A transient peak of infections during onset of rheumatoid arthritis: a 10-year prospective cohort study

Abstract

Objectives: The role of infection in rheumatoid arthritis (RA) has not been determined. We aimed to document the infectious burden and some aspects of antibacterial immunity in a large and prospective cohort study of RA patients in the early and late stages of the disease and in their relatives predisposed to RA.

Setting: Clinical and laboratory examination of all individuals enrolled in the study was performed in the Republican Clinical Hospital, Kazan, Russia.

Participants: 376 patients with RA, 251 healthy first-degree relatives and 227 healthy controls without a family history of autoimmune disease (all females) were examined twice annually over more than 10 years.

Primary and secondary outcome measures: The following parameters were investigated: type, duration and frequency of infections, bacterial colonisation and serum levels of IgG to bacteria, serum levels of total Ig, plasma cytokine levels, granulocyte reactive oxygen species production, lysozyme activity and phagocytosis.

Results: There were no significant differences in infection rate between healthy controls (median 14 days/year) and RA patients (13). However, infection rates were higher (p<0.001) in healthy relatives (53) and early stage patients (62), which groups also showed heavy bacterial skin colonisation. In contrast, late stage patients had fewer infection days (12; p<0.001) than healthy controls, although bacterial colonisation was still heavy. Phagocyte function and antibacterial antibody generation, together with compensatory cytokine production, were observed to be subnormal in the healthy relatives as well as in RA patients.

Conclusions: We observed a marked increase in overall infections at the time of RA onset, and signs of a defective antibacterial defence mechanism, contrasting with fewer infections in the late RA stage. It can be speculated that frequent early infections initiate a compensatory immune hyper-reactivity which reduces the infection load while stimulating the development of RA in predisposed individuals.

Keywords: IMMUNOLOGY.

Figure 1

The number of days with an infection during the 1-year period preceding either the first examination (HC and HR), arthritis onset (eRA) or the last examination (laRA). (A) All subjects; (B) HR developing RA and followed to the late stage (a box symbol) and RA patients followed from time of diagnosis (a circle symbol). **p<0.01, ***p<0.001, as compared with HC (A, Mann–Whitney test) and as compared with the data in the preceding time point of analysis (B, Wilcoxon test). The median is shown, and whiskers denote 5% and 99% percentiles. eRA, early RA patients (<0.5 years RA duration); HC, healthy controls (women with no RA among close relatives); HR, healthy first-degree female relatives of RA patients; laRA, late RA patients (>3 years RA duration); RA, all rheumatoid arthritis patients.

Figure 2

(A) Fraction of subjects showing heavy bacterial colonisation; (B) serum levels of IgG to Escherichia coli, Staphylococcus epidermidis and Staphylococcus aureus. A high bacterial colony-forming unit (CFU) count was defined arbitrarily (see text). In B, the subjects were separated into two subgroups depending on whether there was a high CFU count (‘Positives’) for any of the cultured samples. **p<0.01, as compared with HC; #p<0.01, ##p<0.001, as compared with eRA. The median and 5% and 99% percentiles are shown. eRA, early RA patients (<0.5 years RA duration); HC, healthy controls (women with no RA among close relatives); HR, healthy first-degree female relatives of RA patients; laRA, late RA patients (>3 years RA duration); RA, rheumatoid arthritis.

Figure 3

Serum levels of total IgA, IgM and IgG (A) and IgE (B). **p<0.05, ***p<0.01, as compared with HC. The median and 5% and 99% percentiles are shown. eRA, early RA patients (<0.5 years RA duration); HC, healthy controls (women with no RA among close relatives); HR, healthy first-degree female relatives of RA patients; laRA, late RA patients (>3 years RA duration); RA, rheumatoid arthritis.

Figure 4

Plasma cytokine levels. *p<0.05, **p<0.01, ***p<0.001, as compared with HC. The median and 5% and 99% percentiles are shown. eRA, early RA patients (<0.5 years RA duration); HC, healthy controls (women with no RA among close relatives); HR, healthy first-degree female relatives of RA patients; laRA, late RA patients (>3 years RA duration); RA, rheumatoid arthritis.

Figure 5

Granulocyte phagocytosis functions: spontaneous (A) and stimulated (B) ROS production, time to reach peak ROS production (C), lysozyme activity (D) and phagocytosis of Staphylococcus aureus (E). *p<0.05 as compared with HC. The median and 5% and 99% percentiles (A,B) and mean and SE (C,D) are shown. eRA, early RA patients (<0.5 years RA duration); HC, healthy controls (women with no RA among close relatives); HR, healthy first-degree female relatives of RA patients; laRA, late RA patients (>3 years RA duration); RA, rheumatoid arthritis; ROS, reactive oxygen species.