Background Tumor Necrosis Factor-α inhibitors (TNFi) are immunosuppressive therapies that are known to increase infectious risk. Indeed, patients affected by TNFi requiring conditions are at higher risk of influenza compared with healthy controls. Furthermore, mildly reduced seroconversion rate after influenza vaccination had been reported in TNFi-treated patients. Nonetheless the immune response is considered large enough to recommend influenza vaccination in all patients affected by rheumatoid arthritis, regardless of treatment. However, there are data showing that patients are not being vaccinated as recommended. In addition, given that subjects with autoimmune conditions treated with TNFi are at higher risk for influenza, the exact number needed to vaccinate (NNV) for this condition is still unknown.
Objectives We sought to determine the NNV for influenza in TNFi treated patients and the cost for preventing one case of influenza compared with general population.
Methods The present analysis included data from cohorts of healthy subjects  and TNFi treated patients . We calculated NNV for preventing one case of influenza in each cohort. NNV is the required number of patients receiving vaccination to prevent one case of a given infectious disease. NNV is the inverse of the absolute risk reduction (ARR), which is calculated as following: Control Event Rate (CER) – Experimental Event Rate (EER). In addition, the NNV gives us the opportunity to calculate the cost for preventing one case of influenza, assuming a cost per vaccine from 20 to 40 $.
Results In 71,221 healthy individuals influenza vaccination reduced influenza rate from 2.3% in individuals without vaccination (CER = 0.023) to 0.9% in vaccinated individuals (EER = 0.009). The calculated NNV is 71 (NNV = 1/ARR, ARR = 0.023 – 0.009), namely 71 healthy adults need to be vaccinated to prevent one of them experiencing influenza. The costs to prevent a case of clinical influenza in healthy controls would range from 1,420 to 2,840 $. On 15,132 patients exposed to adalimumab, influenza-related adverse events have been reported in 55 of 382 not-vaccinated patients (CER = 0.14) and in 8 of 179 vaccinated patients (EER = 0.04). In this population (mean age 53.5 years, predominantly white women) the NNV of influenza vaccines is 10 (NNV = 1/ARR, ARR = 0.144 – 0.045) and preventing a case of influenza would cost approximately from 200 to 400 $, which is largely lower when compared to healthy controls’ costs. The relative risk of influenza vaccination in healthy individuals (2.3% to 0.9%, RR 0.41, 95% confidence interval (CI) 0.36 to 0.47) and rheumatoid arthritis patients treated with TNFi (14.4% to 4.5%, RR 0.31, 95% CI 0.15 to 0.64) are similar, while there is a large difference between NNVs (71 vs 10) (Figure 1).
Conclusion When estimating the effectiveness of vaccinations, clinicians should always include the calculation of the NNV and not only the calculation of relative risk, which might be misleading. The difference in NNV for influenza between healthy individuals and TNFi treated patients is due to a greater absolute risk for influenza in the latter group. The present analysis provides further evidences on the effectiveness of influenza vaccination in patients affected by rheumatoid arthritis receiving treatment with TNFi and should represent a call-to-action for all rheumatologists to consider vaccination in such patients.
References  Burmester GR, et al. Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis. Ann Rheum Dis 2017;76:414–7
 Demicheli V, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2018;2:CD001269
Disclosure of Interests Giovanni Adami: None declared, Angelo Fassio Speakers bureau: Abiogen Pharma, Giovanni Orsolini Speakers bureau: Grunenthal, Alessandro Giollo: None declared, Davide Gatti Speakers bureau: Abiogen, Amgen, Janssen-Cilag, Mundipharma, Pfeizer, Maurizio Rossini: None declared
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