Abstract
Immunization represents the most efficient and simplest intervention to prevent certain viral and bacterial infections in the general population as well as in the vulnerable population of patients with inflammatory rheumatic diseases treated with immunosuppressives. Here, we present an updated review of literature data regarding the safety and efficacy of immunizations against different pathogens in rheumatic patients treated with conventional immunosuppressives or the newer biologic agents while at the same time we provide practical guidance for the appropriate vaccine administration in this patient population.
Introduction
Infections remain one of the most common co-morbidities in patients with inflammatory rheumatic diseases regardless of the use of immunosuppressive therapies. Although most of the infections in these patients are mild, serious infections leading to hospitalization can occur and are usually due to common bacterial or viral pathogens that could be prevented by appropriate prophylactic vaccination. The efficacy and safety of vaccinations in patients with inflammatory rheumatic diseases has been the focus of many studies over the last two decades.
Here, we review the literature concerning the risk of various vaccine-preventable infections in patients with inflammatory rheumatic diseases as well as the efficacy and safety of vaccination in these patient populations. The effect of corticosteroids, conventional synthetic (cs-) and biologic (b-) disease modifying anti-rheumatic drugs (DMARDs) in vaccine efficacy is also discussed in detail.
Infection risk in patients with inflammatory rheumatic diseases
There is much data available regarding the risk of contracting serious infections in patients having inflammatory rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic vasculitides. RA patients have been found to carry a 2-fold higher risk for hospitalized infections than the general population , whereas in a recent RA cohort, 40% received at least one course of antibiotics during the previous year . The respective relative risk for hospitalized infections in patients with SLE has steadily increased over the last 20 years, exceeding 12-fold in 2011 . Similar findings have been reported in systemic vasculitides . A recent study showed that almost a quarter of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV) developed a serious infection, with a 4-fold increase in mortality rate during a 3-year follow-up period . Moreover, giant cell arteritis (GCA) patients carry a 2-fold increased risk for severe infections during the first year after diagnosis, with infections accounting for a third of all deaths .
Infection risk in patients with inflammatory rheumatic diseases
There is much data available regarding the risk of contracting serious infections in patients having inflammatory rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic vasculitides. RA patients have been found to carry a 2-fold higher risk for hospitalized infections than the general population , whereas in a recent RA cohort, 40% received at least one course of antibiotics during the previous year . The respective relative risk for hospitalized infections in patients with SLE has steadily increased over the last 20 years, exceeding 12-fold in 2011 . Similar findings have been reported in systemic vasculitides . A recent study showed that almost a quarter of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV) developed a serious infection, with a 4-fold increase in mortality rate during a 3-year follow-up period . Moreover, giant cell arteritis (GCA) patients carry a 2-fold increased risk for severe infections during the first year after diagnosis, with infections accounting for a third of all deaths .
Vaccination rates and reasons for non-vaccination in rheumatic patients
Despite the overwhelming literature and respective guidelines from various scientific organizations supporting immunizations in rheumatic patients , several studies have indicated that the vaccine coverage remains suboptimal in this patient population.
In a recent multicenter, international, cross-sectional study of RA patients (COMOrbidities in Rheumatoid Arthritis-COMORA), the vaccine coverage against influenza and Streptococcus pneumoniae was found to be only 25% and 17%, respectively . Multivariate analysis revealed that age, low disease activity, higher educational level, treatment with biologics, non-treatment with corticosteroids, and the presence of co-morbidities were independent factors that determined vaccine administration . In a study of similar design (Assessment in SpondyloArthritis International Society ASAS-COMOSPA study) for patients with spondyloarthropathies (SpA), the rates for influenza and pneumococcal vaccination were 38% and 17%, respectively .
One study showed that even in countries with acceptable vaccination coverage, such as the UK, although 80% of RA patients had been administered influenza vaccine during their lifetime, only one-third of the patients received regular annual immunization (35%) . In another recent UK study, the high influenza vaccine uptake in patients with RA was confirmed, although the respective rate for pneumococcal vaccination was only 44% . Vaccinated patients had a 79% higher probability of suffering from a comorbidity and a 69% probability of being treated with biologics.
Several studies have explored the main reasons for non-adherence to recommended vaccination schedules in rheumatic patients. In a French study of 137 patients with different rheumatic diseases, the absence of recommendation by the treating physician was the leading reason for non-vaccination against influenza (58%), followed by the fear of adverse events (35%) . Similar findings were reported by Hua et al. in a cohort of RA and SpA patients, where 79% of non-vaccinated patients against pneumococcus and 48%–61% against influenza never received such recommendation by their treating physician .
These findings indicate that the proper training of rheumatologists and general practitioners is a legitimate target for vaccination campaigns. This has been the focus of recent studies conducted in children and adults, which showed that simple strategies can increase vaccination rates in both adults and children with rheumatic diseases. In a study of 3717 rheumatic patients (66% with RA) by Desai et al., a simple intervention (point of care reminder form) applied to patients not up-to-date with pneumococcal vaccination increased vaccination rates from 67.6% to 80% in 1 year . Vaccination rates did not change in the non-intervention group (52.3%–52%). Factors associated with vaccination included the described intervention, diabetes, age 56–65 years, and care from a rheumatologist with <10 years in practice .
