Mosquito-transmitted alphaviruses causing human rheumatic disease are globally distributed and include chikungunya virus, Ross River virus, Barmah Forest virus, Sindbis virus, o'nyong-nyong virus and Mayaro virus. These viruses cause endemic disease and, occasionally, large epidemics; for instance, the 2004-2011 chikungunya epidemic resulted in 1.4-6.5 million cases, with imported cases reported in nearly 40 countries. The disease is usually self-limiting and characterized by acute and chronic symmetrical peripheral polyarthralgia-polyarthritis, with acute disease usually including fever, myalgia and/or rash. Arthropathy can be debilitating, usually lasts weeks to months and can be protracted; although adequate attention to differential diagnoses is recommended. The latest chikungunya virus epidemic was also associated with some severe disease manifestations and mortality, primarily in elderly patients with comorbidities and the young. Chronic alphaviral rheumatic disease probably arises from inflammatory responses stimulated by the virus persisting in joint tissues, despite robust antiviral immune responses. Serodiagnosis by ELISA is the standard; although international standardization is often lacking. Treatment usually involves simple analgesics and/or NSAIDs, which can provide relief, but better drug treatments are clearly needed. However, the small market size and/or the unpredictable and rapid nature of epidemics present major hurdles for development and deployment of new alphavirus-specific interventions.

Chikungunya virus (CHIKV) is a member of a group of globally distributed, mosquito-transmitted arthritogenic alphaviruses that cause sporadic outbreaks of primarily rheumatic disease every 2-50 years 1-4. The largest epidemic of CHIKV disease (hereafter simply referred to as chikungunya) ever recorded began on Lamu Island, Kenya, in 2004 (Fig. 1). The epidemic expanded across four continents, with cases still being reported in 2019 (Fig. 1; Supplementary Table 1). Three major genotypes of CHIKV are now recognized-the Asian, the West African and the Asian and East-Central South African (ECSA) genotypes 5-but a new lineage, the Indian Ocean Lineage (IOL), also emerged from the ECSA genotype during the 2004-2019 epidemic 6. The epidemic reached >100 countries (Supplementary Table 1), caused >10 million cases (Supplementary Table 2), and might arguably be called a pandemic. An estimated 1.3 billion people are at risk of chikungunya 7. Climate change modelling suggests that many more areas of the world (including parts of China, sub-Saharan Africa, South America and the United States) might become able to accommodate transmission of CHIKV in the future 8,9. Chikungunya was previously often viewed as (and for many patients remains) a relatively benign and selflimiting rheumatic disease. However, a considerably more complex spectrum of less common atypical and severe manifestations is now recognized in subgroups of patients, with chikungunya often complicated by comorbidities and co-infections. Hospitalization rates for chikun gunya range from 0.6% to 13% 10-14 and estimates of chikungunya-related mortality range from 0.024% to 0.7% 10,12,15-17. In addition, many patients develop protracted rheumatic disease lasting many months, occasionally years, with a number of sequelae now also recognized 18-22. Estimates for the total economic costs (direct and indirect) of chikungunya have ranged from a median of US$67 for adults and $258 for children in Columbia 23 , to a mean of $150 per outpatient and $3,300 per inpatient in 2006 in Réunion Island 11. In a large study of a chikungunya outbreak in Bangladesh in 2017, >10 days of productivity were lost in ~30% of patients with chikung unya because of severe arthropathy 24. Such costs might be viewed as relatively modest by Western standards; however, the occasionally high attack rate of chikungunya, with up to 30-75% of a given population affected by chikungunya disease at any one time 1,25 , can result in a substantial economic burden, especially in resource-poor communities that are often affected by the disease 26. Considerable research in patients and animal models has now provided extensive insights into the complex Pandemic An epidemic of disease that has spread across a large region; for instance, multiple continents, or even worldwide. Attack rate The total number of new cases of a disease divided by the total population (that is, the percentage of a defined population that is affected by a disease).

Diagnosis of alphaviral arthritides is complicated by nonspecific symptoms and the lack of commercial serodiagnostic kits, except for Ross River and Barmah Forest virus infections in Australia. Differential diagnoses should be actively pursued, especially if symptoms persist. Treatment with nonsteroidal anti-inflammatory drugs appears largely effective, with no evidence of long-term sequelae or relapse.