When treating rheumatoid arthritis be vigilant for influenza (& pneumonia): Don’t ignore, don’t neglect

This is a world of microbes1. Our relationships with them are complex and unpredictable. The immune system needs to constantly wage a war to survive. The microbes constantly evolve to evade and escape. Their fury is often borne by patients with compromised immune systems. Rheumatoid arthritis (RA) is a prime example. Severe infections and coronary artery disease are leading causes of premature mortality in RA2. Respiratory tract is a prime target, and influenza viruses and pneumococci are leading microbes34. Anti-rheumatoid medications such as disease modifying anti-rheumatoid drugs (DMARDs) such as methotrexate (MTX), steroids and biological agents such as infliximab and rituximab add to the risk of infection. MTX is pivotal in the management of RA.

In several parts of the world including India, influenza epidemics are an annual affair and require astute vigilance for timely and effective vaccination5. Several evidence-based guidelines recommend that RA patients should be vigorously protected and vaccinated against influenza and pneumococcal infections678. The recommendations have been further strengthened in view of increased use of the highly targeted, powerful biologicals in RA.

The study by Jain et al9 published in this issue is a rejoinder for the clinicians to seriously consider appropriate immunization in RA patients specifically to influenza. A single dose of inactivated seasonal trivalent [subtype A (two strains - H1N1, H3N2) and B (Yamagata strain)] influenza vaccine was administered to all participants in a three-arm open-label study; two arms were RA patients (51 each) and one arm was healthy control (45 individuals). Patients were either early RA and naive for DMARD use (DMARD naïve) or chronic RA on long-term MTX (≥15 mg weekly). None had a prior history of influenza immunization. Immediately prior and four-week post-vaccination, blood samples were analyzed to evaluate immune response (rise in antibody titre) and seroprotection (≥40 units antibody titre). Based on the study data, the authors made three important conclusions - influenza vaccination was safe, MTX use did not dampen the post-vaccination immune response and that there was a need (in view of high pre-vaccination status) to review the recommendation for an annual influenza vaccination. The DMARD naive subjects were younger with more active disease and higher frequency of steroid use, and these characteristics are likely to have influenced the immune responses to vaccine. However, there was no further follow up to evaluate long-term efficacy and safety.

The world experience with influenza vaccine confirms its safety5. However, it ought to be repeatedly evaluated due to frequent change in the viral antigen characteristics. Post-2009 pandemic, HINI strain is invariably included in the trivalent vaccine10. Only killed inactivated intramuscular influenza vaccine is advocated for the use in RA. Although vaccination has been implicated as a non-specific trigger for a reactive form of autoimmune arthritis11, it is well known that the risk of disease flare or relapse in RA is much higher with infection rather than vaccination.

The literature does not seem to agree with the conclusion of Jain et al9 regarding the effect of MTX on influenza vaccination uptake in RA. The authors based their study sample size on an American study which demonstrated that the antibody titre for influenza H1N1 in the DMARD (MTX)-treated patients was almost one-third of the titre in healthy subjects and about half of the titre reported in RA naive subjects for DMARD/MTX12. Surprisingly, >70 per cent of individuals at baseline (pre-vaccination) showed a seroprotective titre to influenza antigens except for Yamagata strain (26%) in healthy controls9. Tandale et al13 demonstrated seroprotection titre (influenza) in 26.4 per cent H1N1 and 55.3 per cent H3N2 antigen in the regional Indian population. A seroprotection rate of 33 per cent (17-41%) was considered as herd immunity threshold for the Caucasian population14. Thus, the basal immune response (herd immunity) to influenza antigens in the current study is indeed high and reassuring.

Post-vaccination, the seroprotection response increased and was reported to be 94-100 per cent for all the three influenza antigens in RA patients despite MTX exposure; duration of MTX exposure was not described by the authors9. The proportionate increase was much more in the DMARD naive groups as compared to MTX use (H1N1: 39 vs. 24%; H3N2: 27 vs. 14%; Yamagata: 15 vs. 25%). The lower degree of post-vaccination seroprotection for Yamagata B strain in healthy individuals (84.4%) as compared to RA patients (94.1% DMARD naive and 100% MTX use) is difficult to understand. It is likely that the MTX effect in the current Indian study was somehow negated by the high degree of pre-vaccination antibody titre. However, negative influence of MTX on influenza vaccine uptake cannot be totally dismissed in this study9.

Though it is difficult to precisely measure seroprotection, the geometric mean titre for influenza antigens in the MTX group was lower than that of the DMARD naive group and healthy controls following vaccination. Very little data exist to endorse the safe cut-off titre for each of the three influenza antigens that confer maximum protection to RA patients. A general consensus in the world literature suggests that RA patients treated with MTX and/or anti-tumour necrosis factor (TNF) therapy achieve a satisfactory humoral response but is certainly lower than that demonstrated in healthy population1215. MTX decreases humoral response to pneumococcal vaccination16. The immune response to both vaccines is reduced with rituximab, abatacept, but sulphasalazine, anti-TNF inhibitors and tocilizumab do not seem to have a negative effect on vaccine immunogenicity1617.