Similarly, Harris et al. studied the impact of various interventions such as presentations to rheumatologists, creation of vaccination algorithms, pre-visit planning, and hard-copy and electronic reminders to providers on pneumococcal vaccination coverage in a cohort of 299 pediatric rheumatic patients . They reported that conjugate vaccine coverage increased from 6.7% to 48.4% and polysaccharide vaccine coverage from 8.9% to 28.4%, whereas coverage for both vaccines increased from 0% to 23.2% 1 year after the intervention period .
Vaccine efficacy in patients with inflammatory rheumatic diseases
Pneumococcal vaccine
Patients with rheumatic diseases are at high-risk for respiratory infections and increased mortality related to these infections . S. pneumoniae is the most commonly isolated pathogen in lower respiratory tract infections , whereas invasive pneumococcal disease continues to have an unfavorable prognosis. Appropriate pneumococcal vaccination has been shown to protect against pneumococcal infections both in the general population and in rheumatic patients .
Two types of pneumococcal vaccines are currently available, a polysaccharide and a conjugate. The 23-valent pneumococcal polysaccharide vaccine (PPSV23) induces the production of specific antibodies from B lymphocytes through a T cell independent pathway, whereas the 13-valent pneumococcal conjugate vaccine (PCV13) induces humoral responses with the help of antigen-specific CD4 T lymphocytes as well as by the production of antigen-specific memory cells .
In a recent study from the Netherlands that included almost 85,000 adults above 65 years, PCV13 reduced the incidence of invasive pneumococcal disease and pneumococcal pneumonia by 75% and 46%, respectively . Sequential administration of both vaccines to achieve the highest immunogenic effect is currently recommended .
Factors associated with reduced vaccine efficacy in rheumatic patients include advanced age, longer disease duration, the disease itself, and the use of immunosuppressive or immunomodulatory therapies . More specifically, the effect of the different anti-rheumatic therapies is analyzed below (see also Table 1 ).
| Vaccines | |||||||
|---|---|---|---|---|---|---|---|
| Pneumococcal | Influenza | Hepatitis B | Hepatitis A | HPV | Herpes zoster | Meningococcal | |
| Corticosteroids | ↔ <10 mg/d (RA) (JIA) ↓ ≥10 mg/d | ↔ <10 mg/d ↓ (SLE) | ↔ <10 mg/d | ↔ | ↔ 10 mg/d (SLE) | ↔ (SLE) | N/A |
| csDMARDs | ↓ (RA) ↓ (PsA) ↔ (RA, SLE) | ↓ ↔ ↔ (GPA) | ↔ | ↔ ↓ | ↔ (JIA) ↔ (SLE) ↓ (SLE) | ↔ (SLE) | ↔ (JIA) ↔ (AAV) |
| Anti-TNF | ↔ (RA) ↔ (PsA) ↔ (JIA) | ↔ ↓ | ↓ | ↓ | ↔ | N/A | ↔ (JIA) |
| Rituximab | ↓ | ↓ | N/A | N/A | N/A | N/A | N/A |
| Abatacept | ↓ ↔ | ↓ ↔ | N/A | N/A | N/A | N/A | N/A |
| Tocilizumab | ↔ | ↔ | N/A | N/A | N/A | N/A | N/A |
| Secukinumab | N/A | ↔ (healthy subjects) | N/A | N/A | N/A | N/A | ↔ (healthy subjects) |
| Tofacitinib | ↓ | ↔ | N/A | N/A | N/A | N/A | N/A |
Corticosteroids
Corticosteroids in the doses usually prescribed in RA (<10 mg prednisolone daily) do not have any negative impact on specific immune response after pneumococcal vaccination . On the contrary, Patients with systemic autoimmune diseases, and especially those with vasculitis, treated with higher doses of corticosteroids (≥10 mg/day) showed lower immune response rates as well as more rapid decline in specific antibody titers at 12 months post-vaccination .
Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs)
In RA patients treated with csDMARDs, methotrexate (MTX), in particular, humoral immune responses were decreased by 64% after vaccination with polysaccharide or conjugate vaccines (see also Table 1 ). Another study evaluated the immunogenicity of PPSV23 in patients with RA and only 21% of those treated with MTX responded in ≥6 of 12 serotypes tested .
On the contrary, in a study by Elkayam et al., a low vaccination response was seen in csDMARDs-treated RA and SLE patients (33% and 20%, respectively), independent of the MTX dose . A recent study compared PPSV23 immunogenicity in SLE patients treated with mycophenolate mofetil (MMF), cyclophosphamide (CYC), or azathioprine (AZA) vs. untreated SLE patients (both groups were being treated with ≤5 mg prednisolone daily) . Similarly, a low vaccination response was noted regardless of csDMARD treatment (25%–36% vs. 35%–42%, respectively) .
Collectively, these data indicate an attenuated response to pneumococcal vaccination in rheumatic patients during csDMARD (mainly MTX) treatment, emphasizing the need for pre-treatment vaccination to all newly diagnosed rheumatic patients.
