- Email: [email protected]
Vaccination in adults with autoimmune inflammatory rheumatic diseases
indian journal of rheumatology 11 (2016) 68–72
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/injr
Topical Review
Vaccination in adults with autoimmune inflammatory rheumatic diseases Sham Santhanam *, Subramanian Swaminathan Global Hospitals, Chennai, India
article info
abstract
Article history:
There is an increased risk of infections in patients with autoimmune inflammatory rheu-
Received 2 April 2016
matic diseases (AIRDs). The risk is more due to immune dysfunction and increased use of
Accepted 4 April 2016
immunosuppressive drugs (mainly with the introduction of biologicals). Some of these are
Available online 21 April 2016
vaccine-preventable infections. In this narrative review we have appraised the recent literature on vaccinations in AIRDs along with relevant recommendations available in India.
Keywords:
# 2016 Published by Elsevier B.V. on behalf of Indian Rheumatology Association.
Vaccination Adult Influenza vaccines Pneumococcal vaccines Rituximab
1.
Introduction
The number of individuals with autoimmune inflammatory rheumatic diseases (AIRDs) being treated with immunosuppressive drugs is steadily increasing, mainly with the advent of biological disease modifying agents.1 The risk of infections is also more in these groups of patients and vaccination is an effective strategy for prevention.1 We did not have enough data from India1; but in the COMORA (international, crosssectional) study, of 3920 enrolled rheumatoid arthritis (RA) patients only 25.3% had a vaccination for influenza, 17.2% had pneumococcal vaccination and only 10.3% had both.2 So, what is the need for vaccinating patients with AIRDs? Are they at increased risk of vaccine-preventable infections? Then what are the vaccine-preventable infections? What is the immunogenicity, efficacy and safety of these vaccines? These
are some of the questions we shall try to address in this narrative review. A literature search was performed in Pubmed and Scopus from January 2015 to February 2016. Only articles in English and data of patients older than 16 years were included.
2.
Infection in AIRDs
There is an increased risk of infections in AIRDs due to dysfunction of the immune system secondary to disease, use of immunosuppressive drugs and comorbidities.3 In comparison to the general population, there is 1.7 times higher risk of acquiring an infection and 1.8 times higher risk of acquiring an infection necessitating hospitalisation.4 Some of the drugs like TNFi (tumour necrosis factor inhibitors) with glucocorticoids in RA and moderate doses of glucocorticoids in systemic lupus
* Corresponding author. E-mail address: [email protected] (S. Santhanam). http://dx.doi.org/10.1016/j.injr.2016.04.002 0973-3698/# 2016 Published by Elsevier B.V. on behalf of Indian Rheumatology Association.
indian journal of rheumatology 11 (2016) 68–72
erythematosus (SLE) increase the risk of infection. The rate of serious infections is more with biologics compared to synthetic disease modifying agents and 5 times more in SLE compared to RA.5 The increased rate of hospitalisation in AIRDs is for pneumonia and the common causative organisms like influenza, streptococcus pneumonia and hemophilus influenza b (Hib) are vaccine preventable infections.6 There is an increased risk of herpes zoster infection in patients with AIRDs.6 The rate of herpes zoster infection had increased with advent of biologicals and is significantly higher with usage of Tofacitinib.7 Human papilloma virus (HPV) infections are more prevalent in SLE patients due to defective clearance of the virus. Hence, the diagnosis of SLE itself increases the risk of developing cervical dysplasias and pre-malignant lesions. But surprisingly the prevalence of cervical cancer was not increased except for one study.8
3.
Inactivated vaccines
The administration of inactivated vaccines in patients with AIRDs on immunosuppressive drugs is safe, but efficacy might decrease depending on the type of drugs. The ideal time of vaccination is before the start of immunosuppressive therapy and during stable disease.3,4
3.1.
Influenza vaccine
The exact incidence of influenza in AIRDs is unknown, but the morbidity and mortality due to the same are increased.3,6 The limited studies assessing the clinical outcome in vaccinated patients found reduced admission and mortality from influenza pneumonia. There is a strong recommendation for annual administration of (both seasonal and pandemic swine flu) influenza vaccine.3 In patients with RA, rituximab and abatacept reduce the antibody response significantly.6 In SLE patients the vaccine efficacy is reduced with high disease activity, lymphopenia and therapy with azathioprine.3,6
3.2.
