Repurposed Drugs May Treat Chikungunya Symptoms

Diana Phillips

February 02, 2017

Established therapies for autoimmune conditions may have promise in the treatment of the joint pain and inflammation associated with Chikungunya virus (CHIKV) infection, according to the findings of two separate animal studies published February 1 in Science Translational Medicine.

CHIKV infection is a mosquito-borne disease characterized by an abrupt onset of fever frequently accompanied by signs and symptoms that can mimic adult rheumatoid arthritis, including joint pain that can become chronic and debilitating in some individuals, as reported previously by Medscape Medical News.

At this time, no treatments have been approved for preventing or controlling CHIKV infection or disease, but the newly reported mouse studies suggest therapeutic options may be found in existing agents that modulate the host immune response.

Antiviral and T-Cell Suppressive Combination

On the basis of previous data implicating immune cells and proinflammatory cytokines in CHIKV arthritis and their own research indicating that CHIKV arthritis can clinically mimic seronegative rheumatoid arthritis, "We reasoned that established therapies used to treat other forms of inflammatory arthritis (for example, rheumatoid or psoriatic arthritis) also might mitigate CHIKV arthritis," Jonathan J. Miner, MD, from the Department of Medicine at Washington University School of Medicine, St Louis, Missouri, and colleagues write in one of the studies.

To test the hypothesis, the researchers designed a multigroup prospective study in which inoculated mice were treated with eight different disease-modifying antirheumatic drugs (DMARDs), individually or in combination.

They found that two DMARDs approved for the treatment of rheumatoid arthritis — CLTA4-Ig (abatacept), a T-cell co-stimulation modulator, and tofacitinib, an oral janus Kinase inhibitor — reduced joint pathology and periarticular inflammation, but had little effect on viral burden.

"Our experiments identified CLTA4-Ig and tofacitinib as candidate DMARD therapies based on efficacy against acute CHIKV arthritis in mice," the authors write.

Moreover, when they paired CLTA4-Ig with a neutralizing anti-CHIKV human monoclonal antibody, the combination reduced joint pathology and viral burden, with declines in the levels of chemokines, proinflammatory cytokines, and infiltrating leukocytes.

The authors stress that the findings should be "interpreted with caution," given the limitations of the mouse model. "Unlike humans, mice are not natural hosts for CHIKV and therefore do not develop the severe, debilitating arthritis that is commonly observed in humans," they write. "Because CHIKV causes less severe disease in mice, it remains possible that immunomodulatory therapies, including CLTA4-Ig, may have no or even deleterious effects in humans."

If validated in human testing, the combination antiviral and immunomodulatory therapy "has implications for treatment of other viral infections in which both virus- and immune-mediated pathology result in morbidity and mortality," the authors write. "Given the large number of clinically available biological and small molecular DMARDs, this work may provide greater impetus for studies that test combination antiviral and immunomodulatory therapies for the treatment of infectious diseases."

Fingolimod Reduces Joint Pathology

In the second study, Teck-Hui Teo, PhD, from the Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore, and colleagues studied the effect of the multiple sclerosis drug fingolimod on CHIKV-infected mice. Previous research has suggested that CHIKV pathogenesis may be mediated by CD4+T cells, which the drug suppresses.

In their model, the researchers showed that fingolimod treatment suppressed joint pathology in the infected mice by blocking the migration of CD4+T cells into the swollen joints. "This paves the way for therapeutic intervention to reduce severe disease morbidity in CHIKV-infected patients," they write.

With more than 6 million people currently infected with CHIKV worldwide, the disease poses a global threat, Philippe Gasque, MD, PhD, and Marie Christine Jaffar-Bandjee, MD, PhD, both from Université de la Réunion, Saint Denis, France, write in an accompanying editorial. Because no drugs have regulatory approval for the treatment of CHIKV arthritis, "[e]xperimental mouse models are indispensable to the field of CHIKV research and, more generally, for shedding light on the links between virus infection and chronic disease," they stress.

"Miner et al. and Teo et al. now demonstrate the potential value of combination therapies in a mouse model of CHIKV infection for ameliorating heightened T cell responses and their pathogenic role in joint inflammation," they continue.

To better understand the role of the host immune system in CHIKV-associated joint inflammation and arthritis, more robust models are needed, the editorialists write. "Future studies are needed to continue rational targeting of pathogenic steps at all stages of CHIKV infection. Such studies should provide new insights into the immune responses involved in viral infection and persistence and ways to intervene to halt consequent chronic inflammatory tissue damage."

One coauthor disclosed financial relationships with InBios, Visterra, Sanofi, Takeda Pharmaceuticals, Moderna, and OraGene. Another coauthor disclosed relationships with Sanofi, PaxVax, CompuVax, GigaGen, Meissa Vaccines, and Moderna and is a coinventor of the 4N12 antibody, for which a patent application has been filed. The other authors have disclosed no relevant financial relationships.

Sci Transl Med. Published online February 1, 2017. Miner abstract, Teo abstract, Editorial

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