Biologics
Anti–tumor necrosis factor agents (anti-TNFs)
In RA patients treated with anti-TNF monotherapy, the immunogenicity of PPSV23 or PCV is not affected . When infliximab or etanercept was added to MTX in RA patients, this did not result in attenuation of the immune responses . Anti-TNF treated RA patients mounted similar immune responses after vaccination with PPSV23 or PCV . In a study of patients with PsA (psoriatic arthritis), etanercept administrated as monotherapy or in combination with MTX did not have any negative impact on PPSV23 immunogenicity. In contrast, MTX-treated patients had a 2-fold and those ≥47 years a 50% higher risk for non-response . PCV efficacy has been confirmed in pediatric patients with juvenile idiopathic arthritis (JIA) who were treated with csDMARD monotherapy or csDMARD and anti-TNF combined therapy. In both groups, protective titers were observed in >85% of patients .
Altogether, these data and a recent meta-analysis show no effect of anti-TNFs in pneumococcal vaccine efficacy in rheumatic patients ( Table 1 ).
Rituximab
RA patients treated with B cell depleting agents such as rituximab (RTX) have impaired humoral response after vaccination with PPSV, and patients vaccinated 6 months after RTX had worse outcomes than those vaccinated 6 days before . Repeated treatment cycles and prior anti-TNF treatment did not attenuate immunogenicity further. Similar findings were reported in a study, where RTX-treated patients had worse immune response after PCV compared to healthy controls and MTX-treated patients . None of the patients treated with RTX–MTX combination had a positive immune response, whereas only 10% of those receiving RTX as monotherapy were considered responders. In this study, no difference was observed between patients vaccinated ≤180 days and >180 days after RTX administration. In another study that compared the PPSV immunogenicity in the same groups of patients (RTX+MTX vs. MTX), 57% of patients in the combination group achieved 2-fold titer increase in at least 1 serotype tested. The respective proportion in the MTX group was 82% .
Given the above findings as well as similar studies from patients with hematologic diseases , it appears that RTX treatment has a significant negative impact on immunogenicity of pneumococcal vaccines ( Table 1 ). Therefore, vaccines are recommended to be administered at least 4 weeks before RTX initiation .
Abatacept
Regarding the T cell co-stimulatory inhibitor abatacept (ABA), a study of healthy adults (mean age: 34 years) that received a single intravenous dose of the drug showed that immune response after PPSV vaccination was reduced by 22–69% and 24%–68% vaccinated 2 and 4 weeks after ABA administration, respectively . RA patients treated with ABA monotherapy or MTX/ABA combination had a worse response compared to controls and patients treated with MTX monotherapy after PPSV, although no difference in opsonophagocytic antibody capacity was noted . Attenuated immune response was reported in RA patients treated with ABA/MTX combination after the administration of the conjugate vaccine .
On the contrary, a recent study showed that 83.9% of RA patients treated with the subcutaneous form of ABA and DMARDs could mount protective antibody levels after PPSV23 vaccination .
These conflicting results indicate that more data are needed regarding the effect of ABA on pneumococcal vaccine efficacy.
Tocilizumab
There are few studies evaluating the effect of the anti–Interleukin (IL)-6 receptor monoclonal antibody tocilizumab (TCZ) on pneumococcal vaccine immunogenicity. In a randomized trial that compared TCZ/MTX combination to MTX alone in RA patients, a smaller proportion of patients in the combination arm responded to PPSV23 compared to the monotherapy arm (60% vs. 71%), but this difference was not statistically significant . PPSV immunogenicity was also evaluated in a study by Mori et al., where TCZ-treated RA patients had better immune responses than those treated with MTX or TCZ/MTX combination . Kapetanovic et al. showed that PCV vaccination induced a positive immune response in 50% of RA patients treated with TCZ (similar to controls), whereas in patients treated with RTX, ABA, or MTX, the response did not exceed 20% .
The available data thus far do not indicate a negative effect of TCZ on pneumococcal vaccine efficacy ( Table 1 ).
Tofacitinib
In two recent studies in RA patients, tofacitinib treatment (with or without MTX) had a negative effect on PPSV23 immunogenicity .
Belimumab
Data from the BLISS-76 study showed that belimumab initiation in SLE patients did not affect the titers of specific antibodies against S. pneumoniae , influenza, and tetanus in comparison with those treated with a placebo .
Summary of evidence
Low-dose corticosteroid (<10 mg/day), anti-TNF, TCZ, and belimumab treatment do not appear to affect pneumococcal vaccine efficacy in rheumatic patients, while MTX, RTX, and tofacitinib have a negative effect. More data are needed for evaluating ABA and the newer biologics (anti–IL-17: secukinumab, anti–IL12/23: ustekinumab etc.).
Recommendations – guidelines
Regardless of its efficacy, pneumococcal vaccination is recommended for every rheumatic patient, preferably before scheduled or during chronic immunosuppressive therapy, regardless of their age. Current recommended schemes include both pneumococcal vaccines (PCV13 and PPSV23) . PCV13 is administered once, while up to 3 doses of PPSV23 may be offered, depending on the patient’s age (two doses, 5 years apart, before 65 years and one dose after 65 years). In vaccination-naïve patients, PCV13 should precede PPSV23 administration by 8 weeks. In patients already vaccinated with PPSV23, PCV13 should be given at least 12 months later.