Pneumococcal vaccine
The risk of invasive pneumococcal infections is more in patients with AIRDs. The risk is higher in patients with inflammatory arthritis on TNF inhibitors. The risk is also more in patients with SLE, scleroderma and sjogren syndrome.3,6 Most of the studies on vaccination measure the serological response rather than the clinical outcome or endpoints.4 Pneumococcal polysaccharide vaccine (PPSV 23) was found to be safe and effective in terms of serological response. Prolonged use of high-dose steroids was associated with poor vaccine response and increased rate of infections.9 In a study by Nagel et al., the efficacy of pneumococcal conjugate vaccine (PCV 7) was assessed in patients with chronic RA and spondyloarthritis (SpA). They found that the patients with robust serological response had less likelihood of developing serious infections. Similar to the previous study, high-dose glucocorticoids and older age were associated with serious infections.10 Rituximab4,6 and abatacept11 causes a significant reduction in immunogenicity. MTX with or without TNFi4,6 reduces efficacy to some extent. There are two types of
69
pneumococcal vaccine (PPSV 23 and PCV 13) available, and as per the recent recommendations of the Advisory Committee on Immunization Practices (ACIP) the conjugate vaccine (PCV 13) is preferred over polysaccharide vaccine (PPSV 23).12,13 The ideal approach would be to give conjugate vaccine first and follow it up with polysaccharide vaccine (prime and boost strategy). The conjugate vaccines induce higher affinity antibodies with long-lasting immune and memory responses.4,13
3.3.
Human papilloma virus vaccine (HPV)
Three types of HPV vaccine (bivalent HPV vaccine [2vHPV], quadrivalent [4vHPV] and 9-valent vaccine [9vHPV]) are available. All the 3 types can be used in females but only the 4vHPV and 9vHPV in males.12 This is indicated in few highrisk groups, like SLE patients. They have increased risk of HPV infections with a 9-fold increased risk of pre-malignant cervical lesions.8 There is increased reporting of venous thromboembolism events with the 4vHPV type. Hence, extra caution is needed in SLE patients with anti-phospholipid antibody syndrome.14
3.4.
Others
Tetanus toxoid vaccination is efficacious in RA patients on synthetic or biological DMARDS (including rituximab).6 But in high-risk cases, it is safer to administer passive immunisation, if the patient had received rituximab in the last 6 months.14 In SLE patients, active disease and steroids might decrease the vaccine efficacy.4 Both Hepatitis B and Hepatitis A vaccines are recommended in high-risk groups (i.v. drug abusers, health care personnel, multiple sex partners, etc.).12,14 Hepatitis B vaccine had a satisfactory immune response in all rheumatic diseases and with all drugs except TNFi, which severely hampers the immune response.4 The Hepatitis B and Hepatitis A vaccines are safe and immunogenic. But, there have been case reports of worsening of autoimmune diseases with Hepatitis B vaccine.3 In AIRD patients with splenectomy or functional hyposplenism, vaccines against capsulated organisms like H. influenzae, meningococcus, including pneumococcus need to be considered, as per ACIP recommendations.12,14
4.
Live vaccines
In general, live vaccines should be avoided in patients on immunosuppressive drugs and to be given prior to initiation of treatment. The reason is due to risk of replication of the attenuated microorganism. Some vaccines have a high-risk of replication (e.g. yellow fever vaccine) and some have a low risk of replication (e.g. herpes zoster vaccine).3 There is an increased risk of herpes zoster in patients with RA, SLE and granulomatous polyangitis (with renal dysfunction). The risk also increases with the use of cyclophosphamide and steroids with or without DMARDs/TNFi.6 In two of the large retrospective cohort studies, herpes zoster vaccine was found to be safe and immunogenic.4 Similarly, Measles– mumps–rubella (MMR) revaccination was found to be safe and
70
indian journal of rheumatology 11 (2016) 68–72
immunogenic in a randomised control trial and in a retrospective cohort study.4 But, for safety reasons, it is better to wait for a certain time period (12 months for rituximab, 2 years for lefluonomide and an average of 3 months for most of the other drugs) after cessation of the immunosuppressive drug.4 If the degree of immunosuppression is unclear, an inactivated vaccine with neo-antigen can be given. After 4–6 weeks, if the serological immune response to inactivated vaccine is satisfactory and CD4 cell counts are >200/microlitre, then the live vaccine can be administered.4 If a patient on immunosuppressive therapy, who is not protected against measles/varicella, is exposed to an infected person, then immunoglobulins/antivirals are to be considered.4 The commonly used adult vaccines, type of vaccine, dosing schedule and drugs to be avoided are summarised in Table 1.
