Role of vaccinations and prophylaxis in rheumatic diseases




Abstract


Targeted strategies for reducing the increased risk of infection in patients with autoimmune rheumatic diseases include vaccinations as well as antibiotic prophylaxis in selected patients. However, there are still issues under debate: Is vaccination in patients with rheumatic diseases immunogenic? Is it safe? What is the impact of immunosuppressive drugs on vaccine immunogenicity and safety? Does vaccination cause disease flares? In which cases is prophylaxis against Pneumocystis jirovecii required?


This review addresses these important questions to which clinicians and researchers still do not have definite answers. The first part includes immunization recommendations and reviews current data on vaccine efficacy and safety in patients with rheumatic diseases. The second part discusses prophylaxis for Pneumocystis pneumonia.


Introduction


Autoimmune rheumatic diseases (ARDs) are associated with an increased susceptibility to infections . Patients with rheumatoid arthritis (RA) have been shown to have up to twofold higher risk of being hospitalized for infection and higher mortality due to common infections compared with the general population . In several series, infection has been reported as the leading cause of mortality in systemic lupus erythematosus (SLE) patients and as a major cause of early death in patients with vasculitis . The excess mortality from infection along with the frequent occurrence of severe infections suggest that patients with ARDs may be predisposed to develop infections, or infections may run a more severe course in ARDs. The immune system dysfunction in ARDs has been attributed to several parameters such as the immune effects of the disease itself, the immunosuppressive effects of the agents used for ARD treatment, comorbidities, medical/surgical procedures, and frequent clinic visits . Over the years, several policies for reducing this increased risk of infection have been considered. There is little evidence to support that improving general health and nutrition can reduce infection rates. Judicious and careful use of immunosuppressive drugs is recommended; however, significant levels of immunosuppression are unavoidable in severe disease. More targeted strategies include antibiotic prophylaxis with specific antimicrobial agents – for example, co-trimoxazole in the prophylaxis of Pneumocystis jirovecii pneumonia, and, finally, immunizations.




Role of vaccinations in patients with ARDs


Given the increase in infection-related risks in ARD patients, immunizations are the principal preventive care options available to rheumatologists. However, despite the formulation of recommendations, vaccination coverage among ARD patients is lower than in the general population . Possible explanations include controversies about the efficiency and immunogenicity of vaccine administration in ARD patients and its potential hazardous effects on the exacerbation of the underlying disease, or on triggering new autoimmune disorders.


Inactivated vaccines


The majority of published data shows that the administration of inactivated vaccines to ARD patients under immunosuppressive therapy is safe and it is not associated with a higher risk of vaccine reactions, nor with a worsening or reactivation of the underlying disease. However, vaccine immunogenicity may be reduced during the use of corticosteroids, and non-biological and biological disease-modifying anti-rheumatic drugs (DMARDs). Vaccination should preferentially be administered before the initiation of immunosuppressive therapy and during stable disease. Specific inactivated vaccinations that are recommended for ARD patients are listed in Table 1 . Data from studies in ARD patients supporting the development of vaccination recommendations are elaborated in the following paragraphs.



Table 1

Inactivated vaccines that are recommended in ARD patients.









































Vaccine Recommendations
Influenza Adults: annual administration of the intramuscular attenuated vaccine
Pediatric patients: vaccination with the intramuscular attenuated vaccine should be considered
Pneumococcal Adults: PPSV23 vaccination with a booster dose after >5 years was recommended prior to PCV13 license for use in adults . PCV13 is recommended in updated recommendations. Patients who have previously received PPSV23 should be given a dose of PCV13 ≥ 1 years after the last PPSV23 dose was received
Pediatric patients: if anti-pneumococcal vaccination is not included in the national vaccination program, it should be administered to patients with low complement levels or functional asplenia. It can also be considered before treatment with high-dose immunosuppressive drugs or biological agents
HBV Adult patients: vaccination is recommended when the risk of infection is increased (health care personnel, persons with multiple sexual partners, men who have sex with men, drug abusers, travelers to endemic areas, patients on dialysis, with cirrhosis, or HIV) and protective antibodies are absent
Pediatric patients: adhere to national guidelines
HAV Vaccination is indicated for patients traveling into countries with high or intermediate prevalence rates
Tetanus Adult patients: follow recommendations for the general population
Pediatric patients: adhere to national guidelines
Meningococcal Adult patients: two doses of the tetravalent conjugate vaccine to patients with functional asplenia or deficiencies in the complement pathway
Pediatric patients: if anti-meningococcal vaccination is not included in the national vaccination program, it should be administered to patients with low complement levels or functional asplenia. It can also be considered before treatment with high-dose immunosuppressive drugs or biological agents
HPV Adult patients: vaccination of patients of appropriate age, starting or currently receiving synthetic DMARDs or biologic agents , especially women with SLE until the age of 25 years
Pediatric patients: vaccination according to national recommendations. SLE patients should be advised to be vaccinated in the adolescence

