Seroconversion in Patients With Rheumatic Diseases Treated With Immunomodulators or Immunosuppressants, Who Were Inadvertently Revaccinated Against Yellow Fever

Revaccination against yellow fever is contraindicated in patients receiving immunomodulators or immunosuppressants, and a mass campaign to vaccinate the population against yellow fever resulted in the inadvertent revaccination of patients with rheumatic diseases who attended the Hospital of the University of Brasilia (HUB) or a private rheumatology clinic in Brasilia, Brasil between December 2007 and May 2008. Vaccination is strongly recommended to all people living in Brasilia; thus, for the purposes of this study, we assumed that nearly 100% of the population was vaccinated. In 2007 and 2008, we collected relevant data (pertaining to rheumatic disease diagnoses, use of immunosuppressants, date of revaccination, and adverse events) within 30 days of the revaccination. Two years later, we evaluated the protective immune response in this group by analysis of neutralizing antibodies. Our study group comprised 31 patients (all women) (Table 1). A single serum analysis was conducted using a plaque reduction neutralization test. Patients with values of 794 mIU/ml were considered seropositive for protection against yellow fever. Twenty patients (64.5%) were recruited from HUB and 11 (35.5%) from the private clinic. The diagnoses among our patients were as follows: rheumatoid arthritis (RA) (n 23), systemic lupus erythematosus (SLE) (n 5), systemic sclerosis (SSc) (n 2), and ankylosing spondylitis (AS) (n 1). Seropositivity was observed in 27 individuals (87.1%). Among the 31 patients, the mean titer of neutralizing antibodies was 2,865.58 mIU/ml. (A large study by Camacho and colleagues [1] demonstrated that the geometric mean titer in revaccinated healthy individuals was equal to 14,000 mIU/ml.) Mean, geometric mean, and median titers of neutralizing antibodies were 2,535.4, 1,543.5, and 2,015.0 mIU/ ml, respectively, in the patients with RA (interquartile range [IQR] 923–3,353) and 1,934, 2,066.9, and 1,668 mIU/mL, respectively, in those with SLE (IQR 1,208.5–2,792.5). Among the RA patients, 16 were taking methotrexate (mean SD dosage 13.28 5.73 mg/week), 9 were taking leflunomide (20 mg/day), 3 were taking infliximab (3 mg/kg every 8 weeks), and 3 patients were taking rituximab (1,000 mg twice every 15 days). Four patients reported mild adverse events up to 30 days after vaccination, 24 reported no reactions, and 3 did not recall the occurrence of any adverse reaction. One patient with AS (who was taking 3.2 gm of mesalamine per day) and another patient with RA (who was taking 10 mg of prednisone per day) developed myalgia. One patient with SSc (who was receiving 1.2 gm of cyclophosphamide per month) had fever and rhinorrhea, and another patient with RA (who was taking 20 mg of methotrexate per week and 1.5 gm of sulfasalazine per day) had arthralgia. The mean SD titers of neutralizing antibodies in the patients who presented with adverse reactions and in the asymptomatic patients were 5,461 6,817 mIU/ml and 2,610.46 2,033.04 mIU/ml, respectively. No correlation was observed between the neutralizing antibodies and occurrence of adverse reactions ( 0.19) or age ( 0.246) at the time of revaccination in a sample of 28 of 31 patients. It is noteworthy that the patient with the lowest antibody titer was treated with 2 gm of rituximab 4 months before being revaccinated against yellow fever. The data presented herein are the only data currently available regarding protective immunity following yellow fever revaccination in patients with rheumatic disease. Our assessment was performed using the method that is considered to be the reference test. Although the titers of neutralizing antibodies were lower among the rheumatic disease patients than among healthy individuals, they were high enough to confer a protective response despite the use of immunosuppressive drugs. These results are compatible with the data already existing in the literature regarding revaccination in the general population (2,3). Dr. Oliveira’s work was supported by a scholarship from the National Council for Scientific and Technological Development. Dr. Mota has received speaking fees from Roche, Janssen, AbbVie, Bristol-Myers Squibb, and AstraZeneca Pharmaceuticals.