Influenza vaccine
Influenza infection is one of the most common respiratory infections in the general population and is accompanied by significant morbidity and mortality, especially in high-risk groups. Influenza vaccination is an effective preventive measure and it is estimated to prevent ∼60% of influenza cases in adults . As mentioned above, rheumatic patients are at an increased risk for respiratory tract infections. In a large cohort of RA patients (n = 46,030), the influenza infection and complication risk was 1.2 and 1.8 times higher, respectively, compared to a matched healthy population . The difference was more pronounced in patients 60–69 years old. In another study of RA patients, 6% reported influenza-like illness during the epidemic period. High body mass index (BMI), absence of remission, and history of lung diseases were independent risk factors for influenza infection .
As mentioned earlier, although influenza vaccination rate is suboptimal in rheumatic patients , recent real-life data indicate a clear clinical benefit in rheumatic patients . In a recent analysis of many RA patients (n = 15,152) treated with ADA for ∼10 years, the rate of influenza-related adverse events was estimated in a sub-cohort of 553 patients . Influenza-related adverse events were much less common in vaccinated (5%) than in non-vaccinated (14%) patients.
Recent high-quality data indicate that a high-dose inactivated influenza vaccine was safer and more efficacious in adults >65 years compared to the standard-dose vaccine . Similar studies in rheumatic patients have not been performed thus far.
Although influenza vaccine is the most widely studied vaccine in patients with rheumatic diseases in terms of immunogenicity and safety, available studies report variable results ( Table 1 ). This lack of consensus may be due to heterogeneity stemming from different types of vaccines (seasonal or pandemic, adjuvant or non-adjuvant), differences in residual immunity against specific viral strains from past epidemic seasons, mismatch between the circulating strains and those included in the vaccine, or variations in sample size, sample homogeneity, or outcome definition.
Corticosteroids
Most studies using low-dose corticosteroids (<10 mg/day) in rheumatic patients with RA, SpA, or GPA (granulomatosis with polyangiitis) showed no effect on the influenza vaccine efficacy, same as the pneumococcal vaccine ( Table 1 ). In contrast, a recent meta-analysis in SLE patients showed an attenuated response in corticosteroid-treated SLE patients compared to healthy controls, although no detailed data regarding the effect of different corticosteroid doses was provided . In a small study, a dose >10 mg/day was associated with decreased responses in this patient population .
Conventional synthetic DMARDs
Regarding csDMARDs, data are conflicting with some studies showing an attenuated and others an intact response ( Table 1 ). In a Swiss study of 173 patients with various rheumatic diseases, the patients needed two doses of pandemic influenza vaccine to mount the immune response same as that mounted by healthy controls after one dose. A negative impact on immunogenicity was seen on treatment with csDMARDs and immunosuppressants, but not with antimalarials, corticosteroids, or sulfasalazine . Similarly, RA patients treated with MTX had a 49% lower chance for seroprotection after pandemic influenza vaccine administration . In a randomized phase-4 trial of certolizumab pegol (CZP), MTX use was associated with attenuated immune response in both CZP and placebo arms (CZP: 70% vs. 46%, placebo: 85% vs. 51%) . A negative effect of MTX on antibody responses and specific B cell production was also reported by Kobie et al. .
Regarding other rheumatic diseases, a recent meta-analysis of several studies in SLE patients showed a decreased influenza vaccine response in patients receiving AZA or other immunosuppressives, but not with antimalarials . In a study evaluating the cell-mediated immune response of SLE patients after vaccination against the trivalent seasonal vaccine, AZA and corticosteroid use was associated with lower numbers of Interferon (IFN)-γ+ T cells, as well as lower frequencies of CD4+IL-2+ and CD4+TNF+ T cells compared to controls . Disease activity was not found to have any impact on immune response to pandemic A(H1N1)pdm09 strain .
Adler et al. reported that patients with systemic vasculitides had the lowest seroprotection rates in comparison with SpA, connective tissue diseases, or RA . The role of treatment in immunogenicity of influenza vaccination in patients with AAV has not been clarified, with some studies associating the number of immunosuppressants with impaired humoral responses , while others reported no correlation between AZA and antibody titers . Similar cell-mediated responses, in terms of antigen-specific CD4 and CD8 T cells and their cytokine expression, were found between patients with GPA and healthy controls .
Taken together, these data indicate that csDMARDs appear to have no or a mild negative effect on influenza vaccine immunogenicity.
Biologics
Anti-TNFs
Contradictory results have been also reported for anti-TNFs on influenza vaccine immunogenicity. Most studies showed no effect , while others report decreased vaccine efficacy in rheumatic patients ( Table 1 ).
França et al. reported that SpA, but not RA, patients treated with anti-TNFs had lower immune response after influenza vaccination than healthy controls and csDMARDs-treated patients . This effect was notable only for the monoclonal antibodies infliximab and adalimumab, but not for the soluble TNF receptor etanercept. Kobie et al. reported a 30%–65% reduction in influenza mean antibody titers and influenza-specific B cells in anti-TNF–treated RA patients, compared to healthy controls and RA patients off-treatment . In a study of 64 patients treated with anti-TNF for various indications (RA: 81%), the authors concluded that TNF inhibition resulted in lower antibody titers, but without lowering protection rates .
