Purpose of Review Persistent joint pain is a common manifestation of arthropod-borne viral infections and can cause long-term disability. We review the epidemiology, pathophysiology, diagnosis, and management of arthritogenic alphavirus infection. Recent findings The global re-emergence of alphaviral outbreaks has led to an increase in virus-induced arthralgia and arthritis. Alphaviruses, including Chikungunya, O’nyong’nyong, Sindbis, Barmah Forest, Ross River, and Mayaro viruses, are associated with acute and/or chronic rheumatic symptoms. Identification of Mxra8 as a viral entry receptor in the alphaviral replication pathway creates opportunities for treatment and prevention. Recent evidence suggesting virus does not persist in synovial fluid during chronic chikungunya infection indicates that immunomodulators may be given safely. Summary The etiology of persistent joint pain after alphavirus infection is still poorly understood. New diagnostic tools along and evidence-based treatment could significantly improve morbidity and long-term disability.

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ObjectiveChikungunya virus (CHIKV) causes persistent arthritis, and our prior study showed that approximately one third of CHIKV arthritis patients had exacerbated arthritis associated with exercise. The underlying mechanism of exercise-associated chikungunya arthritis flare (EACAF) is unknown, and this analysis aimed to examine the regulatory T-cell immune response related to CHIKV arthritis flares.MethodsIn our study, 124 Colombian patients with a history of CHIKV infection four years prior were enrolled and 113 cases with serologically confirmed CHIKV IgG were used in this analysis. Patient information was gathered via questionnaires, and blood samples were taken to identify total live peripheral blood mononuclear cells, CD4+ cells, T regulatory cells, and their immune markers. We compared outcomes in CHIKV patients with (n = 38) vs. without (n = 75) EACAF using t-tests to assess means and the Fisher’s exact test, chi-squared to evaluate categorical variables, and Kruskal-Wallis tests in the setting of skewed distributions (SAS 9.3).Results33.6% of CHIKV cases reported worsening arthritis with exercise. EACAF patients reported higher global assessments of arthritis disease ranging from 0-100 (71.2 ± 19.7 vs. 59.9 ± 28.0, p=0.03). EACAF patients had lower ratios of T regulatory (Treg)/CD4+ T-cells (1.95 ± 0.73 vs. 2.4 ± 1.29, p = 0.04) and lower percentage of GARP (glycoprotein-A repetitions predominant) expression per Treg (0.13 ± 0.0.33 vs. 0.16 ± 0.24 p= 0.020).ConclusionThese findings suggest relative decreases in GARP expression may indicate a decreased level of immune suppression. Treg populations in patients with CHIKV arthritis may contribute to arthritis flares during exercise, though current research is conflicting.

Objective: The primary objective of this research was to explore the link between sleep and flare pain associated with chikungunya virus (CHIKV) infection. The secondary objective was to investigate if cytokines and T regulatory (Treg) cells have an influence on this relationship. Methods:A cross-sectional study was performed using data collected in Barranquilla, Colombia, which enrolled patients with and without chronic arthritis with a history of chikungunya infection. Flare severity was measured by a version of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) flare questionnaire adapted for CHIKV arthritis, including metrics for pain, difficulty with physical activity, fatigue, stiffness and difficulty maintaining social activities due to arthritis that contribute to flare severity. In addition, four sleep disturbance items, five inflammatory cytokine levels, four anti-inflammatory cytokine levels, and six Treg levels were measured. Then, multivariable linear regression models were used to test the direct and indirect effects of flarepain on sleep disturbance, and to determine whether this relationship was mediated by cytokines or Tregs. Finally, the SAS CALIS procedure was used to test path models showing possible causal effects with mediators and confounds.Results: The analysis showed that sleep disturbance is positively correlated with CHIKV arthritis flare pain, and that it is a significant predictor of flare severity after adjusting for demographic variables, cytokine, and T cell levels. Further, neither T cells nor cytokines mediate the pain/sleep relationship in CHIKV arthritis. Conclusion:There is a strong association between sleep disturbance and arthritis flare pain and severity; however, this relationship is not mediated by cytokines or T cells. Since this study is unable to determine causation, further research is needed to determine the mechanism underlying the relationship between sleep disturbances and CHIKV arthritis flares.

