Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis

Chikungunya virus (CHIKV) is a mosquito-borne, single-stranded, positive-sense RNA virus (genus alphavirus) that has caused sporadic outbreaks of predominantly rheumatic disease every 2–50 years, primarily in Africa and Asia (1). Most recently, during 2004–2011, CHIKV produced the largest epidemic ever recorded for an alphavirus, affecting an estimated 1.4–6 million patients. Imported cases were also reported in nearly 40 countries, including Europe, Japan, and the US. The word “chikungunya” is derived from the Makonde language (Tanzania) and means “that which bends up,” referring to the severe joint pain–induced posture of afflicted individuals (1,2). CHIKV belongs to a group of mosquito-borne arthritogenic alphaviruses, which include the Australasian Ross River virus (RRV) and Barmah Forest virus, the African o’nyong-nyong virus, and the European Ockelbo and Pogosta viruses(1). Although many viruses can cause arthralgia/arthritis, none do so with the reliability of these alphaviruses. In adults, symptomatic infections are nearly always associated with arthropathy (1,3). The disease is characterized by acute and chronic polyarthritis/polyarthralgia, which is usually symmetric and often incapacitating. Other symptoms, such as fever, rash, myalgia, and/or fatigue, are often also present during the acute phase (1). The joints most commonly affected are multiple peripheral small joints (interphalangeal joints, wrists, and ankles) and large joints such as the shoulders, knees, and spine. The arthropathy usually resolves progressively over several weeks to months, usually without long-term sequelae, although CHIKV can sometimes produce severe disease manifestations and mortality (1,2). Chronic alpha-viral rheumatic disease is likely due to the persistence of viral replication in the joint tissue (1,4–6), with no evidence that autoimmune responses are responsible (3). Alphaviral arthritides are generally treated with simple analgesics, such as paracetamol and/or nonsteroidal antiinflammatory drugs (NSAIDs), which can provide relief, although symptom reduction is often inadequate (1,2). The small market size for alphaviral arthritides generally, and the rapid, sporadic, and unpredictable nature of outbreaks caused by certain alpha-viruses like CHIKV (1), present major hurdles for the development and deployment of virus-specific interventions such as vaccines (7) or antibodies (8). Thus, therapeutic drug treatment will likely remain the only option for most patients. A number of new treatments for CHIKV disease have been investigated. Unfortunately, chloroquine treatment was ineffective in human trials (9). Findings from murine studies suggest that interferon-α (IFNα) treatment is only effective if given before infection (10), and that anti–tumor necrosis factor (anti-TNF) agents may, if administered during the acute phase, exacerbate disease (11). Steroid treatment (12) and steroid treatment combined with NSAIDs (13) appeared to provide clinical benefit in patients with RRV disease and in those with CHIKV disease, respectively; however, steroid treatment may not be appropriate for these self-limiting diseases, given the potential side effects (12). The most active area of antirheumatic drug development is for RA (14–16). The market size is large, with an estimated RA prevalence of ∼1% among adult white populations in Europe and the US. Importantly, there is also a growing awareness that ideal new therapeutic agents for RA should not compromise antipathogen immunity (16), a consideration that is also clearly important in treatments of viral arthritides (3). Although there are some similarities between alphaviral arthritides and RA (3), there are also key differences. RA is generally a progressive disease that results in bone and cartilage erosion, has a female:male prevalence ratio of ∼2.5:1, is more common in people older than age 65 years, is associated with specific HLA–DRB1 alleles (17), involves neutrophils, and is believed to be driven by autoimmune T cells (primarily Th17) and B cells specific for citrullinated proteins (18). In contrast, alphaviral arthritides are generally self-limiting, do not normally show erosive changes, have a female:male prevalence ratio of ∼1.2:1, are rare in children, are characterized by mononuclear infiltrates (2,4,5,10), have no established HLA association, and have T and B cell responses that are generally directed at CHIKV antigens (5,10). Results from murine studies also suggest that the contribution of T and B cells to alphaviral rheumatic disease may be limited (19–21). We recently developed an experimental model of CHIKV arthritis in adult wild-type mice that mimics many of the features of human CHIKV disease, including a 4–5-day viremia that is followed by arthritic disease (10). In the present study, we report data from a microarray analysis of foot tissues from mice following infection with 2 CHIKV isolates, an Asian isolate from the 1960s and an isolate from the recent epidemic on Reunion Island (10). These data were used to identify a consensus CHIKV arthritis gene signature, which was compared with the signatures previously reported for patients with RA (22) and for collagen-induced arthritis (CIA), a mouse model of RA (23). There was a surprisingly significant overlap between the CHIKV arthritis and the RA gene signatures, and the CHIKV arthritis and the CIA gene signatures. These results provide hope that at least some of the antiinflammatory drugs and biologic agents being developed for RA might also be effective in the treatment of alphaviral arthritides.