A literature review on the patients with autoimmune diseases following vaccination against infections

Abstract

Due to immune abnormalities and the use of steroids and immunosuppressant treatment, patients with rheumatic diseases are susceptible to infections. Vaccination is one of the most important prevention tools in modern medicine. A discussion on risk-benefit or cost-benefit analysis, and advisory on individual vaccines or vaccination programs falls outside the scope of this review. In particularly, this review summarizes the knowledge about the effectiveness and safety vaccinations in patients with autoimmune inflammatory rheumatic diseases (AIIRD) treated with biologics. Finally, we aim to provide vaccination plans basis for clinical management of rheumatic patients depending upon prevaccination antibody titers, drug treatments and immunological potential.

Keywords:

• autoimmune diseases
• vaccination
• infections
• biologics

Introduction

Autoimmune and auto-inflammatory diseases affect about 1 in 15 individuals in developed countries and are in many instances a devastating health problem to the individual patient, thereby representing a heavy burden to society. Although significant progresses have been achieved in the development of new treatment modalities, the long-term outcome is still poor for many patients with autoimmune diseases.¹

Infection remains a major cause of morbidity and mortality in rheumatic diseases. The development of vaccines is a major contribution to the inhibition of infection in rheumatic diseases.² However, vaccination is also a powerful immune system stimulus that has the theoretical potential to induce or exacerbate immune disturbances that manifest as serological indices of immune system dysregulation or as clinically manifest autoimmune disease.³ The association between vaccines and autoimmune inflammatory rheumatic diseases (AIIRD) is a complex one. This review will discuss the current understandings for the function of vaccination in autoimmune patients. Hopefully, the information obtained will benefit for developing novel therapeutic strategies.

Vaccination in Autoimmune Diseases

Since the extent of immunosuppression of a patient with a specific autoimmune rheumatic diseases (AIRDs) under a given medication is not clearly defined, there are still a lot of questions to be answered concerning when and how often which vaccines should be given, and what protection for how long can be expected against a given infectious agent. The role of different medication combinations, age, disease duration, sex, and disease activity, also still warrants research. Due to this complex situation, in 2011, EULAR assembled an expert panel, which—after extensive literature research—published recommendations concerning vaccination in patients with AIRDs.^4,5

Influenza A/H1N1 Vaccination

Influenza A/H1N1 viruses infect large numbers of warm-blooded animals, including wild birds, domestic birds, pigs, horses, and humans. Influenza A/H1N1 viruses can switch hosts to form new lineages in novel hosts.⁷ Although A/H1N1 has proven to be mild in most cases, immunosuppressed patients and patients with chronic diseases are deemed to be at an increased risk for severe infection.⁷ Therefore, vaccination against influenza viruses is recommended for patients with autoimmune diseases to decrease infections and improve health. A recent study from Europe evaluated a single dose of an adjuvant variant A/H1N1 influenza vaccine on patients with different rheumatic diseases. They included 47 patients with rheumatoid arthritis (RA), 59 with spondyloarthritis (SpA), 15 with vasculitis, 28 with connective tissue disease (CTD) of which 9 had SLE, 15 with vasculitis, 28 with CTD 28 (9 SLE) and 40 healthy individuals. Antibody titers to the vaccine increased significantly in patients and controls with a maximum at week 3, declining to levels below protection at month 6.⁸ Additionally, Aikawa et al. assessed the immunogenicity of non-adjuvanted influenza A H1N1/2009 vaccine in patients with juvenile AIRDs and healthy controls.⁹ They results have shown that 3 weeks after immunization, seroprotection rate, seroconversion rate, and the factor-increase in geometric mean titer were significantly lower in patients with juvenile ARD versus controls.⁹

The safety of adjuvant and nonadjuvant influenza A/H1N1 vaccination was proven in research studies and population-based surveys. Abu-Shakra et al.¹⁰ reported that although the influenza A/H1N1vaccine may trigger the generation of autoantibodies in patients with lupus, this effect is usually short term and has no clinical significance. In addition, the immune response to influenza vaccine of patients with SLE is lower than that seen in adults in the general population, in particular among older patients and those treated with immunosuppressive therapy.¹¹ Together, these data suggested that adjuvant and nonadjuvant influenza vaccination is effective and well tolerated in rheumatic diseases.