Furthermore, in most studies, no negative impact of anti-TNFs on influenza seasonal or pandemic vaccine immunogenicity was noticed. In a randomized phase-4 trial, the immune response was similar between adalimumab and placebo-treated groups (73% vs. 74%, respectively) . Kapetanovic et al. reported higher rates of immune response to pandemic influenza vaccine in anti-TNF–treated than MTX-treated RA and SpA patients (53% vs. 42%) . Milanetti et al. evaluated the immunogenicity of adjuvant pandemic and non-adjuvant seasonal influenza vaccines in RA patients treated with biologic DMARDs (bDMARDs). Comparable protective antibody titers were observed between patients treated with anti-TNFs and healthy controls . Elkayam et al. studied the relationship between seasonal vaccine immunogenicity and the timing of vaccine administration in RA and ankylosing spondylitis (AS) patients treated with infliximab . The rates of responders did not differ between those vaccinated at the time of infusion or 3 weeks later. Only RA patients in whom infliximab was administered 3 weeks before vaccination were shown to have impaired response in 2 out of 3 strains . In an earlier study, Gelinck et al. showed that anti-TNF–treated RA patients with moderate disease activity had similar responses to all three strains of seasonal vaccine when compared to healthy controls . Moreover, in a recent meta-analysis of 5 studies of anti-TNF–treated RA patients, Hua et al. did not observe any significant influence of anti-TNFs on immune response after influenza vaccination .
Overall, these findings suggest no or minimal effect of anti-TNFs in influenza vaccine protection in rheumatic patients.
Rituximab
Few studies have shown similar vaccine immunogenicity between RTX and csDMARD-treated RA patients . Oren et al. evaluated the impact of RTX on immunogenicity of the trivalent seasonal influenza vaccine and found a similar humoral response in 2 out of 3 strains between RTX- and csDMARD-treated RA patients , whereas a study from Israel showed that RTX-treated RA patients mounted similar counts of influenza-specific CD4 T cells to those taking csDMARDs, despite the significantly impaired antibody response .
Most studies though have indicated an attenuated response ( Table 1 ). In a study by Eisenberg et al., only 17% of RTX-treated patients achieved a 4-fold increase in antibody titers compared to 67% in controls . All non-responders in the RTX group were B cell depleted . In a study from Netherlands, humoral immune response was severely impaired in RA patients treated with RTX compared with MTX-treated patients or healthy controls . Seroconversion occurred in 3/23 (13%) of RTX patients, all of whom were vaccinated at least 6 months after RTX infusion. Six out of twenty-three (26%) of RTX patients achieved seroprotective antibody levels post-vaccination, with most of them (5/6) belonging to the late RTX group . Despite the small number of patients included in the RTX group (n = 8), Adler et al. reported that RTX-treated patients showed the worst immune responses among several conventional or biologic treatments, with only 25% them achieving seroprotection and seroconversion . Similar findings were also reported by other investigators .
Several studies have evaluated the role of timing of RTX administration in immune response following influenza vaccination. Arad et al. reported higher antibody titers in patients vaccinated ≥5 months after the last RTX infusion than in those that received the vaccine earlier . In another study, RTX-treated patients vaccinated <12 weeks after RTX infusion had 10 times lower antibody titers than those vaccinated >24 weeks post-RTX administration . Partial recovery of immune response over time was also reported by Westra et al., with patients vaccinated 6–10 months after RTX having higher influenza-specific IgG titers than those vaccinated 4–8 weeks after drug administration . In a smaller study, repeated RTX cycles or prior anti-TNF use did not further affect antibody production. When humoral immune response between those vaccinated 6 days before and 6 months after RTX initiation was compared, lower antibody titers were observed in the latter group, 3 weeks post-vaccination .
Despite the heterogeneity in vaccination responses due to the timing of influenza vaccine and RTX administration, most studies reported decreased post-vaccination antibody titers in RTX-treated patients.
Abatacept
Few studies have evaluated the role of ABA in influenza vaccine immunogenicity. Recently, Alten et al. studied 191 RA patients treated with ABA . A total of 82% of the participants developed protective antibody titers in ≥2 strains of the trivalent influenza vaccine . In the subgroup of patients with non-protective levels at baseline, 61% mounted a 4-fold increase and protective titers in ≥2 strains. MTX and corticosteroid use were not associated with attenuated response. Furthermore, patients <55 years had 2.4–3 times greater chance for achieving adequate immune responses. A major drawback of this study was the absence of a control group .
In a study from Brazil, ABA-treated RA patients had lower rates of seroprotection, seroconversion, and increase in antibody titers after the administration of monovalent pandemic influenza vaccine compared to MTX-treated patients and healthy controls . Treatment duration and interval from the last ABA infusion did not affect immunogenicity. Finally, in a group of 20 patients treated with ABA and vaccinated against the pandemic strain, 45% achieved seroprotective titers and 35% seroprotection after 3 weeks. The respective rates for anti-TNF were 91% and 83%, and for MTX 50% for both outcomes. Only RTX-treated patients showed worse immune responses (25% for both seroprotection and seroconversion) .
Despite the limited body of evidence, it seems that ABA-treated patients show attenuated responses following influenza vaccination.