A recent well-designed randomized study evaluated the effect of tofacitinib (TNB) (JAK inhibitor) on the success of 2011-2012 trivalent influenza and 23-valent pneumococcal polysaccharide (PPSV-23) vaccination in RA patients18. Patients were also stratified for concomitant MTX use. Primary endpoints of vaccination success were predefined and depended on increased antibody titre to two or more of the three influenza antigens and six or more of 12 pneumococcal serotypes. In TNB naive patients, the immune response to both influenza and pneumococci vaccine was much less compared to healthy controls. Intriguingly, the immune response to both the vaccinations was much better in patients on long-term management with TNB as compared to mono- or combination therapy with MTX. The negative effect of MTX on antibody titre was more pronounced in case of pneumococcal vaccine. Amongst the influenza antigens, the lowest response was shown for B antigen. Responses to the H1N1 and H3N2 vaccine components were more robust. The authors concluded that to maximize PPSV-23 responsiveness, clinicians should vaccinate before TNB or MTX treatment. However, in case of influenza, vaccination could be undertaken yearly (as recommended) regardless of TNB and or MTX therapy18. Live attenuated pneumococcal polysaccharide vaccine 23 is considered to be less immunogenic than the inactivated protein conjugate form. Several but not all studies have shown that MTX reduces immune response to pneumococcal vaccine1920.

Do we need to address the questions of administering influenza vaccine to our RA patients every year? The current study provides ample evidence that the basal seroprotection against influenza A antigens in Indian RA patients seems to be high and comparable to healthy individuals and demonstrated an impressive increment in antibody titres and seroprotection following vaccination. Therefore, there seems to be a case to administer influenza vaccine to RA patients irrespective of MTX exposure in high-risk categories such as elderly age and concomitant morbidity, before immunosuppressants. We need careful evaluation of the risk profile for infections. The vaccine ought to match the seasonal, variable and unpredictable behaviour of influenza.

In the study by Jain et al9, there was reduction in RA disease activity (disease activity score on 28 joints/DAS 28) in the DMARD naive group following influenza vaccination, implying that vaccination per se has a therapeutic effect in RA. Even the pre-vaccination proportion of seroprotection against influenza antigens in DMARD naive group was lower and this could be due to high disease activity. In the TNB study, disease control led to an improved response to PPV-23 but not influenza18. The beneficial association between vaccination and disease activity in RA is an exciting possibility but needs further research.

It is important to acknowledge the burden of RA in the Indian population. The adjusted prevalence of RA is 0.3 per cent; there may be over five million patients of RA in the community21. Immunization programme for such a huge burden is no mean task, but it is reassuring that Indians have a robust level of herd immunity as discussed above. The synergism between influenza virus and pneumococcus can cause severe life-threatening complications22. Thus, RA patients may need both influenza and pneumococcal vaccination.

Although there is strong evidence that adequate immune antibody titres are achieved with vaccination in RA patients, this may not translate into clinically visible protection levels. The vaccination studies typically focus on immunogenicity of the vaccine in terms of antibody titre. The protective antibody titres for healthy volunteers may not correlate with protection in RA patients. It is also not clear how long protective antibody titre exists in RA patients. We need to have prospective controlled trials to address clinical efficacy (prevention and/or reduction in infections) and safety of vaccination in RA patients.

There are a few other factors such as age, hormonal status, smoking and alcohol intake, which influence immune responses and should be considered in vaccination studies. However, Dougados et al23 reported that age, sex and DMARD treatment did not affect the immune response to influenza vaccine. Pre-vaccination seroprotection was significantly associated with positive immune response. In countries where immunization was more frequent, the predictive factors of vaccination were older age, lower disease activity, higher educational level, use of biotherapy, absence of corticosteroid therapy and presence of comorbidities23.

Vaccination of RA patients in a clinical setting worldwide seems to be deplorably dismal and erratic. Rheumatologists and other care providers do not seem to pay adequate attention to vaccination in patients of RA beginning DMARD therapy2324. A four-fold reduction in both admissions and case fatality rates due to respiratory infection was demonstrated in RA patients, following implementation of a successful ’rheumatologist-led’ vaccination programme24.

We need a close liaison between primary and secondary care to maximize vaccination in our population, RA in particular. It is likely that all patients of RA do not require vaccination and there seems to be a favourable case arising out of a robust herd immunity in our population as demonstrated by Jain et al9. However, patients with RA certainly need to be protected against influenza and pneumococcal infection. Apart from vaccination, hygiene, sanitation, good disease control, minimum use of immunosuppressants are recommended. An individual approach beginning with risk ascertainment for infections may be an attractive proposition for influenza and pneumococcal vaccination in a socioeconomically challenged setting such as ours.