Pneumococcal Vaccination

Due to the increased susceptibility to pulmonary complications in immunocompromised patients, vaccination against pneumococci should be strongly considered. Two vaccines against S. pneumoniae are currently commercially available, including 23-valent polysaccharide vaccine (PPV23) and heptavalent pneumococcal conjugate vaccine (PCV7). Pneumococcal vaccinations are safe and do not seem to favor autoimmune diseases flares. To assess the effect of vaccination against streptococcus pneumoniae on the generation of autoantibodies in patients with SLE, 24 consecutive patients with SLE were vaccinated against streptococcus pneumonia. The results reported that at the time of vaccination, 10 patients had anti-dsDNA, 2 patients had anti-Sm, 5 had anti-nRNP, and 9 had anti-Ro/SSA, 4 had anti-La/SSB, 4 had anticardiolipin IgG and IgM. Two months after vaccination, no change was observed in the proportion of patients with anti-Sm, anti-dsDNA, anti-RNP, anti-Ro/SSA and anticardiolipin IgM. Hence, vaccination against streptococcus pneumoniae did not trigger the generation of autoantibodies and confirms the clinical safety of this vaccine in SLE patients.¹² Kapetanovic et al. have investigated the influence of anti-inflammatory treatments, such as methotrexate (MTX), on antibody response following vaccination using PCV7 vaccine in adult patients with established arthritis and they results reported that treatment with MTX and higher age are predictive of an impaired antibody response.¹³ Furthermore, one study have investigated the impact of type of vaccine on antibody response following pneumococcal vaccination in patients with RA, and the results revealed that PCV7 elicits similar antibody response as PPV23 in patients with RA receiving immunosuppressive treatment. Again, higher age and MTX treatment predict impaired antibody response.¹⁴

A second problem is when should patients with chronic AIRDs be revaccinated? The revaccination remains still a topic of dispute for healthy individuals and, thus, even more in immunocompromised patients. Recently, one study has explored the persistence of an antibody response 1.5 years after vaccination with PCV7 in patients with RA or spondyloarthropathy (SpA) treated with different antirheumatic drugs. The results found that after initial increase, 1.5 years after vaccination with PCV-7, postvaccination antibody levels decreased significantly, reaching levels before vaccination in this cohort of patients with established arthritis treated with different antirheumatic drugs.¹⁵ Thus, to boost antibody response, early revaccination with conjugate vaccine might be needed in patients receiving potent immunosuppressive remedies.

In addition to PCV7, the 13-valent pneumococcal CRM 197 conjugate vaccine (PCV13) was licensed in the United States in February 2010 and replaces PCV7 for the prevention of invasive pneumococcal disease and otitis media.¹⁶ This vaccine contains serotypes 1, 3, 5, 6A, 7F, and 19A in addition to the serotypes found in PCV7. PCV13 elicited significantly higher enzyme-linked immunosorbent assay (ELISA) IgG-binding antibody responses than did PCV7 for the additional PCV13 serotypes (serotypes 1, 3, 5, 6A, 7F, and 19A), and for the common serotype 19F, with similar or lower responses for the remaining common serotypes.¹⁷

Human Papilloma Virus (HPV) Vaccination

HPV infection is associated with an increased risk of cervical cancers as well as anogenital and some other non-genital malignancies. HPV vaccine efficacy must last at least 15 years to contribute to the prevention of cervical cancers.^18,19 Numerous reports have raised the possibility of an association between HPV vaccine with autoimmune diseases, but the results are inconsistent. SLE diagnosis was documented in several case reports and case series as well as by 2 controlled studies: one study used the tetanus toxoid vaccine for control²⁰ and the second study compared post-vaccination SLE with the prevalence or SLE in the same community.²¹ The results pointed to an evidence of a link between SLE and the vaccine against the human papillomavirus. Moreover, one study form 32 arthritis (RA or other) cases and 3 controlled studies have found similar results.²² These observations were, however, not confirmed by subsequent analyses by Soybilgic et al.²³ showing quadrivalent HPV vaccine seems generally safe in this series of adolescents and young women with SLE, with no increase in mean SLEDAI(systemic lupus erythematosus disease activity index) scores. Moreover, they found that progression to renal failure in 2 patients is most likely secondary to pre-existing severe renal chronicity and not secondary to HPV vaccination.

