Rheumatology 2009;48:144-148
CDC Travelers' Health - Yellow Book
http://wwwn.cdc.gov/travel/yellowBookCh9-Immunocompromised.aspx
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
47. References General Recommendations on Immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP)Morbidity and Mortality Weekly ReportRecommendations and Reports December 1, 2006 / Vol. 55 / No. RR-15 Centers for Disease Control and Prevention www.cdc.gov/mmwr
Extended practical Belgian guidelines on travel medicine
Gezondheidsadviezen voor reizigers 2008-9; uitgave bestemd voor het medisch korps;
Conseils de santé pour voyageurs, édition 20008-9; édition destinée au corps médical;
10e uitg. / 10e éd. Bruxelles (MEDASSO Headlines) CMP Medica Belgium, 2008: 230 pp.
Van Gompel A, editor
only electronic publication
http://www.itg.be/ITG/Uploads/MedServ/nmedasso.pdf
http://www.itg.be/ITG/Uploads/MedServ/fmedasso.pdf