The Natural History of Post-Chikungunya Viral Arthritis Disease Activity and T-cell Immunology: A Cohort Study

Abstract

Background: Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes arthralgias and arthritis that may last for years. The objective of this study was to describe the arthritis progression and T cell immunology over a two-year period.

Methods: A cohort of 40 cases of serologically confirmed CHIKV from Magdalena and Atlántico, Colombia were followed in 2019 and again in 2021. Arthritis disease severity, disability, pain, stiffness, physical function, mobility, fatigue, anxiety, sleep disturbances and depression were assessed. Serum cytokines and T-cell subsets were measured and tested for change. Correlations within each of the 2 time periods for laboratory parameters were also examined.

Results: Although, arthritis disease severity, as measured by the Disease Activity Score-28 (DAS-28) did not change significantly over a two-year period, a new metric- the Chikungunya Disease Activity Score (CHIK-DAS)- was more sensitive to detect changes in disease severity than the Disease Activity Score-28 (DAS-28) and showed some improvement in average disease severity from moderate to mild over two years. Cases were characterized by moderate disability, pain, and stiffness with mild alterations of physical function, mobility, fatigue, anxiety, sleep disturbances and depression that did not change significantly over time. Small joints including the fingers and wrists were most affected without significant change over time. The percentage of effector T cells (Teffs) and regulatory T cells (Tregs) of CD4⁺ T cells both decreased over time. Teff percentages decreased more significantly resulting in a halving of the Teff/Treg ratio two years later. Furthermore, markers of Treg immunosuppressive function such as CTLA4, Helios, CD28, CD45RA and 41bb decreased over time. Cytokines did not change significantly over time.

Conclusions: The presented data suggest that arthritis persists almost seven years after chikungunya infection in some patients with waning Teff and Treg numbers and activation markers over time. Treg activation may be a promising therapeutic target for further investigation.

Keywords: Arthritis; Arthritis disease severity; Chikungunya virus; Disability; Pain; Stiffness; T-cell populations.

Figure 1.. Disease activity over time shown by the Disease Activity Score-28 and Chikungunya arthritis disease activity score (CHIK-DAS) (n=40).

Comparisons made by paired samples T-test. Horizontal bars indicate mean and standard deviation. *p<0.05. ns indicates non-significant.

Figure 2.. Patient-reported disability, pain, stiffness, physical function, mobility, fatigue, sleep disturbances, depression, and anxiety over time.

Disability is measured by the Health Assessment Questionnaire. Pain was measured on a visual analog scale. Stiffness is measured by SPARRA stiffness score. Mobility, fatigue, sleep disturbances, depression and anxiety were measured via the Patient Reported Outcome Measurement Information System (PROMIS). Comparisons made by paired samples T-test. N=40 for all comparisons except for stiffness for which N=38. Horizontal bars indicate mean and standard deviation. *p<0.05. ns indicates non-significant.

Figure 3.. Effector T cells (Teff) and regulatory T cell (Treg) populations over time.

Comparisons made by Wilcoxon signed-rank test. Horizontal bars indicate median and interquartile range. *p<0.05, **** p<0.0001.

Figure 4.. Regulatory T cell markers over time.

Comparisons made by Wilcoxon signed-rank test. Horizontal bars indicate median and interquartile range. *p<0.05, ***p<0.001, ****p<0.0001.