4.1.
Indian data and recommendations
A literature search was performed in Pubmed and Scopus. Due to paucity of Indian data, the search was extended to previous
ten years were included. Infections are the common cause of hospital admissions in RA and SLE patients, with respiratory infection being the commonest in both groups.15 The overall frequency of infections in patients with AIRDs was 18.2%, with SLE accounting for the majority. The commonest urinary and respiratory tract pathogens were Escherichia coli and Klebsiella pneumoniae.15 Porkodi et al. reported increased frequency of K. pneumoniae causing urinary tract and respiratory tract infections in SLE patients.16 The concept of adult immunisation in developing countries is controversial and lack of consensus still exists.17 So, the Association of Physicians of India (API) in 2009 came up with guidelines for adult immunisation. According to the guidelines, influenza vaccine is not recommended in patients with AIRDs due to lack of epidemiological data on the serotypes prevalent in India. They recommended against the use of pneumococcal polysaccharide vaccine (PPSV 23) due to lack of published data in Indian population. They also stated regarding the lack of evidence, to support its use in the prevention of invasive pneumococcal disease. Similarly, due to lack of epidemiological evidence, they recommended
Table 1 – Commonly used adult vaccines in AIRDs (type of vaccine, dosing schedule, indications, drugs to be avoided). Vaccines4,6
Inactivated/live12
Influenzaa
Inactivated
Pneumococcala
Inactivated
Human papilloma virus (HPV)a
Inactivated
Hepatitis Bb Hepatitis Ab Tetanusb
Inactivated Inactivated Inactivated
Hemophilus influenza bb Meningococcalb
Inactivated
Varicellab (Herpes) zostera Measles, mumps, rubella (MMR)b
Live Live Live
Inactivated
Schedule12
During therapy4,6,7
Annual dosing Can be givenf Age > 6 months ! IIV Age > 18 years egg allergy ! RIV Can be givenf PCV 13 – single dose PPSV 23 – 1, 2 or 3 doses Can be givenf 3 doses; for those aged 13 through 26 years (for both females and males) 3 doses (0, 1, 6 months) Can be givenf 2 dose schedule Can be givenf Tdap once, then Td booster every 10 Can be givenf years Unvaccinated/incomplete primary vaccination – Begin or complete it One or three doses depending on Can be givenf indication Contraindica ted Depends on type of vaccine and – indication Contraindicated 2 doses (4 weeks apart) Single dose Contraindicated 1 or 2 doses depending on indication
Drugs to be avoided (reducing efficacy)4,6,7 Definite: RTXc,d, abataceptc,d Relative: MTXc,d TNFi, AZAe Definite:RTXc, abataceptc Relative: MTXc TNFid Relative: prednisolonee and MMFe on certain strains Definite: TNFid Relative: MTXc Relative: MTXc
– Due to increased risk of – reactivation, it’s better to avoid live vaccines during therapy except under special circumstances
IIV, inactivated influenza vaccine; RIV, recombinant influenza vaccine; PPSV 23, pneumococcal polysaccharide vaccine; PCV 13, pneumococcal conjugate vaccine; Tdap, tetanus, diphtheria and acellular pertussis vaccination; Td, tetanus, diphtheria vaccination RTX, rituximab; MTX, methotrexate; TNFi, tumour necrosis factor inhibitors; MMF, mycophenolate mofetil. a Commonly indicated. b Only if required. c Rheumatoid arthritis. d Spondyloarthritis. e Connective tissue disorders. f Preferable to start before initiating treatment. If started after treatment, efficacy might decrease depending on drugs used but there is no concern regarding safety. g Live vaccines are generally contraindicated during treatment. But some vaccines (e.g. zoster/varicella) may be considered under special circumstances. [Patients on steroids<20 mg/day, hydroxychloroquine, sulfasalazine, methotrexate < 0.4 mg/kg/day, azathioprine < 3 mg/kg/ day, after assessing the risk–benefit ratio.]
