vaccinations in patients with immune mediated inflammatory diseases

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-Barr� 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 ! K�bner 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 � Similar response rate in RA compared to controls� Lower response rate in RA patients treated with anti TNF� 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

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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 sant� pour voyageurs, �dition 20008-9; �dition destin�e au corps m�dical; 10e uitg. / 10e �d. 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