Infections are a major cause of morbidity and mortality in patients with autoimmune rheumatic diseases. The immune response in these patients is impaired, and the immunosuppressive medications used for treatment have adverse effects. Infections are the biggest threat in the management of rheumatic conditions. Common infections seen in rheumatic diseases, which are associated with high morbidity and mortality, are vaccine-preventable. In particular, influenza, invasive pneumococcal infection, herpes zoster, and hepatitis B are the major vaccine-preventable infections seen in our patients.

Vaccination in rheumatic disease is associated with a unique set of challenges. Vaccination leads to an immune response to a particular antigen; however, a non-specific response might lead to autoimmune disease. Ideally, studies on efficacy should use clinical endpoints to assess the role of vaccines in rheumatic diseases, to establish their clinical benefits. Such studies, wherein the clinical endpoints are logistically demanding, require an adequate sample size. Hence, most current studies use laboratory parameters (serologic titers of antibodies or T cell reactivity against antigen) to establish the efficacy of vaccines. However, laboratory surrogates lack correlation with the clinical endpoints of reducing infection. Studies related to vaccination need to be interpreted with this consideration in mind.

In this write-up, we will focus on the efficacy of various vaccines in rheumatic diseases and conclude with the current recommendations pertaining to vaccination.

Influenza Virus

The influenza vaccines currently available in the market include inactivated and live, attenuated. trivalent and tetravalent vaccines containing three and four strains; however, the most commonly used vaccine is the trivalent inactivated vaccine. Multiple studies, including a prospective,¹ retrospective, large registry-based Taiwanese study,2 suggest a reduction in the incidence of pneumonitis, bronchitis, and hospitalization in rheumatoid arthritis and SLE patients vaccinated with the influenza vaccine, compared to unvaccinated patients. In SLE, the serological response to the influenza subunit varied among studies. A few studies showed a mild reduction in seroprotection, while others did not show any difference in seroconversion between vaccinated and unvaccinated patients.^3,4 Serologic evidence of protection in systemic sclerosis,⁵ granulomatosis with polyangiitis,⁶ and Sjogren’s syndrome⁷ have been observed after influenza vaccination. Significant evidence exists to suggest the efficacy of influenza vaccination with the concomitant use of glucocorticoids, cDMARDs, and anti-TNF therapy and tocilizumab. In one study, patients on combination therapy with methotrexate and anti-TNF had lower titers of antibodies to influenza as compared to patients on methotrexate alone; however, multiple studies have shown a good response with combination therapy as well.⁸ Studies with rituximab in RA, however, have documented significantly lower seroconversion rates.⁹ None of the studies have raised concerns regarding the safety or flare of underlying autoimmune disease.

The processes of antigenic drift and shift lead to changing immunogenicity of the influenza strains each year. Depending on the strains in circulation in a particular demographic area, the manufacturers ‘update’ their vaccine to include the recent strains. This should be kept in mind while administering the vaccine to patients. The best time to vaccinate with the yearly shot is before the onset of monsoon (April-May),¹⁰ since influenza infection is particularly more common during the monsoon and winter.

Thus, current evidence suggests that influenza vaccines are well tolerated but underutilized in rheumatic diseases patients and are generally immunogenic even with immunosuppression, except for rituximab. Vaccines should ideally be administered before B-cell-depleting biological therapy (BCDT) is started, or when patients are on such a treatment already, at least 6 months after the start but 4 weeks before the next course. The European League Against Rheumatism (EULAR) recommends yearly vaccination with influenza for all patients with rheumatic diseases.¹¹

Streptococcus pneumoniae
Currently, two forms of pneumococcal vaccines are available. PPSV23 is derived from a polysaccharide capsule, while PCV13 is a conjugated vaccine with diphtheria carrier protein. PPSV23’s response is T-cell-independent, while PCV13 is T-cell-dependent. The immunological response is more robust with PCV13 compared to PPSV23. Hence, boosters are required with PPSV23, while a single dose is sufficient with PCV13. The majority of the available literature has studied the use of PPSV23 in rheumatic diseases. Another reason for heterogeneity among the available data is lack of generally accepted serologic protection criteria for immunologic response to the pneumococcal vaccine.

In rheumatoid arthritis (RA), sound evidence exists to suggest an adequate serologic response to pneumococcal vaccination, independent of disease activity and the DMARDs used for treatment.¹² However, newer studies have documented mildly reduced seroconversion with a methotrexate-anti-TNF combination and severely impaired humoral response with BCDT.^13,14 Recent studies on PPSV23 in SLE suggest a reduced immunogenicity as compared to healthy controls.¹⁵ The efficacy of the pneumococcal vaccine has also been established in systemic sclerosis¹⁶ and psoriatic arthritis patients.¹⁷

The Centers for Disease Control recommends PCV13 followed by PPSV23 at least 8 weeks later for the general population. For those who have already received PPSV23, PCV13 should be given at least 1 year later with; an additional PPSV23 booster dose is given, as usual, 5 years following the first vaccination.18
The EULAR guidelines strongly recommend pneumococcal vaccination for all patients with rheumatic diseases.¹¹

Table 1: Immunogenicity of various vaccines in the presence of various immunosuppressants in RA and SLE

± Doubtful; ↓ Reduced; + Intact immunogenicity. NA: Not available; TNFi: TNF inhibitor.

Hepatitis B
Studies conducted among RA, SLE, ankylosing spondylitis, and Behcet’s disease patients suggest the immunogenicity of the hepatitis B vaccination irrespective of disease activity, steroid or DMARD use. However, the data available are insufficient to draw meaningful conclusions. The EULAR guidelines recommend hepatitis B vaccination for patients at risk, including for intravenous drug abuse, multiple sex partners in the previous 6 months, and healthcare personnel.¹¹ Hepatitis B vaccination is a part of the universal immunization program in India.