indian journal of rheumatology 11 (2016) 68–72
against the use of herpes zoster vaccine.17 In 2011, Directorate general of health services (Government of India) came up with recommendations on adult immunisation. They also recommended against the routine use of influenza, pneumococcal and varicella vaccines due to lack of enough evidence.18 But in 2015, API had discussed about pneumococcal vaccine in their respective journal. The authors were in favour of pneumococcal conjugate vaccine (PCV 13), preferably followed by PPSV 23 after 6–12 months.13,19 In a couple of review articles, the Indian authors have recommended the routine administration of influenza, pneumococcal vaccination and hepatitis B vaccines in patients with AIRDs.20,21 In 2010, Malaviya et al.22 studied the vaccination compliance in patients with AIRDs. In their cohort, approximately 50% [pneumococcal vaccine (52.9%), influenza vaccine (43.48%), hepatitis B (51.4%)] of the patients had complied with vaccination advice and the results were pretty encouraging.
5.
Conclusion
In India, adult immunisation is still not given much importance.23,24 The barriers for adult immunisation have to be recognised and should be overcome.25 We need more data from India on communicable diseases, adult vaccination and immunisation in rheumatic diseases. These data, and recommendations based on that, have to be updated periodically.23,24 We also need trials to assess the clinical endpoints post vaccination rather than checking for the serological response.4
Take home messages:
Assess vaccination status at the time of diagnosis. Ideal time to vaccinate (Inactivated and live vaccines) is prior (preferably 4 weeks) to starting of immunosuppressive drugs and during stable disease. Inactivated vaccines can be given during immunosuppressive therapy. Rituximab (wait till 6 months for revaccination and 12 months for primary vaccination) and abatacept significantly decreases the immune response post vaccination. Live vaccines usually should be avoided in patients with AIRDs under treatment. Live vaccines like Varicella and Herpes zoster may be considered under special circumstances during immunosuppressive therapy after assessing the riskbenefit ratio.
Conflicts of interest The authors have none to declare.
71
references
1. Malaviya AN, Nigil H. Infections associated with the use of biologic response modifiers in rheumatic diseases: a critical appraisal. Indian J Rheumatol. 2011;6:99–112. 2. Hmamouchi I, Winthrop K, Launay O, Dougados M. Low rate of influenza and pneumococcal vaccine coverage in rheumatoid arthritis: data from the international COMORA cohort. Vaccine. 2015;33:1446–1452. 3. Papadopoulou D, Tsoulas C, Tragiannidis A, Sipsas NV. Role of vaccinations and prophylaxis in rheumatic diseases. Best Pract Res Clin Rheumatol. 2015;29:306–318. 4. Bühler S, Eperon G, Ribi C, et al. Vaccination recommendations for adult patients with autoimmune inflammatory rheumatic diseases. Swiss Med Wkly. 2015;145: w14159. 5. Botha-Scheepers SA, Sarembock B. Infections in the management of rheumatic diseases: an update. S Afr Med J. 2015;105:1076. 6. Westra J, Rondaan C, Van Assen S, Bijl M. Vaccination of patients with autoimmune inflammatory rheumatic diseases. Nat Rev Rheumatol. 2015;11:135–145. 7. Lahiri M, Dixon WG. Risk of infection with biologic antirheumatic therapies in patients with rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2015;29:290–305. 8. Grein IH, Groot N, Lacerda MI, Wulffraat N, Pileggi G. HPV infection and vaccination in systemic lupus erythematosus patients: what we really should know. Pediatr Rheumatol Online J. 2016;14:12. 9. Fischer L, Gerstel PF, Poncet A, et al. Pneumococcal polysaccharide vaccination in adults undergoing immunosuppressive treatment for inflammatory diseases – a longitudinal study. Arthritis Res Ther. 2015;17:151. 10. Nagel J, Geborek P, Saxne T, et al. The association between antibody levels before and after 7-valent pneumococcal conjugate vaccine immunization and subsequent pneumococcal infection in chronic arthritis patients. Arthritis Res Ther. 2015;17:124. 11. Migita K, Akeda Y, Akazawa M, et al. Effect of abatacept on the immunogenicity of 23-valent pneumococcal polysaccharide vaccination (PPSV23) in rheumatoid arthritis patients. Arthritis Res Ther. 2015;17:357. 12. Kim DK, Bridges CB, Harriman KH. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older: United States, 2016. Ann Intern Med. 2016;164:184–194. 13. Handa R, Chaturvedi V, Danda D, Krishnamurthy V. Pneumococcal vaccination in rheumatic diseases. J Assoc Physicians India. 2015;63:40–42. 14. Ranjan P, Chakrawarty A, Kumari A, Kumar J. Immunization in patients with rheumatic diseases: a practical guide for general practitioners. J Clin Diagn Res. 2015;9:OE01–OE04. 15. Rajendra Vara Prasad I, Nagaprabu VN, Suresh K, Agrawal S, Narsimulu G. Infections in rheumatology practice: an experience from NIMS, Hyderabad. Indian J Rheumatol. 2011;6:25–30. 16. Porkodi R, Ravichandran R. Infections in a rheumatology setting—Chennai experience. Indian J Rheumatol. 2011;6: 31–35. 17. Expert Group of the Association of Physicians of India on Adult Immunization in India. The Association of Physicians of India Evidence-Based Clinical Practice Guidelines on Adult Immunization. Expert Group of the Association of Physicians of India on Adult Immunization in India. J Assoc Physicians India. 2009;57:345–356. 18. National Centre for Disease Control. Directorate General of Health Services. Government of India. Adult immunization.
