Prevalence and Incidence of Upper Respiratory Tract Infection Events Are Elevated Prior to the Development of Rheumatoid Arthritis in First-Degree Relatives

Abstract

Introduction: The aim of this study was to characterize infection events in a longitudinal cohort of first-degree relatives (FDR) of probands with rheumatoid arthritis (RA) and explore their associations with RA development. To this end, newly diagnosed RA patients (n = 283), unaffected related FDR and age-matched healthy women were ascertained from the Caucasian triple women prospective Tatarstan cohort. Methods: In this cohort initiated in 1997, 26/283 (9.2%) FDR developed RA (incidence: 9.1 cases/1,000/year). At baseline and during the follow-up, information regarding infectious events (prevalence) and their incidence and duration per year were collected from all individuals. Results: Results reveal in the unaffected FDR developing RA subgroup: (i) a higher prevalence and/or incidence at baseline of upper respiratory infections (URI), otitis, tonsillitis, herpes reactivation, and skin infections; (ii) Mycoplasma sp detection was increased during pregnancy; (iii) a peak of infections started in the 3 years preceding RA onset, and thereafter decreased following RA diagnosis and treatment initiation with disease-modifying anti-rheumatic drugs (DMARDs) when considering URI, and acute tonsillitis; (iv) herpes virus reactivation, at baseline, was associated with a higher report of morning stiffness and arthralgia while independent from rheumatoid factors and anti-citrullinated peptide (CCP)2 Ab positivity; and (v) infection events represent an independent environmental factor associated with RA development. Conclusion: In conclusion, an annual increase of respiratory tract infections was found at the pre-clinical stage of RA. This could be due to alterations in the immune system that result in susceptibility to infection, controlled by DMARDs, or that the infectious events predispose to RA.

Keywords: first-degree relatives; herpes virus; infections; rheumatoid arthritis; upper respiratory tract infection symptoms.

Figure 1

Study cohort. (A) The 20-year longitudinal Tatarstan women cohort is subdivided in three groups: women with newly diagnosed rheumatoid arthritis (< 1 year from diagnosis, new RA), unaffected first degree relatives (FDR), and healthy controls that are age matched with FDR. Among FDR, a subgroup has developed RA during its follow-up and was referred as FDR-RA in contrast to non-RA FDR who have not developed RA. (B) Follow-up of the 26 FDR having developed RA and for each individual available data are indicated according to the year of diagnosis (time = 0). n, number.

Figure 2

Infection prevalence, incidence and duration are increased in the FDR-RA subgroup at baseline. (A,B): total (A) and individual (B) infection prevalence in the previous year in controls, non-RA FDR, FDR-RA and new RA. (C,D): total (C) and individual (D) infection incidence (number of event/year). (E,F): total (E) and individual (F) infection duration (day/event/year). new RA, newly diagnosed RA patients; FDR, first degree relatives; FDR-RA, FDR individuals having developed RA; FDR, individuals not having developed RA; URI, upper respiratory infections; HSV, herpes simplex virus infection. Hatched squares mean that no data were available. Statistics are indicated when p < 0.05 and for individual infections the p-values were corrected using the Benjamini–Hochberg method (58 tests).

Figure 3

A transient peak of infection events is observed during the preclinical stage of RA. (A,B) total (A) and individual (B) infection prevalence from follow-up of the 26 first degree relative individuals having developed rheumatoid arthritis (FDR-RA); (C,D): total (C) and individual (D) infection incidence (events/year). The time point is defined in relation to the diagnosis and DMARDs initiation (−3 or more years, −2 years, −1 year, 0 = diagnosis, +1/2 years and >3 years). new RA, newly diagnosed RA patients; FDR, individuals not having developed RA; URI, upper respiratory infections; HSV, herpes simplex virus infection; DMARDs, disease-modifying anti-rheumatic drugs. Statistics are indicated when p < 0.05 and for individual infections the p-values were corrected using the Benjamin–Hochberg method (17 tests).

Figure 4

Herpes simplex virus (HSV) reactivation is associated with clinical but not with serological factors at baseline. (A) Morning stiffness (>30 min) in the previous year. (B) Arthralgia in the last year. (C) Non-erosive arthralgia in life. (D) Serological status regarding rheumatoid factor (RF) and anti-cyclic peptide citrullinated (anti-CCP2). Neg, subgroup negative for the clinical/biological factor tested; Pos, subgroup positive for the clinical/biological factor tested; FDR, first degree relatives not having developed RA during the follow-up; FDR-RA, FDR individuals having developed RA; URI, upper respiratory infections; HSV, herpes simplex virus infection. The p-values were corrected using the Benjamini–Hochberg method (17 tests) and statistics are indicated when p < 0.05.