Herpes Zoster
The risk of herpes zoster infection is increased among patients with rheumatic diseases. Special concerns regarding herpes zoster have been raised in view of the increased risk in patients of RA receiving tofacitinib. As HZV is a live, attenuated vaccine, its use in immunosuppressed patients is controversial. However, evidence from larger registry-based studies suggests its safety in immunosuppressed patients with rheumatic diseases.¹⁹ The American Advisory Committee on Immunization Practices (ACIP) recommends using HZV in the general population aged ≥50 years, in individuals anticipating immunosuppression (at least two weeks prior to administration of immunosuppressive agent), and in individuals taking low-dose immunosuppressive therapy (e.g. <20 mg/day of prednisone or equivalent or using inhaled or topical steroids).²⁰ Temporary discontinuation of immunosuppressive medications before vaccination with live, attenuated vaccines might also be considered; however, there are no studies supporting this strategy.

Box 2 summarizes the EULAR recommendations for the vaccination of individuals with AIRDs. Recently, an update to these guidelines was presented at the EULAR meeting in Amsterdam in 2018. It is under the process of publication. Newer recommendations include: immunocompetent household members of patients with AIRDs should be encouraged to receive vaccines according to national guidelines, with the exception of oral poliomyelitis vaccine; and live, attenuated vaccines should be avoided for the first 6 months in a newborn whose mother received biologics in the second half of pregnancy.

References

1. Stojanovich, L. Influenza vaccination of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Clin. Dev. Immunol. 2006:13;373–375.
2. Chang, C.-C., Chang, Y.-S., Chen, W.-S., Chen, Y.-H. & Chen, J.-H. Effects of annual influenza vaccination on morbidity and mortality in patients with Systemic Lupus Erythematosus: A Nationwide Cohort Study. Sci. Rep. 2016:6;37817.
3. Louie, J. S. et al. Clinical and antibody responses after influenza immunization in systemic lupus erythematosus. Ann. Intern. Med. 1978:88;790–2.
4. Holvast, A. et al. Safety and efficacy of influenza vaccination in systemic lupus erythematosus patients with quiescent disease. Ann. Rheum. Dis. 2005:65;913–918.
5. Setti, M. et al. Flu vaccination with a virosomal vaccine does not affect clinical course and immunological parameters in scleroderma patients. Vaccine. 2009:27;3367–3372.
6. Holvast, A. et al. Wegener’s granulomatosis patients show an adequate antibody response to influenza vaccination. Ann. Rheum. Dis. 2009:68;873–878.
7. Pasoto, S. G. et al. Short and long-term effects of pandemic unadjuvanted influenza A(H1N1)pdm09 vaccine on clinical manifestations and autoantibody profile in primary Sjögren’s syndrome. Vaccine 2013:31;1793–1798.
8. Westra, J., Rondaan, C., Van Assen, S. & Bijl, M. Vaccination of patients with autoimmune inflammatory rheumatic diseases. Nat. Rev. Rheumatol. 2015:11;135–145.
9. Kapetanovic, M. C. et al. Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis. Arthritis Res. Ther. 2014:16;R2.
10. Kumar, S., Rath, P. & Malaviya, A. A practical guide to adult vaccination for patients with autoimmune inflammatory rheumatic diseases in India. Indian J. Rheumatol. 2017:12;160.
11. van Assen, S. et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann. Rheum. Dis. 2011:70;414–422.
12. Friedman, M. A. & Winthrop, K. Vaccinations for rheumatoid arthritis. Curr. Opin. Rheumatol. 2016:28;330–336.
13. Bingham, C. O. et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial. Arthritis Rheum. 2010:62;64–74.
14. Kapetanovic, M. C. et al. Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology. 2006:45;106–111.
15. Mathian, A., Pha, M. & Amoura, Z. Lupus and vaccinations. Curr. Opin. Rheumatol. 1 (2018). doi:10.1097/BOR.0000000000000525.
16. MERCADO, U., ACOSTA, H. & DIAZ-MOLINA, R. Antibody Response to Pneumococcal Polysaccharide Vaccine in Systemic Sclerosis. J. Rheumatol. 2009:36;1549–1550.
17. Mease, P. J. et al. Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept. J. Rheumatol. 2004:31;1356–1361.
18. Kobayashi, M. et al. Intervals Between PCV13 and PPSV23 Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Morb. Mortal. Wkly. Rep. 2015:64;944–947.
19. Yun, H. et al. Risk of Herpes Zoster in Autoimmune and Inflammatory Diseases: Implications for Vaccination. Arthritis Rheumatol. 2016:68;2328–2337.
20. Dooling, K. L. et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR. Morb. Mortal. Wkly. Rep. 2018:67;103–108.
21. Krasselt, M., Baerwald, C. & Seifert, O. Insufficient vaccination rates in patients with systemic lupus erythematosus in a German outpatient clinic. Z. Rheumatol. 2018:77;727–734.
22. Lawson, E. F., Trupin, L., Yelin, E. H. & Yazdany, J. Reasons for failure to receive pneumococcal and influenza vaccinations among immunosuppressed patients with systemic lupus erythematosus. Semin. Arthritis Rheum. 2015:44;666–671.

 

 

 



Left to right: Dr. Pravin Hissaria, Royal Adelaide Hospital, Adelaide; Dr. Rutviz Mistry, 3rd year DM resident, SGPGI, LKO