Research Article: Reduced IgG titers against pertussis in rheumatoid arthritis: Evidence for a citrulline-biased immune response and medication effects

Date Published: May 28, 2019

Publisher: Public Library of Science

Author(s): Caitlyn L. Holmes, Chloe G. Peyton, Amy M. Bier, Tobias Z. Donlon, Fauzia Osman, Christie M. Bartels, Miriam A. Shelef, Pierre Roques.


The antibody response to pertussis vaccination in rheumatoid arthritis is unknown, a concerning omission given the relatively low efficacy of the pertussis vaccine, a rise in pertussis infections, and a general increased susceptibility to infection in rheumatoid arthritis. Additionally, the contributions from an intrinsically dysregulated immune system in rheumatoid arthritis and immune-suppressing medications to the response to pertussis vaccination is poorly defined. This study examines antibody titers against pertussis in vaccinated rheumatoid arthritis patients and controls as well as evaluates potential contributions from demographic factors, immune suppressing medications, and reactivity against citrullinated pertussis.

Serum IgG titers against native and citrullinated pertussis and tetanus were quantified by enzyme-linked immunosorbent assay in rheumatoid arthritis subjects and controls who were vaccinated within 10 years. Titers were compared by t-test and percent immunity by Fisher’s exact test. Multivariable logistic regression was used to identify clinical factors that correlate with native pertussis titers.

Compared to controls, rheumatoid arthritis subjects had lower titers against pertussis, but not tetanus, and reduced immunity to pertussis. These results were even more prominent at 5–10 years post-vaccination, when rheumatoid arthritis patients had 50% lower titers than controls and 2.5x more rheumatoid arthritis subjects were not considered immune to pertussis. Multiple logistic regression demonstrated that female sex and methotrexate use, but not TNF inhibiting medications, correlated with reduced immunity to pertussis. Finally, rheumatoid arthritis patients had higher IgG titers against citrullinated pertussis than native pertussis.

Pertussis titers are lower in vaccinated rheumatoid arthritis patients with evidence for contributions from female sex, a citrulline-biased immune response, and methotrexate use.

Partial Text

Patients with rheumatoid arthritis, a chronic progressive autoimmune disease with a lifetime risk of about 3% [1], are at increased risk for infection [2], but data are mixed regarding response to vaccination. Following influenza or pneumococcus immunization, which are both recommended for rheumatoid arthritis patients given overall efficacy [3, 4], rheumatoid arthritis patients have a normal response to some vaccine strains and serotypes and an impaired response to others [5–8], which may be improved by the use of adjuvant [9]. Also, patients with rheumatoid arthritis have similar antibody levels against tetanus compared to controls, but differences in antibody affinity and subclass [10]. Given the variability seen in the response of rheumatoid arthritis patients to different vaccines, it is necessary to separately assess the response to each vaccine. However, no studies have addressed the antibody response to the pertussis vaccine in rheumatoid arthritis.

Ninety-eight rheumatoid arthritis patients and seventy-seven controls who received the Tdap vaccine within 10 years of blood collection were selected from the UW Rheumatology Biorepository. Controls and rheumatoid arthritis patients were similar with regards to age, sex, race/ethnicity, smoking status, BMI, time since vaccination, and age at vaccination (S1 Table). Time since vaccination demonstrated a trend towards being slightly shorter for rheumatoid arthritis subjects as compared to controls, by an average of 9.6 months (p = 0.06). Also, consistent with the one point given for a rheumatoid arthritis diagnosis in the scoring system, the Charlson comorbidity score was higher in rheumatoid arthritis subjects.

In this report, we have demonstrated that pertussis IgG titers are significantly lower in rheumatoid arthritis subjects compared to controls. Moreover, the percent of rheumatoid arthritis subjects considered immune to pertussis is two-fold lower than controls. Both of these findings were even more prominent in subjects who received the pertussis vaccine 5–10 years prior to serum collection. These results could suggest that hundreds of thousands of rheumatoid arthritis patients in the United States alone may be susceptible to pertussis infection, despite receiving the Tdap vaccine according to national guidelines. Further, our findings, combined with the extremely low vaccination rates against pertussis in rheumatoid arthritis patients in Germany [34], could suggest that as the numbers of pertussis infections rise in general, pertussis could become a significant problem for rheumatoid arthritis patients.

We have shown that vaccinated rheumatoid arthritis patients have lower titers against pertussis than controls with a potential role for female sex, methotrexate, and a citrulline-biased immune response. Our findings have potential clinical importance since they are the first to identify lower pertussis titers in rheumatoid arthritis, suggesting that these patients could be more susceptible to pertussis infection and might benefit from more frequent vaccination. Additionally, we provide the first evidence that a citrulline-biased immune system may complicate the response to immunization in rheumatoid arthritis, providing a novel mechanism for abnormal vaccine response.