Chikungunya viral arthritis in the United States: a mimic of seronegative rheumatoid arthritis

Abstract

Objective: Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV-infected patients develop inflammatory arthritis that can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV-related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.

Methods: Patient history was obtained and physical examination and laboratory tests were performed. All patients with CHIKV-related arthritis had detectable levels of anti-CHIKV IgG. Using cytometry by time-of-flight (CyTOF), we analyzed peripheral blood mononuclear cells in CHIKV-infected patients, healthy controls, and patients with untreated, active RA.

Results: Among 10 CHIKV-infected individuals, 8 developed persistent symmetric polyarthritis that met the American College of Rheumatology/European League Against Rheumatism 2010 criteria for (seronegative) RA. CyTOF analysis revealed that RA and CHIKV-infected patients had greater percentages of activated and effector CD4+ and CD8+ T cells than healthy controls.

Conclusion: In addition to similar clinical features, patients with CHIKV infection and patients with RA develop very similar peripheral T cell phenotypes. These overlapping clinical and immunologic features highlight a need for rheumatologists to consider CHIKV infection when evaluating patients with new, symmetric polyarthritis.

Figure 1

Clinical features of disease in patients with CHIKV infection. A) Distribution of joint involvement in the most severely affected patients (Patients #1 and #2), based on clinical history in the acute phase and physician examination at the chronic stage. B) Maculopapular rash during the acute infectious phase in Patient #1. In this patient, rash was distributed over the entire body, resolved after a few days, and was followed by desquamation. C) Active symmetric, synovitis in the MCPs and PIPs of a patient with active CHIKV-related arthritis during the persistent phase. D) Timeline (drawn to scale) depicting onset of acute symptoms, persistence of arthritis, and time of clinical evaluation with blood collection. Most patients' acute symptoms resolved within 7 days. The red box indicates the time period in which at least some patients were still having acute symptoms.

Figure 2

Comparison of cell surface receptor and lymphocyte subset percentages in uninfected, CHIKV-infected, and untreated RA patients from two experiments. (A) Cell counts for each subset were derived from sequential manual gating of CyTOF data based on multiple cell surface marker expression. Representative data points from individual patients are shown with the mean percentage depicted by a line. One patient with CHIKV arthritis was unable to donate sufficient blood for PBMC collection. The results were validated by two independent CyTOF experiments performed using separate PBMC aliquots from patients with CHIKV arthritis (n=7), untreated RA (n=6; four seropositive and two seronegative RA), and healthy control subjects (n=4). Statistical significance was tested by one-way ANOVA followed by Bonferroni's post-test (*, p<0.05). (B) Representative SPADE plots from 3 different patient groups (left panel, control; middle panel, CHIKV; right panel, RA) showing expression of L-selectin (CD62L) are presented. Clustering of cell groups was performed manually. Relative fold-expression is indicated by the color scale. Each circle represents a cluster of cells expressing similar levels of all 22 markers and its relation to other cluster of cells expressing similar combination of 22 markers. The size of the circle correlates with the number of cells in each cluster.