Chikungunya-Induced Arthritis in Reunion Island: A Long-Term Observational Follow-Up Study Showing Frequently Persistent Joint Symptoms, Some Cases of Persistent Chikungunya Immunoglobulin M Positivity, and No Anticyclic Citrullinated Peptide Seroconversion After 13 Years.

BACKGROUND: Reunion Island was struck by a massive Chikungunya outbreak in 2005-2006. Chikungunya infection is characterized by inflammatory joint symptoms, which may evolve into chronic arthritis. METHODS: In this long-term longitudinal observational monocentric study, after the 2005-2006 outbreak in Reunion Island, 159 patients were first referred to a rheumatologist for post-Chikungunya chronic musculoskeletal pain, 73 of them were diagnosed with classifiable Chikungunya-related chronic inflammatory rheumatic diseases (>3 month symptom duration from the initial viral infection). Thirty of these 73 patients were clinically evaluated by a second rheumatologist in 2018-2019. The main objective of this second examination was to estimate the proportion of patients with persistent Chikungunya-related inflammatory joint symptoms after 13 years. RESULTS: Inflammatory joint symptoms persisted in 17/30 patients after 13 years (therefore in at least 23.3% of the 73 patients initially diagnosed with Chikungunya-related inflammatory joint symptoms and 10.7% of the 159 patients referred for post-Chikungunya chronic musculoskeletal pain). In the symptom persistence subgroup, the prevalence of positive autoantibodies (antinuclear or ACPA) was significantly higher - without any seroconversion, Chikungunya IgG and IgM levels were higher, long-term IgM positivity and radiographic damage were more frequent. Overall, after 13 years, pain and fatigue levels remained significant, 5 patients were still treated by methotrexate, 3 by TNF-blockers, highlighting long-term Chikungunya-related patient burden. CONCLUSIONS: Such a long-term persistence of Chikungunya-related chronic inflammatory rheumatic diseases had not been reported so far. Furthermore, the long-term Chikungunya IgM positivity we observed in some cases might corroborate the hypothesis of residual viral antigen-driven chronic arthritis.

Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.

Alphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection. Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the "recovered" or the "chronic" groups to identify prognostic markers of arthritis-like pathology after CHIKV disease. We found that the chronic group consisted mainly of more elderly patients (>60 y) and with much higher viral loads (up to 10(10) viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups. Interestingly, the antiviral immune response witnessed by high levels of IFN-alpha mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group. CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4(++) but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly(ADP-ribose) polymerase staining] were observed in the injured synovial tissue. These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence.

Rheumatic manifestations associated with Chikungunya virus infection: A study of 307 patients with 32-month follow-up (RHUMATOCHIK study).

OBJECTIVES: In the wake of the Chikungunya epidemic which struck Reunion Island in 2005 and 2006, we conducted a prospective, multicentre study (RHUMATOCHIK) whose main objective was analyse the characteristics and progression of rheumatic manifestations in patients with post-Chikungunya joint pain. METHODS: A cohort of 307 consecutively included patients underwent rheumatological examinations for pain secondary to Chikungunya virus infection. The long-term evaluation was conducted by telephone survey 1 and 2 years after the onset of the viral infection. RESULTS: At inclusion, mean age was 54 years (24-87) and 83.1% of the patients were female. Chronic joint pain was associated with synovitis in 64.2% of the patients, affecting primarily the wrists, the proximal interphalangeal joints of the fingers, and the ankles. Attempts to detect the viral genome in joint fluid (10 patients) and synovial tissue (6 patients) using the RT-PCR technique were repeatedly unsuccessful. With a mean follow-up of 32 months, joint pain persisted in 83.1% of the patients. Functional impairment, however, was moderate, with a HAQ score of 0.44±0.5. CONCLUSION: Chikungunya virus infection is frequently the cause of joint manifestations that can persist for several months, or even several years. In some cases, the clinical symptoms closely resemble those usually associated with rheumatoid arthritis. Further studies are necessary to improve the therapeutic management of these patients.

Specific management of post-chikungunya rheumatic disorders: a retrospective study of 159 cases in Reunion Island from 2006-2012.

BACKGROUND: Since 2003, the tropical arthritogenic chikungunya (CHIK) virus has become an increasingly medical and economic burden in affected areas as it can often result in long-term disabilities. The clinical spectrum of post-CHIK (pCHIK) rheumatic disorders is wide. Evidence-based recommendations are needed to help physicians manage the treatment of afflicted patients. PATIENTS AND METHODS: We conducted a 6-year case series retrospective study in Reunion Island of patients referred to a rheumatologist due to continuous rheumatic or musculoskeletal pains that persisted following CHIK infection. These various disorders were documented in terms of their clinical and therapeutic courses. Post-CHIK de novo chronic inflammatory rheumatisms (CIRs) were identified according to validated criteria. RESULTS: We reviewed 159 patient medical files. Ninety-four patients (59%) who were free of any articular disorder prior to CHIK met the CIR criteria: rheumatoid arthritis (n=40), spondyloarthritis (n=33), undifferentiated polyarthritis (n=21). Bone lesions detectable by radiography occurred in half of the patients (median time: 3.5 years pCHIK). A positive therapeutic response was achieved in 54 out of the 72 patients (75%) who were treated with methotrexate (MTX). Twelve out of the 92 patients (13%) received immunomodulatory biologic agents due to failure of contra-indication of MTX treatment. Other patients mainly presented with mechanical shoulder or knee disorders, bilateral distal polyarthralgia that was frequently associated with oedema at the extremities and tunnel syndromes. These pCHIK musculoskeletal disorders (MSDs) were managed with pain-killers, local and/or general anti-inflammatory drugs, and physiotherapy. CONCLUSION: Rheumatologists in Reunion Island managed CHIK rheumatic disorders in a pragmatic manner following the outbreak in 2006. This retrospective study describes the common mechanical and inflammatory pCHIK disorders. We provide a diagnostic and therapeutic algorithm to help physicians deal with chronic patients, and to limit both functional and economic impacts. The therapeutic indication of MTX in pCHIK CIR could be approved in future efficacy trials.

Emergence and clinical insights into the pathology of Chikungunya virus infection.

Major epidemics of Chikungunya have re-emerged with millions of cases worldwide. What was once largely a tropical disease in poorer countries is now recognized as a major global health issue. The disease is perpetuated by the alphavirus Chikungunya, and is transmitted by Aedes mosquitoes. The infection is highly symptomatic, with fever, skin rash and incapacitating arthralgia, which can evolve to chronic arthritis and rheumatism in elderly patients. Mother-to-child transmission, encephalitis, Guillain-Barré syndrome and deaths have been noted. In this article, we will highlight the epidemiological, clinical, virological and immunological aspects of the disease and mention the therapies that have been used during recent epidemics. Novel prevention measures to control the mosquito and a new vaccine are highly warranted.

Chikungunya virus takes centre stage in virally induced arthritis: possible cellular and molecular mechanisms to pathogenesis.

Chikungunya virus (CHIKV) causes an acute symptomatic illness with fever, skin rash (hypersensitivity vasculitis), incapacitating arthralgia which can evolve to chronic arthritis in elderly patients. Clinical observations from cohort studies have been corroborated with data from experimental infection in several mouse and non-human primate models as discussed herein.