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19. 20.
21.
22.
indian journal of rheumatology 11 (2016) 68–72
2011, February–March. Retrieved from: http://www.ncdc.gov. in/writereaddata/linkimages/February_Final_020862513827. pdf. Sureshkumar D. Pneumococcal vaccination in different specialities. J Assoc Physicians India. 2015;63:29–30. Joshi VR, Kharbanda P, Tembe A. Prevention of infections in patients with rheumatic diseases. Indian J Rheumatol. 2008;3:58–63. Shobha V. Common anti-infective prophylaxis and vaccinations in autoimmune inflammatory rheumatic diseases. Indian J Rheumatol. 2012;7:21–28. Malaviya AN, Zaheer Q, Negi P, Gogia SB. Vaccination compliance in patients with rheumatic diseases: EMR helps
in tracking compliance.IRACON. Indian J Rheumatol. 2010;5: S1–S32. P69. 23. Verma R, Khanna P, Chawla S. Adult immunization in India: importance and recommendations. Hum Vaccin Immunother. 2015;11:2180–2182. 24. National Vaccine Policy. Ministry of Health and Family Welfare. Government of India; 2011, April. Available from: http:// mohfw.nic.in/WriteReadData/l892s/1084811197NATIONAL% 20VACCINE%20POLICY%20BOOK.pdf. 25. Tan L. Adult vaccination: now is the time to realize an unfulfilled potential. Hum Vaccin Immunother. 2015;11: 2158–2166.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/injr
Topical Review
Vaccination in adults with autoimmune inflammatory rheumatic diseases Sham Santhanam *, Subramanian Swaminathan Global Hospitals, Chennai, India
article info
abstract
Article history:
There is an increased risk of infections in patients with autoimmune inflammatory rheu-
Received 2 April 2016
matic diseases (AIRDs). The risk is more due to immune dysfunction and increased use of
Accepted 4 April 2016
immunosuppressive drugs (mainly with the introduction of biologicals). Some of these are
Available online 21 April 2016
vaccine-preventable infections. In this narrative review we have appraised the recent literature on vaccinations in AIRDs along with relevant recommendations available in India.
Keywords:
# 2016 Published by Elsevier B.V. on behalf of Indian Rheumatology Association.
Vaccination Adult Influenza vaccines Pneumococcal vaccines Rituximab
1.
Introduction
The number of individuals with autoimmune inflammatory rheumatic diseases (AIRDs) being treated with immunosuppressive drugs is steadily increasing, mainly with the advent of biological disease modifying agents.1 The risk of infections is also more in these groups of patients and vaccination is an effective strategy for prevention.1 We did not have enough data from India1; but in the COMORA (international, crosssectional) study, of 3920 enrolled rheumatoid arthritis (RA) patients only 25.3% had a vaccination for influenza, 17.2% had pneumococcal vaccination and only 10.3% had both.2 So, what is the need for vaccinating patients with AIRDs? Are they at increased risk of vaccine-preventable infections? Then what are the vaccine-preventable infections? What is the immunogenicity, efficacy and safety of these vaccines? These
are some of the questions we shall try to address in this narrative review. A literature search was performed in Pubmed and Scopus from January 2015 to February 2016. Only articles in English and data of patients older than 16 years were included.