Tocilizumab
There are only 2 studies that have assessed the impact of TCZ on influenza vaccine immunogenicity. Mori et al. reported higher antibody titers and seroprotection levels after vaccination in TCZ-treated RA patients than in those receiving MTX or MTX/TCZ combination . Similarly, Tsuru et al. did not notice any difference in immune responses after vaccination between patients treated with TCZ and those treated with MTX monotherapy or a combination of MTX and anti-TNF .
According to these studies, TCZ seems to have no effect on the immunogenicity of influenza vaccine.
Belimumab
Data from the randomized BLISS-76 trial showed that in SLE patients vaccinated before belimumab initiation, influenza-specific antibody titers did not decrease after 52 weeks of treatment . In patients who were vaccinated while on treatment, those in the belimumab arm had lower antibody responses than those in the placebo arm .
Secukinumab (anti–IL-17)
IL-17 has been shown to have a pivotal role in the differentiation of B cells to plasma cells and the subsequent clearance of influenza virus from the lung tissue . To date, the only available data are derived from a study of 50 healthy volunteers who had received secukinumab and influenza vaccine . 80% of participants mounted a 4-fold increase in influenza antibody titers 2 weeks after vaccination, which was similar to those that received one 150-mg dose of secukinumab and those given placebo .
Tofacitinib
The effect of tofacitinib, a Janus kinase (JAK) inhibitor approved for RA in many countries worldwide, on influenza vaccine immunogenicity has been studied in the context of a well-designed randomized controlled trial . Patients treated with tofacitinib monotherapy had similar rates of “satisfactory” (≥4-fold titer increase against ≥2 of 3 influenza antigens) response to those in the placebo group (57% vs. 62%). The combination of MTX and tofacitinib was associated with decreased seroprotection rates (65%) compared to MTX (93%) and tofacitinib (91%) monotherapy. Vaccination after temporary discontinuation of tofacitinib was not associated with better immune responses compared with continuous treatment .
Summary of evidence
In rheumatic patients, low-dose corticosteroids (<10 mg/day), anti-TNFs, csDMARDs (mainly MTX), TCZ, belimumab, and tofacitinib appear to have no or a minimal effect on influenza vaccine immunogenicity, whereas high-dose steroids (especially in SLE patients), ABA, and RTX impair respective immune responses. More data are needed for the newer biologics like secukinumab.
Recommendations – guidelines
We recommend yearly vaccination against influenza of all rheumatic patients treated with corticosteroids, cs- or bDMARDs with the inactivated vaccine. Vaccination should be offered ideally before the beginning of the epidemic period while a booster dose during this period is not currently supported. Preferably patients should be vaccinated before treatment initiation. For patients on treatment, no interruption in treatment is recommended. Specifically, for patients treated with RTX, the vaccine should be administered (if feasible) at least 4 weeks prior to the forthcoming or at least 6 months after the last cycle.
Hepatitis B vaccine
Several studies have indicated the potentially severe course of hepatitis B virus (HBV) reactivation in rheumatic patients receiving immunosuppressive therapies . This risk is apparent in patients with chronic HBV infection (HBsAg+) and to a much lesser degree in those with past/resolved infection (HBsAg−/anti-HBc+) . Vaccination is the most effective preventive measure for acute or chronic infection after virus exposure. The available recombinant vaccine against HBV shows excellent efficacy both in younger (≤40 years: >90%) and older (>60 years: 75%) individuals .
Corticosteroids – csDMARDs
Most studies in rheumatic patients treated with low-dose corticosteroids or csDMARDs showed no effect of therapy on HBV vaccine immunogenicity. Elkayam et al. showed that 68% of RA patients treated with corticosteroids (mean daily dose 7.5 mg) and csDMARDs (MTX: 77%, AZA: 9%) achieved protective anti-HBs titers . Similarly, in SLE patients, vaccination led to protective titers in 80%–93% compared to 100% in healthy controls. Treatment with corticosteroids or AZA did not affect immune response .
Biologics
Data for bDMARDs are scarce. A well-designed study showed that anti-TNF treatment had a negative impact on anti-HBs antibody production through suppression of germinal center reaction in patients with AS . To date, there are no data regarding the effect of non–anti-TNF bDMARDs (ABA, TCZ, and RTX) on HBV vaccine immunogenicity.
Is there a need for booster HBV vaccination in patients with low anti-HBs titers after vaccination?
The duration of protective anti-HBs levels after vaccination or natural infection in patients receiving immunosuppressive therapies remains uncertain. Treatment with MTX or anti-TNFs has been shown to correlate with a slight decrease (approximately 10%) in anti-HBs titers, although only 5% of patients had a decrease below the protective cut-off value (10 mIU/mL) . A similar decrease has been described in patients treated with non–anti-TNF bDMARDs (RTX, ABA, and TCZ) . The clinical significance of these findings is unknown. Decrease of anti-HBs titers below the protective threshold of 10 mIU/mL in the general population is not interpreted as loss of protective immunity, and therefore, booster vaccination is not recommended . Furthermore, a booster dose is recommended in heavily immunosuppressed patients (on hemodialysis, with HIV infection, on chemotherapy, or undergone bone transplantation), who continue to be at risk for HBV infection and in whom anti-HBs titers fall to <10 mIU/mL . Similar guidelines or recommendations for patients with rheumatic diseases on cs- or bDMARDs are not currently available.
