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 alphaviral 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 alphaviruses 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.
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Herein we show a remarkable similarity between the gene signatures of CHIKV arthritis and RA, with the concordance between the signatures appearing to increase with the severity of the RA inflammation score. The similarity is particularly surprising given the different species (mouse and human), the distinct disease etiologies, and the different tissues sampled (feet versus synovial biopsy tissue). The arthritis genes identified by GSEA analysis of the CHIKV arthritis and RA data sets were associated with a wide range of canonical pathways that involved T cells, autoimmunity, antigen presentation, NK cells, innate sensing, monocyte/macrophages, apoptosis, B cells, cytokines/chemokines, and complement. An important conclusion from this analysis is that drugs and biologic agents being developed for RA that target these pathways may therefore also find utility in the improved treatment of CHIKV and perhaps other alphaviral arthritides.
Some recent studies have suggested that CHIKV disease may lead to RA (37–39). However, these studies may simply have identified patients with RA who were also infected with CHIKV (1, 40). Given the high attack rate of CHIKV disease (38% in Reunion Island ) and an RA prevalence of ∼1% in the general population, such patients are likely to be common in epidemic areas. Whether the rate of RA is ultimately found to be higher in CHIKV epidemic areas remains to be established, and any studies attempting to address this issue would have to account for increased detection rates simply arising from a greater general awareness of rheumatic disease after a CHIKV epidemic. Currently, there is no good evidence to support the notion that viral arthritides lead to autoimmune disease (3), and the current study should not be interpreted as providing insights into etiology. Nevertheless, a small number of elderly patients with CHIKV disease do appear to develop protracted RA-like illness (5, 39), and in these patients, treatment with methotrexate seems to be effective (5).
The broad spectrum of overlapping pathways between CHIKV and RA opens up a range of potential new treatment options for alphaviral arthritides. For instance, a number of drugs that modify T cell activities are being developed (14–16, 18), which may also work for alphaviral arthritides. A range of cytokines and chemokines are being targeted in a quest to develop drugs for autoimmune diseases such as RA (41). Unfortunately, human studies of cytokine/chemokine production following CHIKV infection have, so far, not provided an overly coherent picture (5, 36, 42), complicating any choice of optimal targets. Observations from small-scale trials have suggested that anti-IFNγ antibodies might be effective against RA (43), and the results from our studies suggest that targeting IFNγ may be an effective approach for ameliorating CHIKV arthritis. This observation is consistent with the findings from previous studies showing that anti-IFNγ antibodies can ameliorate RRV disease in young mice (44).
Targeting induction of MCP-1/CCL2, a chemokine strongly up-regulated in CHIKV disease (4, 10, 36, 42), with bindarit was shown to be effective in mouse models of CHIKV disease (45). Although this cytokine is also up-regulated in RA, trials of a CCL2 receptor–blocking antibody in RA have been disappointing (46). Drugs blocking complement activation are being developed for a number of diseases, including RA (47), with evidence from studies of mice suggesting that complement activation also contributes to alphaviral disease (48).
Promotion of apoptosis of T cells and fibroblast-like-synoviocytes may emerge as another useful approach in the treatment of RA (49). Whether interventions that modulate apoptosis would be of benefit for alphaviral arthritides remains to be established (30). Although IFNα/IFNβ and B cell responses are likely to play important roles in the pathologic processes of RA (18, 50), targeting these as a treatment strategy for alphaviral arthritides may be considered too risky. Chronic CHIKV arthritis is likely due to the persistence of replication-competent virus (4), and the presence of IFNα/IFNβ and antibodies is clearly important for antiviral activity (10).
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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Suhrbier had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Nakaya, Pulendran, Suhrbier.
Acquisition of data. Nakaya, Gardner, Poo, Major.
Analysis and interpretation of data. Nakaya, Suhrbier.