2.
Infection in AIRDs
There is an increased risk of infections in AIRDs due to dysfunction of the immune system secondary to disease, use of immunosuppressive drugs and comorbidities.3 In comparison to the general population, there is 1.7 times higher risk of acquiring an infection and 1.8 times higher risk of acquiring an infection necessitating hospitalisation.4 Some of the drugs like TNFi (tumour necrosis factor inhibitors) with glucocorticoids in RA and moderate doses of glucocorticoids in systemic lupus
* Corresponding author. E-mail address: [email protected] (S. Santhanam). http://dx.doi.org/10.1016/j.injr.2016.04.002 0973-3698/# 2016 Published by Elsevier B.V. on behalf of Indian Rheumatology Association.
indian journal of rheumatology 11 (2016) 68–72
erythematosus (SLE) increase the risk of infection. The rate of serious infections is more with biologics compared to synthetic disease modifying agents and 5 times more in SLE compared to RA.5 The increased rate of hospitalisation in AIRDs is for pneumonia and the common causative organisms like influenza, streptococcus pneumonia and hemophilus influenza b (Hib) are vaccine preventable infections.6 There is an increased risk of herpes zoster infection in patients with AIRDs.6 The rate of herpes zoster infection had increased with advent of biologicals and is significantly higher with usage of Tofacitinib.7 Human papilloma virus (HPV) infections are more prevalent in SLE patients due to defective clearance of the virus. Hence, the diagnosis of SLE itself increases the risk of developing cervical dysplasias and pre-malignant lesions. But surprisingly the prevalence of cervical cancer was not increased except for one study.8
3.
Inactivated vaccines
The administration of inactivated vaccines in patients with AIRDs on immunosuppressive drugs is safe, but efficacy might decrease depending on the type of drugs. The ideal time of vaccination is before the start of immunosuppressive therapy and during stable disease.3,4
3.1.
Influenza vaccine
The exact incidence of influenza in AIRDs is unknown, but the morbidity and mortality due to the same are increased.3,6 The limited studies assessing the clinical outcome in vaccinated patients found reduced admission and mortality from influenza pneumonia. There is a strong recommendation for annual administration of (both seasonal and pandemic swine flu) influenza vaccine.3 In patients with RA, rituximab and abatacept reduce the antibody response significantly.6 In SLE patients the vaccine efficacy is reduced with high disease activity, lymphopenia and therapy with azathioprine.3,6
3.2.
Pneumococcal vaccine
The risk of invasive pneumococcal infections is more in patients with AIRDs. The risk is higher in patients with inflammatory arthritis on TNF inhibitors. The risk is also more in patients with SLE, scleroderma and sjogren syndrome.3,6 Most of the studies on vaccination measure the serological response rather than the clinical outcome or endpoints.4 Pneumococcal polysaccharide vaccine (PPSV 23) was found to be safe and effective in terms of serological response. Prolonged use of high-dose steroids was associated with poor vaccine response and increased rate of infections.9 In a study by Nagel et al., the efficacy of pneumococcal conjugate vaccine (PCV 7) was assessed in patients with chronic RA and spondyloarthritis (SpA). They found that the patients with robust serological response had less likelihood of developing serious infections. Similar to the previous study, high-dose glucocorticoids and older age were associated with serious infections.10 Rituximab4,6 and abatacept11 causes a significant reduction in immunogenicity. MTX with or without TNFi4,6 reduces efficacy to some extent. There are two types of
69
pneumococcal vaccine (PPSV 23 and PCV 13) available, and as per the recent recommendations of the Advisory Committee on Immunization Practices (ACIP) the conjugate vaccine (PCV 13) is preferred over polysaccharide vaccine (PPSV 23).12,13 The ideal approach would be to give conjugate vaccine first and follow it up with polysaccharide vaccine (prime and boost strategy). The conjugate vaccines induce higher affinity antibodies with long-lasting immune and memory responses.4,13
3.3.
Human papilloma virus vaccine (HPV)
Three types of HPV vaccine (bivalent HPV vaccine [2vHPV], quadrivalent [4vHPV] and 9-valent vaccine [9vHPV]) are available. All the 3 types can be used in females but only the 4vHPV and 9vHPV in males.12 This is indicated in few highrisk groups, like SLE patients. They have increased risk of HPV infections with a 9-fold increased risk of pre-malignant cervical lesions.8 There is increased reporting of venous thromboembolism events with the 4vHPV type. Hence, extra caution is needed in SLE patients with anti-phospholipid antibody syndrome.14
3.4.