Epstein–Barr Virus (EBV) Vaccination

Current data suggest that infection with chronic viral pathogens such as EBV is a consequence or a cause of the autoimmune disease. Vaccines that have a long duration of action and/or purified neutralizing antibodies specific for EBV have been developed and may in the future be available for chronic pathogens such as EBV. Vaccination of healthy EBV-seronegative young adults with recombinant gp350 have demonstrable efficacy in preventing the development of infectious mononucleosis induced by EBV infection.²⁴ Because EBV infection manifesting as infectious mononucleosis in adolescents and young adults is a risk factor for MS, vaccination with gp350 might decrease the incidence of MS by reducing the incidence of infectious mononucleosis.²⁵ In people who have already been infected with EBV and have subsequently developed RA, SLE or MS, vaccination for EBV might be beneficial in inhibiting disease progression.²⁶

Live Vaccines

Bacillus calmette-guerin (BCG)

Infections and/or immune-mediated reactions may occur after intravesical instillation of BCG for the treatment of bladder carcinoma.²⁷ An association between BCG with arthritis (i.e. RA, PsA, reactive arthritis etc.) was reported in 56 cases including 1 case of a flare-up of ankylosing spondylitis²⁸ with vasculitis in 7 case,²⁹ dermatomyositis in 3 cases,³⁰ lupus vulgaris in 20 cases.^31,32

Varicella zoster vaccine (VZV)

Varicella Zoster vaccine (VZV) is a relatively new vaccine indicated for elderly people or those at high risk of herpes zoster mainly for the prevention of post herpetic neuralgia.

To evaluate the immune response and tolerability of VZV in children and adolescents with SLE previously exposed to VZV, Barbosa et al. performed a prospective and controlled study on a group of 54 SLE patients that were chosen at random to be or not to be vaccinated (28 were vaccinated and 26 were not). Twenty-eight healthy controls, of matching age and sex were also vaccinated. The results have shown that the VZV was well tolerated in SLE group, who had pre-existing immunity to varicella. The VZV immunogenicity measurement by serum antibody titers was appropriate.³⁴ Similar results also confirmed by Pileggi et al. Twenty-five patients with juvenile rheumatic diseases (ages 2–19 years) and 18 healthy children and adolescents (ages 3–18 years) received a single dose of VV. All 25 patients were receiving methotrexate; 13 were also receiving prednisone and 5 were also receiving other disease-modifying antirheumatic drugs. They reported that VV appears to be safe in patients with juvenile rheumatic diseases receiving methotrexate, as long as continuous prospective vigilance for side effects is performed.³⁵

Measles mumps and rubella vaccines (MMR)

MMR carry a risk of joint symptoms particularly in children under 5 years. A boy who present with an inflamed knee after measles and mumps vaccination is reported; synovial fluid aspirated from the joint contained high levels of leucocytes.³⁶ In addition, wild rubella infection in adult populations is associated with a higher incidence, increased severity, and more prolonged duration of joint manifestations than is seen after RA 27/3 rubella immunization.^22,37 Thus, currently this vaccine is considered as contraindicated in states of immune suppression.

Hepatitis B Vaccine (HBVv)

To obtain an overview of rheumatic disorders occurring after HBVv, 22 patients were included in one study by Maillefert et al. Criteria for entry were rheumatic complaints of 1 week's duration or more, occurrence during the 2 months following hepatitis B vaccination, no previously diagnosed rheumatic disease and no other explanation for the complaints. Twenty-two patients were included. The observed disorders were as follows: RA for 6 patients; exacerbation of a previously non-diagnosed systemic lupus erythematosus for 2; post-vaccinal arthritis for 5; polyarthralgia-myalgia for 4; suspected or biopsy-proved vasculitis for 3; miscellaneous for 2. These data suggest that HBVv might be followed by various rheumatic conditions and might trigger the onset of underlying inflammatory or AIRDs. However, a causal relationship between hepatitis B vaccination and the observed rheumatic manifestations cannot be easily established.³⁸ Further epidemiological studies are needed. In addition, a case-control epidemiological study was conducted to evaluate serious autoimmune adverse events prospectively reported to the vaccine adverse events reporting system (VAERS) database following HBVv and the results supported an association of the vaccine with SLE.³⁹ By contrast, 2 studies compared the risk of RA following HBVv with RA controls or with the prevalence of RA in the same community, and the result shown that HBVv was not associated with an appreciable deterioration in any clinical or laboratory measure of disease.^40,41 The explanation for this difference is still unclear.