Abbreviations: PPSV: pneumococcal polysaccharide vaccination, PCV: pneumococcal conjugate vaccine.


Influenza vaccine


Epidemiology of influenza in ARDs


The morbidity and mortality due to influenza infection is increased in ARD patients; however, the incidence of influenza in ARD patients is unknown . In a cohort study assessing the risk of hospitalization or death associated with influenza among subgroups of elderly members of managed-care organizations, 4.5–7% of patients with ARDs (including vasculitis), dementia, or stroke who were not vaccinated for influenza were admitted for pneumonia/influenza or died, compared to 0.8% of unvaccinated healthy controls (HC) . In another large retrospective study, hospital admissions due to influenza or pneumonia were demonstrated to be significantly more frequent in elderly (aged over 65 years) patients with ARDs compared to age-matched controls .


Vaccine efficacy


The majority of studies have examined the immune response to vaccination as a substitute for vaccine efficacy. Clinical outcome end points have been addressed in limited studies. The available data demonstrate fewer influenza attacks and bacterial complications in vaccinated versus unvaccinated ARD patients . Consistent with the findings of studies in the general population, increased age has been associated with decreased immunological response to influenza vaccination in ARD patients . Vaccine response may also be dependent on disease-specific differences, as lower protection has been demonstrated in RA compared to spondylarthritis (SpA) and other ARD controls .


RA and juvenile idiopathic arthritis


The majority of studies have been conducted in RA patients. Most studies have demonstrated similar immunogenicity for RA patients compared to HC or patients with other ARDs. Nonetheless, RA patients receiving immunosuppressive drugs may be less protected than RA controls . Previous studies did not find an impaired vaccine response in RA patients on steroids and/or synthetic DMARDs . However, recent studies revealed that methotrexate (MTX) can reduce the immunogenicity of flu vaccination . The use of biologic DMARDs in RA has also been associated with impaired response to influenza vaccine . In most studies, tumor necrosis factor alpha (TNFα)-blocking treatment did not result in diminished humoral response, but different results suggesting a modestly impaired response in RA or SpA patients treated with anti-TNF agents have also been reported . Disease- and drug-specific differences may also apply, as immune response has been reported to be significantly lower for SpA patients treated with anti-TNF monoclonal antibodies . In patients treated with non-TNF biologics, influenza vaccine immunogenicity may be significantly impaired. Rituximab (RTX) has been shown to severely hamper the humoral response and cellular response to both seasonal and pandemic flu vaccination . A decreased response to influenza vaccination in RA patients treated with abatacept (ABA) has also been reported. On the contrary, tocilizumab (TCZ) has not been shown to blunt antibody response to influenza vaccine in RA patients .


Systemic lupus erythematosus


Several controlled studies have shown a similar or modestly lowered humoral response in SLE patients compared to HC or patients with other ARDs . A decrease in cellular immunity following influenza vaccination has also been reported . Lower response in SLE patients has been associated with high disease activity, hematological abnormalities, and lymphopenia . Reduced response was associated with immunosuppressive drugs, and/or steroids in many studies. However, in other studies, the use of immunosuppressive drugs did not affect the vaccination response .


Other ARDs


Controlled studies have showed similar protection rates after influenza vaccination between patients with dermatomyositis, systemic sclerosis, Wegener’s granulomatosis (WG), mixed connective tissue disease, and HC .


Booster vaccination


Two studies have addressed the effectiveness of booster influenza vaccination in ARDs. They both demonstrated that decreased response to influenza immunization can be corrected with a booster vaccine dose administered 3–4 weeks after the first dose . However, the value of a booster influenza vaccination may be limited to particular patients who were not vaccinated in the previous year .