Summary of evidence
Although compared to the pneumococcal and influenza vaccine, the available data for vaccine immunogenicity in biologic-treated rheumatic patients are limited for the HBV vaccine, corticosteroids and csDMARDs do not appear to affect its efficacy.
Recommendations – guidelines
We recommend that HBV vaccine should be administered in all unvaccinated or non–HBV-exposed (anti-HBc-/anti-HBs-) patients with rheumatic diseases and HBV exposure risk factors, preferably prior to the initiation of immunosuppressive treatment . Patients with end-stage renal disease should be vaccinated with double-dose regimens. There is insufficient data to support serial measurement of anti-HBs titers or administration of booster vaccination in rheumatic patients.
Human papilloma virus vaccine
Human papilloma virus (HPV) infection is one of the most common sexually transmitted diseases worldwide. Amongst the different HPV genotypes, HPV 16 and 18 strains are responsible for almost all cervical neoplasias, whereas HPV 6 and 11 for genital warts. Regarding rheumatic patients, a study by Kim et al. showed a 50% increased risk for high-grade cervical dysplasia and cervical cancer among RA and SLE patients . In another recent study from Sweden, RA patients had 39%–53% higher risk for low- and high-grade cervical dysplasia, while the risk for cervical cancer was not increased . Interestingly, the authors showed a statistically significant higher risk for high-grade dysplasia and cervical cancer in patients treated with anti-TNFs .
Until recently, available HPV vaccines included non-infectious recombinant, virus-like particle (VLP) bivalent, and a quadrivalent one, while a 9-valent vaccine of the same structure was also recommended by Centers for Disease Control (CDC) Advisory Committee on Immunization Practices (ACIP) recently . Data have shown that the quadrivalent vaccine reduces HPV 6/11/16/18 infection and genital warts by approximately 90%, low-grade cytological cervical abnormalities by 45%, and high-grade histologically proven cervical abnormalities by 85% . Despite these findings, vaccine uptake seems to be suboptimal in both the general population and in patients with inflammatory diseases . A study showed that among females aged 9–26 years, the rate of vaccination with ≥1 dose was 20.6% and 23.1% in those with and without a systemic inflammatory disease, respectively . Furthermore, of those vaccinated with at least one dose of HPV vaccine in the above-mentioned groups, only 53% and 51% completed the 3-dose schedule, respectively .
Regarding HPV vaccine safety in terms of autoimmune adverse events, a population-based study from Denmark and Sweden of almost 300,000 vaccinated girls aged 10–17 years concluded that vaccine administration was not associated with 20 of the 23 predefined autoimmune outcomes . Additionally, in the remaining three (Behcet’s syndrome, Raynaud’s disease, and type 1 diabetes), strength of the correlation was weak and the temporal association between vaccine administration and outcomes random. Similarly, neurological and venous thromboembolic adverse events were also not significantly associated with the vaccine use. Taken together, these data provide a reassuring body of evidence regarding HPV vaccine safety.
Corticosteroids – csDMARDs
A study evaluating the immunogenicity of the bivalent vaccine showed that all JIA patients and healthy controls became seropositive 7 months after the first dose. Specific antibody concentrations were lower in the JIA group, but this finding was not statistically significant. The study of HPV-specific memory B cells in a subset of patients revealed similar kinetics, but lower numbers in patients with JIA . In another study with the quadrivalent variant, Mok et al. demonstrated seroconversion in 74%–92% of SLE patients compared to 93%–98% in healthy controls. Treatment regimens were not found to affect seroconversion, except for MMF administered together with low-dose corticosteroids . Safety and immunogenicity of the quadrivalent vaccine was also studied by Soybilgic et al. in a cohort of 27 female SLE patients 12–26 years old, all of whom were treated with hydroxychloroquine, 59.2% with prednisone, 33% with MMF, 33% with AZA, and 22% with MTX . Seropositivity was observed in 94%–100% of participants after vaccine administration, depending on genotype.
Summary of evidence
Available data for young women with JIA and SLE indicate that the HPV vaccine is efficacious and safe, regardless of concomitantly administered corticosteroids or csDMARDs. There are no detailed data for the effect of bDMARDs in this patient population.
Recommendations – guidelines
Vaccination against HPV should be strongly encouraged and offered in young girls and women with rheumatic diseases, according to the indications already existing for the general population and regardless of the underlying treatment, as recently proposed by the American College of Rheumatology (ACR) .
Herpes zoster vaccine
Herpes zoster is a common infection caused by the reactivation of latent varicella zoster virus (VZV), with an annual incidence of 1% in persons ≥60 years . Zoster can be accompanied by a number of complications with post-herpetic neuralgia being the one with the highest morbidity and effect on quality of life . A recent study by Calabrese et al. showed an increased risk for stroke after zoster infection in patients with inflammatory diseases (the majority of them with RA), especially during the first 3 months after infection and if not promptly treated with antivirals .
The role of cell-mediated immunity in the prevention of viral reactivation has been strongly established . Patients with rheumatic diseases are at increased risk for herpes zoster. SLE or GPA patients, especially when treated with cyclophosphamide, have been found to carry an up to 20 times higher risk. Furthermore, in SLE, the majority of infections occur in patients with low disease activity or remission . Similarly, high incidence of zoster was described in patients with PsA , whereas RA patients experience a 2-fold increased risk in comparison with the general population . In this former group of patients, corticosteroid use, treatment with cs- or bDMARDs, disease severity, and comorbidities are all risk factors for herpes zoster .