Post-vaccination Autoimmunity

Most patients with AIRDs may benefit from immunization. However, adverse events following vaccinations have been reported. The mechanisms of autoimmune phenomena after vaccination may be analogous to those following natural infections, so that biological plausibility may be based on factors that including: epitope spreading (the activation and expansion of T cells with additional specificities);⁴² molecular mimicry (peptides from microbial proteins that have sufficient structural similarity with self-peptides can activate autoreactive T cells);⁴³ bystander activation (expansion of previously activated T cells at an inflammatory site);⁴⁴ activation of superantigens (infectious particles may cross-link the T cell receptor and major histocompatibility complex molecule independent of specific antigen recognition);⁴⁵ direct inflammatory damage;⁴⁶ the vascular deposition of circulating immune-complexes (CIC) and complement.⁴⁷ However, patients with AIRDs are more prone to infectious complications during the course of their disease, causing significant morbidity and mortality. Some infections can be prevented by vaccination which used appropriately will decrease the burden of infection. Thus, it is important to determine if patients with AIRD have normal responses to vaccines. Indeed, the autoimmune disease itself may impair vaccine responses; other factors influencing the response include immunosuppressed drugs, advanced age, comorbid diseases, history of influenza vaccination and infection.⁴⁸ Treatment with MTX and higher age are predictive of an impaired antibody response to PCV7, as already suggested.¹² In addition, Mathian et al.⁴⁹ have assessed the factors influencing the efficacy of 2 injections of a pandemic 2009 H1N1 vaccine in patients with SLE, and they results shown that the efficacy of the vaccine is impaired in patients who are receiving immunosuppressive drugs or who have lymphopenia. A second injection increases vaccine immunogenicity without reaching all efficacy criteria for a pandemic vaccine in patients receiving an immunosuppressive agent. These results open possibilities for improving anti-influenza vaccination in SLE. Furthermore, other factors including antipyretic drugs may also influence the efficacy of vaccine in patients with autoimmune diseases. Prymula et al.⁵⁰ have demonstrated that prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended, because antibody responses to infant vaccines are reduced.

Biologics

Recently, the introduction of biologics has been a major achievement in treating autoimmune diseases, but an increased risk of infection associated with these therapies has become evident. Ideally, some infections can be prevented by vaccination. However, some biologics can influence the efficacy of vaccinations. Thus, it is important to summarize the knowledge about the effectiveness and safety vaccinations in patients with AIRD treated with biologics (Table 1).

Table 1. Vaccines and biologics

Diseases	Year	Vaccine	Biologic	Responses	Ref
RA	2007	influenza vaccine	Adalimumab	impaired	^51
RA	2007	influenza vaccine	InfliximabEtanercept	impaired	^52
RA; JIA; Still's disease; PsA; SpA; Crohn's disease	2008	influenza vaccine	InfliximabEtanerceptAdalimumab	impaired	^53
RA	2010	influenza vaccine	InfliximabEtanerceptAdalimumab	impaired	^54
RA; AS	2010	influenza vaccine	Infliximab	no impaired	^55
RA	2007	influenza vaccine	Infliximab	no impaired	^56
RA; AS; PsA	2012	influenza vaccine	InfliximabEtanerceptAdalimumab	impaired (Infliximab; Adalimumab)no impaired (Etanercept)	^57
RA; SpA	2013	HBV vaccinePPSV23	InfliximabEtanerceptAdalimumab	impaired	^58
RA	2008	PPSV23	Infliximab	no impaired	^60
RA	2008	influenza vaccine	RITUXIMAB	impaired	^61
RA	2010	influenza vaccine	RITUXIMAB	impaired	^62
RA; Sjogren's disease; SLE;	2013	influenza vaccine	RITUXIMAB	impaired	^63
RA	2010	PPSV23	RITUXIMAB	impaired	^64
RA	2012	influenza vaccine	TOCILIZUMAB	no impaired	^65
RA	2013	PPSV23	TOCILIZUMAB	no impaired	^66
RA	2013	influenza vaccinePPSV23	TOCILIZUMAB	no impaired	^67
RA	2013	Influenza vaccine	ABATACEPT	no impaired	^68

AS, ankylosing spondylitis; JIA, juvenile inflammatory arthritis; PPSV23, 23-valent pneumococcal polysaccharide vaccine; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SpA, spondyloarthropathy

Anti-tumor necrosis factor (TNF) agents

The effect of anti-TNF therapy on the antibody responses to influenza vaccinations is the subject of ongoing debate. A study showed that the antibody response to influenza vaccination in patients treated with anti-TNF is impaired, although the proportion of patients that achieves a protective titer is not significantly diminished by the use of TNF blocking therapies.^51-54 In contrast, other studies reported that influenza vaccine generates a good humoral response in RA patients treated with infliximab.^55-56 The differences may be due to the different types of anti-TNF agents, as demonstrated by fact that spondyloarthritis patients receiving infliximab or adalimumab have a significantly lower seroconversion rate compared with healthy controls or those on DMARDs, whereas no difference is observed for patients on etanercept.⁵⁷