Vaccine safety


No study has reported an increase in serious adverse events (AEs) in vaccinated ARD patients compared to unvaccinated ARD controls or vaccinated HC. Some uncontrolled studies and studies comparing ARD patients with HC demonstrated the possible causal role of influenza vaccine administration and disease flares in a minority of vaccinated patients. However, these studies did not include disease controls and, therefore, the flares may represent the natural course of ARDs and not be causally related to the vaccine . No difference in disease flares between vaccinated and unvaccinated ARD patients has been observed in controlled trials.


Pneumococcal vaccine


Streptococcus pneumoniae epidemiology in ARDs


Invasive infections with S. pneumoniae seem to be increased in ARD patients, although direct comparisons with the general population are lacking . In RA, mortality due to respiratory infections has been reported 5.3 times higher compared to what might be expected in the general population . It can be assumed that S. pneumoniae is the causative organism in a significant number of these patients, as, in general, >80% of community-acquired respiratory infections are due to pneumococci. Pneumococcal infection risk is higher among inflammatory arthritis patients treated with TNF inhibitors . Retrospective cohort studies in SLE reported invasive pneumococcal infection in up to 2.40% over long-term follow-up .


Vaccine efficacy


Clinical end points have been addressed in two studies, which both demonstrated that unvaccinated ARD patients, particularly those on steroids, are more likely to develop pneumococcal disease compared to vaccinated patients . As in the case of the influenza vaccine, most studies have evaluated pneumococcal vaccine efficacy by measuring the vaccine-induced humoral response. Higher age has been associated with impaired positive antibody response.


RA and juvenile idiopathic arthritis


In RA, both similar and lower responses to pneumococcal vaccination between patients on synthetic and biologic DMARDs have been reported . Many studies have reported a negative impact of MTX on the response to pneumococcal vaccination, either when used as monotherapy or in combination with anti-TNFα agents . On the contrary, TNFα inhibitors have not been demonstrated to reduce the efficacy of pneumococcal vaccination except for three studies, two in RA and one in SpA . As for other biologics, RTX has been shown to impair the humoral and cellular response to both pneumococcal polysaccharide and conjugate vaccine . Treatment with ABA may also impair antibody production following pneumococcal vaccination . On the contrary, TCZ treatment has not been linked to reduced efficacy of pneumococcal vaccination.


Systemic lupus erythematosus


Adequate as well as reduced responses after pneumococcal vaccination have been observed in different studies of SLE patients. In most studies, the immunological response was not affected by the use of steroids and/or other immunosuppressives .


Other ARDs


Pneumococcal vaccination has been demonstrated to significantly elevate antibody concentrations against all capsular serotypes measured, reaching adequate protective antibody levels in patients with systemic sclerosis and Sjögren’s syndrome .


Safety


No controlled studies comparing disease activity between vaccinated and unvaccinated RA patients have been performed. Data from uncontrolled studies do not show an increase in RA activity following pneumococcal vaccination. No disease exacerbations have been observed in controlled trials comparing vaccinated with unvaccinated patients with SLE or Sjögren’s syndrome .


Hepatitis B virus vaccine


Hepatitis B virus epidemiology


Data on the incidence of hepatitis B infection in patients with ARDs are lacking.


Vaccine efficacy in ARDs


The efficacy of hepatitis B virus (HBV) vaccination in ARDs has been examined in patients with RA, juvenile idiopathic arthritis (JIA), SLE, ankylosing spondylitis (AS), and Behçet disease (BD) . In the majority of cases, a satisfactory vaccination response was demonstrated, irrespective of the underlying disease. The effect of immunosuppressives on vaccine efficacy has been addressed by few studies, which found no impact of steroids or synthetic DMARDs . On the contrary, TNFα-blocking agents have been reported to severely hamper the response to HBV vaccine .


Vaccine safety


A potential association of HBV vaccination with autoimmune AEs has been described in several case reports. However, in a large retrospective cohort analysis, no statistically significant association between exposure to hepatitis B vaccine and onset of RA was found . As regards disease flares, HBV vaccination has not been associated with increased disease activity in vaccinated compared to unvaccinated ARD patients .


Hepatitis A virus vaccine


A single study addressing hepatitis A virus (HAV) vaccine effectiveness in ARD patients has been conducted, in which HAV vaccine proved safe and immunogenic in patients with JIA, except for children with active systemic JIA receiving anti-TNF agents where vaccine response was lower .