Others
Tetanus toxoid vaccination is efficacious in RA patients on synthetic or biological DMARDS (including rituximab).6 But in high-risk cases, it is safer to administer passive immunisation, if the patient had received rituximab in the last 6 months.14 In SLE patients, active disease and steroids might decrease the vaccine efficacy.4 Both Hepatitis B and Hepatitis A vaccines are recommended in high-risk groups (i.v. drug abusers, health care personnel, multiple sex partners, etc.).12,14 Hepatitis B vaccine had a satisfactory immune response in all rheumatic diseases and with all drugs except TNFi, which severely hampers the immune response.4 The Hepatitis B and Hepatitis A vaccines are safe and immunogenic. But, there have been case reports of worsening of autoimmune diseases with Hepatitis B vaccine.3 In AIRD patients with splenectomy or functional hyposplenism, vaccines against capsulated organisms like H. influenzae, meningococcus, including pneumococcus need to be considered, as per ACIP recommendations.12,14
4.
Live vaccines
In general, live vaccines should be avoided in patients on immunosuppressive drugs and to be given prior to initiation of treatment. The reason is due to risk of replication of the attenuated microorganism. Some vaccines have a high-risk of replication (e.g. yellow fever vaccine) and some have a low risk of replication (e.g. herpes zoster vaccine).3 There is an increased risk of herpes zoster in patients with RA, SLE and granulomatous polyangitis (with renal dysfunction). The risk also increases with the use of cyclophosphamide and steroids with or without DMARDs/TNFi.6 In two of the large retrospective cohort studies, herpes zoster vaccine was found to be safe and immunogenic.4 Similarly, Measles– mumps–rubella (MMR) revaccination was found to be safe and
70
indian journal of rheumatology 11 (2016) 68–72
immunogenic in a randomised control trial and in a retrospective cohort study.4 But, for safety reasons, it is better to wait for a certain time period (12 months for rituximab, 2 years for lefluonomide and an average of 3 months for most of the other drugs) after cessation of the immunosuppressive drug.4 If the degree of immunosuppression is unclear, an inactivated vaccine with neo-antigen can be given. After 4–6 weeks, if the serological immune response to inactivated vaccine is satisfactory and CD4 cell counts are >200/microlitre, then the live vaccine can be administered.4 If a patient on immunosuppressive therapy, who is not protected against measles/varicella, is exposed to an infected person, then immunoglobulins/antivirals are to be considered.4 The commonly used adult vaccines, type of vaccine, dosing schedule and drugs to be avoided are summarised in Table 1.
4.1.
Indian data and recommendations
A literature search was performed in Pubmed and Scopus. Due to paucity of Indian data, the search was extended to previous
ten years were included. Infections are the common cause of hospital admissions in RA and SLE patients, with respiratory infection being the commonest in both groups.15 The overall frequency of infections in patients with AIRDs was 18.2%, with SLE accounting for the majority. The commonest urinary and respiratory tract pathogens were Escherichia coli and Klebsiella pneumoniae.15 Porkodi et al. reported increased frequency of K. pneumoniae causing urinary tract and respiratory tract infections in SLE patients.16 The concept of adult immunisation in developing countries is controversial and lack of consensus still exists.17 So, the Association of Physicians of India (API) in 2009 came up with guidelines for adult immunisation. According to the guidelines, influenza vaccine is not recommended in patients with AIRDs due to lack of epidemiological data on the serotypes prevalent in India. They recommended against the use of pneumococcal polysaccharide vaccine (PPSV 23) due to lack of published data in Indian population. They also stated regarding the lack of evidence, to support its use in the prevention of invasive pneumococcal disease. Similarly, due to lack of epidemiological evidence, they recommended
Table 1 – Commonly used adult vaccines in AIRDs (type of vaccine, dosing schedule, indications, drugs to be avoided). Vaccines4,6
Inactivated/live12
Influenzaa
Inactivated
Pneumococcala
Inactivated
Human papilloma virus (HPV)a
Inactivated
Hepatitis Bb Hepatitis Ab Tetanusb
Inactivated Inactivated Inactivated
Hemophilus influenza bb Meningococcalb