A live attenuated vaccine has been shown to reduce the risk for herpes zoster by approximately 50% and for post-herpetic neuralgia by 67% in people ≥60 years . Vaccine efficacy wanes over time and the respective rates are 21% and 35%, 7–10 years after vaccination .
Currently this live vaccine is indicated for the general population for people over the age of 60 (US, Australia, and Canada) although other countries have established lower (>50 years: Sweden) or higher (>70 years: UK) cut-offs. For immunosuppressed patients, high-dose corticosteroids (≥20 mg/day x > 2 weeks) and bDMARDs (anti-TNFs) are contraindications to vaccination . The vaccine is indicated regardless of a history of prior herpes zoster.
Corticosteroids – DMARDs
Nevertheless, the available data for patients with rheumatic diseases are rather reassuring ( Table 1 ). In a large retrospective study of 463,541 patients with RA, PsA, AS or inflammatory bowel diseases, vaccine administration (n = 18,683) led to a 40% decrease in herpes zoster incidence . Vaccination was also efficient and safe (no case of herpes zoster within 6 weeks after vaccination) in patients treated either with usual doses of corticosteroids, cs-, or bDMARDs. More specifically, 633 patients were vaccinated while on bDMARD therapies (anti-TNF = 551, ABA/RTX = 82) .
Furthermore, in a small pilot study of 10 SLE patients ≥50 years who were in remission, zoster vaccine was found to elicit satisfactory cell-mediated immune responses without any cases of herpes zoster .
Summary of evidence
Although limited, the available data indicate that this live vaccine is safe in patients treated with the usual doses of corticosteroids or csDMARDs. Although bDMARDs (mainly anti-TNFs) in one study appeared to be safe too, more data are needed regarding the vaccines’ safety in this patient population.
Recommendations – guidelines
The ACR conditionally recommended the zoster vaccine for all RA patients ≥50 years who are scheduled to start or are already receiving csDMARDs and prior to the initiation of bDMARDs (>2 weeks) . Similarly, the Swiss Federal Commission for Vaccination Issues recommends zoster vaccine to patients with rheumatic diseases over the age of 50 treated with low-dose csDMARDs or corticosteroids (prednisolone <10 mg daily) , whereas the British Society of Rheumatology (BSR) recommended that csDMARDs such as MTX or AZA, and low-dose corticosteroids (prednisolone ≤10 mg daily) are not a contraindication to the zoster vaccine, but it should be offered only to patients over the age of 70 years . All available guidelines agree that the vaccine is currently contraindicated for patients receiving bDMARDs. In general, for patients receiving high-dose corticosteroids and biologics, the vaccine can be administered 1 month after drug discontinuation .
Concerns regarding the reduced immunogenicity of the zoster vaccine when it is co-administered with the PPSV23 pneumococcal vaccine are not supported , and therefore, the CDC recommends concomitant administration when both vaccines are indicated .
Meningococcal vaccine
Currently available meningococcal vaccines include polysaccharide and conjugate against serogroups A, C, W, and Y and the recently licensed recombinant vaccine against serogroup B.
Corticosteroids – DMARDs
Regarding vaccine immunogenicity, investigators from the Netherlands studied the efficacy and safety of the meningococcal conjugate vaccine against serogroup C in patients with JIA ( Table 1 ). The vaccine mounted antibody titers above the pre-specified threshold for high responders in the majority (97%) of patients. Adequate responses were noticed even in the subgroup of patients treated with high-dose MTX or anti-TNFs . During the long-term follow-up of this cohort, mean anti-MenC titers decreased and were similar with controls after 4.2 years.
Initiation of anti-TNF, but not MTX, therapy induced a more rapid decline in specific antibody titers . Morgan et al. reported an adequate response in 92 patients with systemic vasculitides (predominantly AAV) in remission . Only few of them (9/92) were receiving bDMARDs (RTX) at the time of vaccination.
There is a paucity of data on the newer biologic agents and immunogenicity of meningococcal vaccines. With regard to the anti–IL-17A monoclonal antibody secukinumab, a study including healthy volunteers showed similar rates of ≥4-fold increase and protective levels in anti-MenC antibody titer between subjects treated with a single 150 mg dose of secukinumab and those not treated .
Summary of evidence
Overall, it appears that immunosuppressives, both non-biological and biological, have no or minimal effect on meningococcal vaccine immunogenicity in rheumatic patients.
Recommendations – guidelines
There is no difference in the indications for vaccination against Neisseria meningitidis between patients with rheumatic diseases and the general population. Therefore, adult patients with complement deficiencies, anatomic or functional asplenia, microbiologists routinely exposed to N. meningitidis isolates, travelers to “meningitis belt” of sub-Saharan Africa, or pilgrims to Mecca during the annual Hajj should be vaccinated as recommended. Patients also treated with eculizumab, a monoclonal antibody that targets complement protein C5 and inhibits the formation of membrane-attack complex C5b-C9, are considered complement deficient and at increased risk for N. meningitidis infections, and thus, they should be vaccinated against all available serogroups .
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Vasculitis and inflammatory arthritis
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