Tetanus vaccine


Tetanus toxoid vaccination has been demonstrated to be efficacious in patients with JIA, juvenile-onset systemic lupus erythematosus (JSLE), RA, or SLE . Antibody levels following vaccination are comparable to HC, even in patients using synthetic DMARDs . RTX has not been shown to impair positive response to vaccination . A diminished response to tetanus vaccination in SLE patients, possibly associated with increased SLE activity, has been reported . Additionally, it has been suggested that tetanus vaccination responses in ARDs may be initially similar to HC, but the persistence of specific antibody concentrations may be shorter . Titers of anti-tetanus antibodies are significantly lower in the elderly . The safety of tetanus–diphtheria vaccines has not been assessed.


Meningococcal vaccine


A single study evaluating the efficacy of meningococcal vaccine in ARDs has been conducted. Patients were able to mount protective anti-meningococcal immunoglobulin G (IgG) serum levels; however, those receiving highly immunosuppressive medications demonstrated lower meningococcal-specific antibody responses .


Human papillomavirus (HPV) vaccine


Human papillomavirus epidemiology in ARDs


The prevalence of abnormal Pap smears is significantly increased in SLE patients compared with non-SLE controls, as is the prevalence of high-grade squamous intraepithelial lesions (HSIL) of the cervix. Compared with controls, SLE patients are more commonly infected with at least one high-risk type of human papillomavirus (HPV) and have multiple HPV infections . In a recent meta-analysis, the pooled odds ratio for the risk of HSIL in SLE patients versus healthy female controls was 8.66 (95% CI: 3.75–20.00) . Unlike SLE, RA patients have not been identified as a disease population at an increased risk of developing cervical lesions due to HPV infection. However, a recent study showed a high prevalence of cervical HPV infection in Mexican women with RA .


Vaccine efficacy and safety


Three studies investigating the immunogenicity and safety of HPV vaccination in ARD patients have been conducted. All of these studies demonstrated that HPV vaccine is immunogenic and well tolerated in ARDs. However, HPV-specific geometric mean titers were consistently lower in patients compared with HC . No effect of immunosuppressive drugs on HPV antibody titers was detected . Vaccination did not induce an increase in disease activity or flares . An analysis of the quadrivalent vaccine AE reporting system database found high reporting of venous thromboembolic events (VTEs) following vaccination; thus, vigilance for potential VTEs is recommended .


Live vaccines


The administration of live vaccines to immunosuppressed patients bears the risk of replication of the attenuated microorganism and invasive infections. Live attenuated vaccines should therefore be avoided whenever possible in immunosuppressed ARD patients. Live vaccines with a low risk of replication (measles–mumps–rubella (MMR), varicella-zoster virus (VZV), and herpes-zoster virus (HZV) vaccines) might be exceptions to this rule and may be used with caution in mildly immunosuppressed patients with ARDs . For safety reasons, it is generally advisable to wait for a certain time period after cessation of an immunosuppressive agent before administrating a live vaccine. The duration depends on the half-life of the active drug component and the recovery from the immunological effect . As for pediatric patients with ARDs, it is recommended to adhere to national vaccination guidelines unless patients are on high-dose synthetic DMARDs, high-dose steroids, or biologic DMARDs . Recommendations for specific live vaccines in ARD patients are listed in Table 2 .



Table 2

Recommendations for specific live vaccines in ARD patients.

















Vaccine Recommendation
VZV–HZV Adult patients:


  • If previously exposed to VZV, patients should be vaccinated, preferably before the initiation of synthetic or biologic DMARDs.



  • Vaccination may be considered during treatment with short-term or low to moderate doses of steroid therapy (<14 days, or <20 mg/day of prednisone or equivalent), or MTX <0.4 mg/kg/week, or azathioprine <3 mg/kg/day.



  • Vaccination during treatment with biologic DMARDs is not recommended .

Pediatric patients:


  • Vaccination, ideally before initiation of immunosuppressive therapy, in cases with a negative history for VZV infection or vaccination.



  • Booster vaccination can be considered in patients on MTX <15 mg/m 2 /week or low-dose steroids .