Inactivated
Varicellab (Herpes) zostera Measles, mumps, rubella (MMR)b
Live Live Live
Inactivated
Schedule12
During therapy4,6,7
Annual dosing Can be givenf Age > 6 months ! IIV Age > 18 years egg allergy ! RIV Can be givenf PCV 13 – single dose PPSV 23 – 1, 2 or 3 doses Can be givenf 3 doses; for those aged 13 through 26 years (for both females and males) 3 doses (0, 1, 6 months) Can be givenf 2 dose schedule Can be givenf Tdap once, then Td booster every 10 Can be givenf years Unvaccinated/incomplete primary vaccination – Begin or complete it One or three doses depending on Can be givenf indication Contraindica ted Depends on type of vaccine and – indication Contraindicated 2 doses (4 weeks apart) Single dose Contraindicated 1 or 2 doses depending on indication
Drugs to be avoided (reducing efficacy)4,6,7 Definite: RTXc,d, abataceptc,d Relative: MTXc,d TNFi, AZAe Definite:RTXc, abataceptc Relative: MTXc TNFid Relative: prednisolonee and MMFe on certain strains Definite: TNFid Relative: MTXc Relative: MTXc
– Due to increased risk of – reactivation, it’s better to avoid live vaccines during therapy except under special circumstances
IIV, inactivated influenza vaccine; RIV, recombinant influenza vaccine; PPSV 23, pneumococcal polysaccharide vaccine; PCV 13, pneumococcal conjugate vaccine; Tdap, tetanus, diphtheria and acellular pertussis vaccination; Td, tetanus, diphtheria vaccination RTX, rituximab; MTX, methotrexate; TNFi, tumour necrosis factor inhibitors; MMF, mycophenolate mofetil. a Commonly indicated. b Only if required. c Rheumatoid arthritis. d Spondyloarthritis. e Connective tissue disorders. f Preferable to start before initiating treatment. If started after treatment, efficacy might decrease depending on drugs used but there is no concern regarding safety. g Live vaccines are generally contraindicated during treatment. But some vaccines (e.g. zoster/varicella) may be considered under special circumstances. [Patients on steroids<20 mg/day, hydroxychloroquine, sulfasalazine, methotrexate < 0.4 mg/kg/day, azathioprine < 3 mg/kg/ day, after assessing the risk–benefit ratio.]
indian journal of rheumatology 11 (2016) 68–72
against the use of herpes zoster vaccine.17 In 2011, Directorate general of health services (Government of India) came up with recommendations on adult immunisation. They also recommended against the routine use of influenza, pneumococcal and varicella vaccines due to lack of enough evidence.18 But in 2015, API had discussed about pneumococcal vaccine in their respective journal. The authors were in favour of pneumococcal conjugate vaccine (PCV 13), preferably followed by PPSV 23 after 6–12 months.13,19 In a couple of review articles, the Indian authors have recommended the routine administration of influenza, pneumococcal vaccination and hepatitis B vaccines in patients with AIRDs.20,21 In 2010, Malaviya et al.22 studied the vaccination compliance in patients with AIRDs. In their cohort, approximately 50% [pneumococcal vaccine (52.9%), influenza vaccine (43.48%), hepatitis B (51.4%)] of the patients had complied with vaccination advice and the results were pretty encouraging.
5.
Conclusion
In India, adult immunisation is still not given much importance.23,24 The barriers for adult immunisation have to be recognised and should be overcome.25 We need more data from India on communicable diseases, adult vaccination and immunisation in rheumatic diseases. These data, and recommendations based on that, have to be updated periodically.23,24 We also need trials to assess the clinical endpoints post vaccination rather than checking for the serological response.4
Take home messages:
Assess vaccination status at the time of diagnosis. Ideal time to vaccinate (Inactivated and live vaccines) is prior (preferably 4 weeks) to starting of immunosuppressive drugs and during stable disease. Inactivated vaccines can be given during immunosuppressive therapy. Rituximab (wait till 6 months for revaccination and 12 months for primary vaccination) and abatacept significantly decreases the immune response post vaccination. Live vaccines usually should be avoided in patients with AIRDs under treatment. Live vaccines like Varicella and Herpes zoster may be considered under special circumstances during immunosuppressive therapy after assessing the riskbenefit ratio.
Conflicts of interest The authors have none to declare.
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