A recent study has shown that TNF blockade profoundly suppresses the response to the T cell-dependent vaccination against HBV, whereas the T cell-independent response against pneumococcal polysaccharides is only modestly affected.⁵⁸ Consistent with this finding, TNF inhibitors do not significantly affect antibody responses to the pneumococcal vaccine in this cohort of patients with chronic arthritis.^58,59 In this regard, it is worth to noting that patients who are treated with the combination of methotrexate and anti-TNF demonstrated a significantly impaired immune response following pneumococcal polysaccharide vaccination as compared to patients treated with either methotrexate or anti-TNF only or immunosuppressives excluding these 2 compounds.⁶⁰ Further studies are required to comprehensively explore the features of vaccination induced by and conventional cimmunosuppressive and immunomodulating drugs, biologics and their combination in patients with autoimmune diseases.

Rituximab (RTX)

Poor serological responses upon influenza vaccination are observed in patients with RA treated with RTX. Gelinck et al.⁶¹ found that patients treated with RTX have lower postvaccination antibody titers and protection rates against influenza. Moreover, van Assen et al.⁶² reported that seroconversion and seroprotection occur less often in the RTX-treated vaccinated patients than in the MTX-treated controls. Additionally, they have shown that this defect would lose 6–10 months after RTX administration. Recently, a study reported that the ability to respond to the influenza vaccine appears to be related to the degree of B cell recovery at the time of vaccination. Specifically, patients with RA who have undetectable circulating B cells are much less likely to respond to influenza vaccine, while there are modest responses to the inactivated influenza vaccine among patients who had any level of detectable B cells.⁶³ Hence, vaccines can be administered during the use of disease-modifying antirheumatic drugs (DMARDs) and TNFα-blocking agents, but should ideally be administered before starting B-cell-depleting therapy.

Recall responses to the T cell-dependent protein antigen tetanus toxoid are preserved in RTX-treated RA patients 24 weeks after treatment. In addition, responses to neoantigen and T cell-independent responses to pneumococcal vaccine are decreased, but many patients are able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.⁶⁴

Tocilizumab (TCZ)

Current data suggest that TCZ, a humanized monoclonal anti-interleukin-6 receptor antibody, does not significantly attenuate humoral responses to influenza and pneumococcal vaccines. Mori et al. and Tsuru et al. have assessed the influence of TCZ on antibody response following influenza vaccination in patients with RA and castleman's disease (CD) and they results demonstrated that TCZ does not hamper antibody response to influenza and pneumococcal vaccines.^65,66 In addition, Mori et al. reported that MTX has a negative impact on vaccination immunogenicity, but adequate responses for protection are nevertheless demonstrated in patients treated with MTX. Interestingly, when TCZ is used as a combination therapy with MTX, antibody responses may be reduced.⁶⁷

Abatacept (ABA)

ABA is a soluble fusion protein that selectively modulates the CD80/CD86:CD28 co-stimulatory signaling required for full T cell activation. Ribeiro et al.⁶⁸ revealed that after influenza A/H1N1 vaccine, seroprotection is significantly reduced in RA-ABA patients compared to RA-MTX patients and controls. Lymphocyte counts are comparable in RA groups, but RA-ABA patients had slightly lower gammaglobulin levels than RA-MTX patients, although almost all are within the normal range values. In the cohort of patients with established RA, treatment with ABA is associated with diminished antibody responses following pneumococcal vaccination using PCV7.⁶⁹ Thus, it is likely that ABA can suppress the effectiveness of the immune response, but does not significantly inhibit the ability of healthy subjects and patients with RA to develop a clinically significant positive immune response to influenza and pneumococcal vaccines.

Future Considerations

Vaccination is an important tool for preventing infectious complications in patients with AIRD. This review summarizes the available evidence about the function of vaccination in patients with AIRD. Whether or not vaccination raises the incidence of autoimmune diseases, what is the impact of increasingly crowded vaccination schedules, the vaccination in age groups and the risk of coincidental temporal association are all issues still under debate. Thus, finally, we aim to provide personalized vaccination plans basis for clinical management of rheumatic patients depending upon prevaccination antibody titers, drug treatments and immunological potential, including (1) Most patients with AIIRD may benefit from immunization; however, vaccination status should be assessed in initial investigation of patients (2) live-attenuated vaccines should not be recommended to patients with AIIRD, especially in immunosuppressed patients (3) Among non-live vaccines, influenza and pneumococcal vaccination seem to be safe, even if specific immune response may be weakly reduced (4) Vaccinations should ideally be administered during stable disease (5) Vaccination can be administered during therapy with anti-TNF agents, TCZ and ABA but ideally should be given before B cell depleting biologicals are prescribed.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.