BCG Adult patients:


  • Vaccination may be considered for previously unvaccinated, tuberculin-negative travelers depending on the destination of travel, as well as for persons exposed to M. tuberculosis due to their professional activities.



  • BCG should not be administered before appropriate time following discontinuation of immunosuppressive drugs has elapsed .

Pediatric patients living in endemic areas should be vaccinated prior to starting immunosuppressive therapy .


VZV and HZV vaccines


Epidemiology of VZV in ARDs


The incidence of chickenpox among ARD patients is unknown. Regarding shingles, RA per se is a risk factor for HZV. Additional risk factors include the use of steroids, and/or sDMARDs, and/or anti-TNF monoclonal antibodies. Contrariwise, MTX and etanercept do not seem to increase the risk of HZV . The hazard ratio for HZV infection in SLE was estimated to be 1.7 (95% CI 1.08–2.71) in a large prospective cohort. Increasing age and reduced functional status were independent predictors of HZV, while prednisone and immunosuppressant use conferred additional risk .


Vaccine efficacy and safety


Following vaccination against VZV, the difference in clinical effectiveness, response rates, and safety profile between ARD patients and HC has not been demonstrated to be significant. Additionally, no worsening of disease activity parameters has been detected after vaccination . In small studies evaluating HZV vaccination in adult patients with ARDs, receipt of HZV vaccine was not associated with herpetiform lesions . Furthermore, vaccine recipients had lower HZV incidence during follow-up .


MMR vaccine


All studies regarding MMR vaccination in ARDs have been conducted in juvenile ARD patients. MMR booster has demonstrated good immunogenicity, irrespective of steroids and/or other immunosuppressive drug use, including biologic DMARDs. However, in a large retrospective cross-sectional study that compared MMR-specific antibody concentrations between patients with JIA and HC, patients had lower antibody concentrations and seroprotection rates against mumps and rubella, but not measles . Regarding safety, MMR booster vaccination has not been shown to worsen disease activity .


Bacillus Calmette–Guérin vaccination


The risk of mycobacterial infection is highly dependent on the prevalence of tuberculosis (Tb) in a specific geographic area. In ARD patients, the risk increases when using steroids, synthetic DMARDs, especially MTX and leflunomide, and/or biologic DMARDs, especially TNF inhibitors. However, Tb cases in ADRs have been drastically decreased after implementation of Tb screening and prophylaxis guidelines before anti-TNF treatment initiation. Later trials of newer biologics have followed these guidelines or excluded patients with evidence of previous Tb exposure and hence reported much lower Tb incidence rates. Bacillus Calmette–Guérin (BCG) vaccination during childhood is included in the national vaccination programs of countries where Tb is endemic. In adults, the majority of Tb cases are associated with reactivation of a latent Tb infection, which cannot be prevented by vaccination. Furthermore, the efficacy of BCG in adults is questionable, even in healthy TB-naïve persons.




Role of vaccinations in patients with ARDs


Given the increase in infection-related risks in ARD patients, immunizations are the principal preventive care options available to rheumatologists. However, despite the formulation of recommendations, vaccination coverage among ARD patients is lower than in the general population . Possible explanations include controversies about the efficiency and immunogenicity of vaccine administration in ARD patients and its potential hazardous effects on the exacerbation of the underlying disease, or on triggering new autoimmune disorders.


Inactivated vaccines


The majority of published data shows that the administration of inactivated vaccines to ARD patients under immunosuppressive therapy is safe and it is not associated with a higher risk of vaccine reactions, nor with a worsening or reactivation of the underlying disease. However, vaccine immunogenicity may be reduced during the use of corticosteroids, and non-biological and biological disease-modifying anti-rheumatic drugs (DMARDs). Vaccination should preferentially be administered before the initiation of immunosuppressive therapy and during stable disease. Specific inactivated vaccinations that are recommended for ARD patients are listed in Table 1 . Data from studies in ARD patients supporting the development of vaccination recommendations are elaborated in the following paragraphs.