Background:Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) have been described after chikungunya virus infection. However, the clinical significance of the symptoms and disease severity in the two conditions has not been directly compared.Objectives:To compare, using identical measures of disease severity and patient outcomes, the impact of disease severity measures and symptoms on outcomes in RA and chronic chikungunya disease.Methods:Forty patients with chronic chikungunya arthralgia two years post-infection and 40 matched patients with RA were enrolled in Roraima, Brazil. Twenty-eight joints were assessed for tenderness and swelling, a pain intensity visual analogue scale, musculoskeletal stiffness questionnaire, modified Health Assessment Questionnaire and the EuroQol EQ5D-5L quality of life assessment were completed. The importance of the various measures of disease severity were analysed using Spearman’s rank correlation and regression analysis.Results:Tender and swollen joint counts, pain and stiffness were all predictive of the HAQ disability index in RA, but only stiffness was significantly associated with disability in chikungunya patients (Table 1). Tender and swollen joint counts, pain and stiffness were predictive for all EQ5D quality of life domains (except anxiety/depression) in RA patients. In contrast, in chikungunya disease, tender joint counts were predictive only of usual daily activities; pain was predictive of impaired mobility, self-care and discomfort, while stiffness was predictive for the mobility and anxiety/depression domains (Figure 1). Swollen joint counts were not associated with any of the patient outcomes in chikungunya disease. Linear regression analysis confirmed (p=0.003) that the effect of swollen joint count on the HAQ disability index depends on the underlying disease.Table 1.Association of disease severity with HAQ disability index in rheumatoid and CHIKV+ arthritisSeverity measureRheumatoid arthritisCHIKV+ arthritisr (p)r (p)Tender joint count0.56 (0.0002)0.24 (0.14)Swollen joint count0.60 (<0.0001)0.002 (0.99)Joint pain (VAS)0.55 (0.0002)0.29 (0.07)Stiffness severity0.57 (0.0001)0.38 (0.02)Figure 1.Association of disease severity with quality of life domains in rheumatoid and CHIKV+ arthritisConclusion:The value of all the disease severity measures tested in RA were confirmed, but tender joint counts may have more limited value in the assessment of chronic chikungunya disease. Joint swelling appears to have little impact for chikungunya patients, while stiffness appears to be an important metric to quantify chikungunya arthritis disease severity.Disclosure of Interests:Hugh Watson Shareholder of: Sanofi, Employee of: Sanofi, Ramão Luciano Nogueira-Hayd: None declared, Maony Rodrigues-Moreno: None declared, Felipe Naveca: None declared, Giulia Calusi: None declared, Richard Amdur: None declared, Karol Suchowiecki: None declared, Gary S. Firestein: None declared, Gary Simon: None declared, Aileen Chang: None declared

Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) are described after chikungunya virus infection. We aimed to compare the relevance of joint counts and symptoms to clinical outcomes in RA and chronic chikungunya disease. Forty patients with chronic chikungunya arthralgia and 40 patients with RA were enrolled in a cross-sectional study. The association of tenderness and swelling, clinically assessed in 28 joints, and patient evaluations of pain and musculoskeletal stiffness with modified Health Assessment Questionnaire (HAQ) and quality of life (QoL) assessments were investigated. Tender and swollen joint counts, pain and stiffness scores were all associated with the HAQ disability index in RA (all r > 0.55, p ≤ 0.0002), but only stiffness was significantly associated with disability in chikungunya (r = 0.38, p = 0.02). Joint counts, pain and stiffness were also associated with most QoL domains in RA patients. In contrast, in chikungunya disease, tender joint counts were associated only with one QoL domain and swollen joints for none, while pain and stiffness were associated with several domains. Our results confirm the relevance of joint counts in RA, but suggest that in chronic chikungunya disease, joint counts have more limited value. Stiffness and pain score may be more important to quantify chikungunya arthritis impact.