Table 1

Inactivated vaccines that are recommended in ARD patients.









































Vaccine Recommendations
Influenza Adults: annual administration of the intramuscular attenuated vaccine
Pediatric patients: vaccination with the intramuscular attenuated vaccine should be considered
Pneumococcal Adults: PPSV23 vaccination with a booster dose after >5 years was recommended prior to PCV13 license for use in adults . PCV13 is recommended in updated recommendations. Patients who have previously received PPSV23 should be given a dose of PCV13 ≥ 1 years after the last PPSV23 dose was received
Pediatric patients: if anti-pneumococcal vaccination is not included in the national vaccination program, it should be administered to patients with low complement levels or functional asplenia. It can also be considered before treatment with high-dose immunosuppressive drugs or biological agents
HBV Adult patients: vaccination is recommended when the risk of infection is increased (health care personnel, persons with multiple sexual partners, men who have sex with men, drug abusers, travelers to endemic areas, patients on dialysis, with cirrhosis, or HIV) and protective antibodies are absent
Pediatric patients: adhere to national guidelines
HAV Vaccination is indicated for patients traveling into countries with high or intermediate prevalence rates
Tetanus Adult patients: follow recommendations for the general population
Pediatric patients: adhere to national guidelines
Meningococcal Adult patients: two doses of the tetravalent conjugate vaccine to patients with functional asplenia or deficiencies in the complement pathway
Pediatric patients: if anti-meningococcal vaccination is not included in the national vaccination program, it should be administered to patients with low complement levels or functional asplenia. It can also be considered before treatment with high-dose immunosuppressive drugs or biological agents
HPV Adult patients: vaccination of patients of appropriate age, starting or currently receiving synthetic DMARDs or biologic agents , especially women with SLE until the age of 25 years
Pediatric patients: vaccination according to national recommendations. SLE patients should be advised to be vaccinated in the adolescence

Abbreviations: PPSV: pneumococcal polysaccharide vaccination, PCV: pneumococcal conjugate vaccine.


Influenza vaccine


Epidemiology of influenza in ARDs


The morbidity and mortality due to influenza infection is increased in ARD patients; however, the incidence of influenza in ARD patients is unknown . In a cohort study assessing the risk of hospitalization or death associated with influenza among subgroups of elderly members of managed-care organizations, 4.5–7% of patients with ARDs (including vasculitis), dementia, or stroke who were not vaccinated for influenza were admitted for pneumonia/influenza or died, compared to 0.8% of unvaccinated healthy controls (HC) . In another large retrospective study, hospital admissions due to influenza or pneumonia were demonstrated to be significantly more frequent in elderly (aged over 65 years) patients with ARDs compared to age-matched controls .


Vaccine efficacy


The majority of studies have examined the immune response to vaccination as a substitute for vaccine efficacy. Clinical outcome end points have been addressed in limited studies. The available data demonstrate fewer influenza attacks and bacterial complications in vaccinated versus unvaccinated ARD patients . Consistent with the findings of studies in the general population, increased age has been associated with decreased immunological response to influenza vaccination in ARD patients . Vaccine response may also be dependent on disease-specific differences, as lower protection has been demonstrated in RA compared to spondylarthritis (SpA) and other ARD controls .


RA and juvenile idiopathic arthritis


The majority of studies have been conducted in RA patients. Most studies have demonstrated similar immunogenicity for RA patients compared to HC or patients with other ARDs. Nonetheless, RA patients receiving immunosuppressive drugs may be less protected than RA controls . Previous studies did not find an impaired vaccine response in RA patients on steroids and/or synthetic DMARDs . However, recent studies revealed that methotrexate (MTX) can reduce the immunogenicity of flu vaccination . The use of biologic DMARDs in RA has also been associated with impaired response to influenza vaccine . In most studies, tumor necrosis factor alpha (TNFα)-blocking treatment did not result in diminished humoral response, but different results suggesting a modestly impaired response in RA or SpA patients treated with anti-TNF agents have also been reported . Disease- and drug-specific differences may also apply, as immune response has been reported to be significantly lower for SpA patients treated with anti-TNF monoclonal antibodies . In patients treated with non-TNF biologics, influenza vaccine immunogenicity may be significantly impaired. Rituximab (RTX) has been shown to severely hamper the humoral response and cellular response to both seasonal and pandemic flu vaccination . A decreased response to influenza vaccination in RA patients treated with abatacept (ABA) has also been reported. On the contrary, tocilizumab (TCZ) has not been shown to blunt antibody response to influenza vaccine in RA patients .


Systemic lupus erythematosus


Several controlled studies have shown a similar or modestly lowered humoral response in SLE patients compared to HC or patients with other ARDs . A decrease in cellular immunity following influenza vaccination has also been reported . Lower response in SLE patients has been associated with high disease activity, hematological abnormalities, and lymphopenia . Reduced response was associated with immunosuppressive drugs, and/or steroids in many studies. However, in other studies, the use of immunosuppressive drugs did not affect the vaccination response .


Other ARDs


Controlled studies have showed similar protection rates after influenza vaccination between patients with dermatomyositis, systemic sclerosis, Wegener’s granulomatosis (WG), mixed connective tissue disease, and HC .


Booster vaccination


Two studies have addressed the effectiveness of booster influenza vaccination in ARDs. They both demonstrated that decreased response to influenza immunization can be corrected with a booster vaccine dose administered 3–4 weeks after the first dose . However, the value of a booster influenza vaccination may be limited to particular patients who were not vaccinated in the previous year .


Vaccine safety


No study has reported an increase in serious adverse events (AEs) in vaccinated ARD patients compared to unvaccinated ARD controls or vaccinated HC. Some uncontrolled studies and studies comparing ARD patients with HC demonstrated the possible causal role of influenza vaccine administration and disease flares in a minority of vaccinated patients. However, these studies did not include disease controls and, therefore, the flares may represent the natural course of ARDs and not be causally related to the vaccine . No difference in disease flares between vaccinated and unvaccinated ARD patients has been observed in controlled trials.


Pneumococcal vaccine


Streptococcus pneumoniae epidemiology in ARDs


Invasive infections with S. pneumoniae seem to be increased in ARD patients, although direct comparisons with the general population are lacking . In RA, mortality due to respiratory infections has been reported 5.3 times higher compared to what might be expected in the general population . It can be assumed that S. pneumoniae is the causative organism in a significant number of these patients, as, in general, >80% of community-acquired respiratory infections are due to pneumococci. Pneumococcal infection risk is higher among inflammatory arthritis patients treated with TNF inhibitors . Retrospective cohort studies in SLE reported invasive pneumococcal infection in up to 2.40% over long-term follow-up .


Vaccine efficacy


Clinical end points have been addressed in two studies, which both demonstrated that unvaccinated ARD patients, particularly those on steroids, are more likely to develop pneumococcal disease compared to vaccinated patients . As in the case of the influenza vaccine, most studies have evaluated pneumococcal vaccine efficacy by measuring the vaccine-induced humoral response. Higher age has been associated with impaired positive antibody response.


RA and juvenile idiopathic arthritis


In RA, both similar and lower responses to pneumococcal vaccination between patients on synthetic and biologic DMARDs have been reported . Many studies have reported a negative impact of MTX on the response to pneumococcal vaccination, either when used as monotherapy or in combination with anti-TNFα agents . On the contrary, TNFα inhibitors have not been demonstrated to reduce the efficacy of pneumococcal vaccination except for three studies, two in RA and one in SpA . As for other biologics, RTX has been shown to impair the humoral and cellular response to both pneumococcal polysaccharide and conjugate vaccine . Treatment with ABA may also impair antibody production following pneumococcal vaccination . On the contrary, TCZ treatment has not been linked to reduced efficacy of pneumococcal vaccination.


Systemic lupus erythematosus


Adequate as well as reduced responses after pneumococcal vaccination have been observed in different studies of SLE patients. In most studies, the immunological response was not affected by the use of steroids and/or other immunosuppressives .


Other ARDs


Pneumococcal vaccination has been demonstrated to significantly elevate antibody concentrations against all capsular serotypes measured, reaching adequate protective antibody levels in patients with systemic sclerosis and Sjögren’s syndrome .


Safety


No controlled studies comparing disease activity between vaccinated and unvaccinated RA patients have been performed. Data from uncontrolled studies do not show an increase in RA activity following pneumococcal vaccination. No disease exacerbations have been observed in controlled trials comparing vaccinated with unvaccinated patients with SLE or Sjögren’s syndrome .


Hepatitis B virus vaccine


Hepatitis B virus epidemiology


Data on the incidence of hepatitis B infection in patients with ARDs are lacking.


Vaccine efficacy in ARDs


The efficacy of hepatitis B virus (HBV) vaccination in ARDs has been examined in patients with RA, juvenile idiopathic arthritis (JIA), SLE, ankylosing spondylitis (AS), and Behçet disease (BD) . In the majority of cases, a satisfactory vaccination response was demonstrated, irrespective of the underlying disease. The effect of immunosuppressives on vaccine efficacy has been addressed by few studies, which found no impact of steroids or synthetic DMARDs . On the contrary, TNFα-blocking agents have been reported to severely hamper the response to HBV vaccine .


Vaccine safety


A potential association of HBV vaccination with autoimmune AEs has been described in several case reports. However, in a large retrospective cohort analysis, no statistically significant association between exposure to hepatitis B vaccine and onset of RA was found . As regards disease flares, HBV vaccination has not been associated with increased disease activity in vaccinated compared to unvaccinated ARD patients .


Hepatitis A virus vaccine


A single study addressing hepatitis A virus (HAV) vaccine effectiveness in ARD patients has been conducted, in which HAV vaccine proved safe and immunogenic in patients with JIA, except for children with active systemic JIA receiving anti-TNF agents where vaccine response was lower .


Tetanus vaccine


Tetanus toxoid vaccination has been demonstrated to be efficacious in patients with JIA, juvenile-onset systemic lupus erythematosus (JSLE), RA, or SLE . Antibody levels following vaccination are comparable to HC, even in patients using synthetic DMARDs . RTX has not been shown to impair positive response to vaccination . A diminished response to tetanus vaccination in SLE patients, possibly associated with increased SLE activity, has been reported . Additionally, it has been suggested that tetanus vaccination responses in ARDs may be initially similar to HC, but the persistence of specific antibody concentrations may be shorter . Titers of anti-tetanus antibodies are significantly lower in the elderly . The safety of tetanus–diphtheria vaccines has not been assessed.


Meningococcal vaccine


A single study evaluating the efficacy of meningococcal vaccine in ARDs has been conducted. Patients were able to mount protective anti-meningococcal immunoglobulin G (IgG) serum levels; however, those receiving highly immunosuppressive medications demonstrated lower meningococcal-specific antibody responses .


Human papillomavirus (HPV) vaccine


Human papillomavirus epidemiology in ARDs


The prevalence of abnormal Pap smears is significantly increased in SLE patients compared with non-SLE controls, as is the prevalence of high-grade squamous intraepithelial lesions (HSIL) of the cervix. Compared with controls, SLE patients are more commonly infected with at least one high-risk type of human papillomavirus (HPV) and have multiple HPV infections . In a recent meta-analysis, the pooled odds ratio for the risk of HSIL in SLE patients versus healthy female controls was 8.66 (95% CI: 3.75–20.00) . Unlike SLE, RA patients have not been identified as a disease population at an increased risk of developing cervical lesions due to HPV infection. However, a recent study showed a high prevalence of cervical HPV infection in Mexican women with RA .


Vaccine efficacy and safety


Three studies investigating the immunogenicity and safety of HPV vaccination in ARD patients have been conducted. All of these studies demonstrated that HPV vaccine is immunogenic and well tolerated in ARDs. However, HPV-specific geometric mean titers were consistently lower in patients compared with HC . No effect of immunosuppressive drugs on HPV antibody titers was detected . Vaccination did not induce an increase in disease activity or flares . An analysis of the quadrivalent vaccine AE reporting system database found high reporting of venous thromboembolic events (VTEs) following vaccination; thus, vigilance for potential VTEs is recommended .


Live vaccines


The administration of live vaccines to immunosuppressed patients bears the risk of replication of the attenuated microorganism and invasive infections. Live attenuated vaccines should therefore be avoided whenever possible in immunosuppressed ARD patients. Live vaccines with a low risk of replication (measles–mumps–rubella (MMR), varicella-zoster virus (VZV), and herpes-zoster virus (HZV) vaccines) might be exceptions to this rule and may be used with caution in mildly immunosuppressed patients with ARDs . For safety reasons, it is generally advisable to wait for a certain time period after cessation of an immunosuppressive agent before administrating a live vaccine. The duration depends on the half-life of the active drug component and the recovery from the immunological effect . As for pediatric patients with ARDs, it is recommended to adhere to national vaccination guidelines unless patients are on high-dose synthetic DMARDs, high-dose steroids, or biologic DMARDs . Recommendations for specific live vaccines in ARD patients are listed in Table 2 .


Nov 10, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Role of vaccinations and prophylaxis in rheumatic diseases

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