Saint-Louis: Combining a drug for rheumatoid arthritis with one that targets the chikungunya virus can eliminate the signs of chikungunya arthritis in mice in the disease’s earliest stage, according to researchers at Washington University School of Medicine in St. Louis. The findings could lead to a drug therapy for the painful, debilitating condition for which there currently is no treatment.
“We found that combining these two drugs could abolish the signs of arthritis in mice during the acute phase,” said Deborah Lenschow, MD, PhD,
an associate professor of medicine and the study’s co-senior author,
referring to the phase in the first weeks after infection.
The study is published Feb. 1 in Science Translational Medicine.
Until about a decade ago, chikungunya virus, which is transmitted by
mosquitoes, mainly was restricted to East Africa and South Asia. But in
recent years the virus has spread around the world. The first case
originating in the Western Hemisphere was reported in late 2013, and by
the end of 2015, the virus had infected an estimated 1.8 million people
in the Americas.
Chikungunya infection causes fever and severe joint pain, as well as
rash, muscle pain and fatigue. The majority of patients continue to
experience joint pain six months after infection, and for some, the
arthritis continues for years.
“We were seeing people at our rheumatology clinic whose signs and
symptoms really mimicked rheumatoid arthritis but who had been infected
with chikungunya,” Lenschow said. “This raised the question in our
minds, ‘Would therapeutics we use to treat rheumatoid arthritis be of
any benefit to patients with chikungunya arthritis?’”
To find out, Lenschow, co-senior author Michael Diamond, MD, PhD,
and colleagues tested a panel of six rheumatoid arthritis drugs – all
approved by the Food and Drug Administration for use in patients – on
mice infected with chikungunya virus.
All six drugs work by suppressing the activity of the immune system.
Although different in many ways, rheumatoid arthritis and chikungunya
arthritis both involve out-of-control immune activity in the joints.
The researchers injected seven groups of mice with the virus and
three days later administered one of the six arthritis drugs or a
placebo to each group of mice. A week after infection – when the mice’s
arthritis signs were at their peak – the researchers measured the amount
of swelling around the joints as well as the numbers of immune cells
and molecules in the affected areas.
Two of the drugs – abatacept and tofacitinib – significantly reduced
the swelling and the levels of immune cells and molecules. Importantly,
the levels of live virus did not increase in the animals given the
immunosuppressive arthritis drugs.
“There was a significant concern that administering any
immunosuppressive drug would allow the virus to escape from immune
control, leading to worse outcomes in the long term,” said Diamond, the
Herbert S. Gasser Professor of Medicine. “We’ve seen that with other
viruses, but in this case, none of the drugs seemed to exacerbate viral
replication. This raises the possibility that these drugs can be safely
investigated in humans.”
The treatment was only partially successful at resolving the
arthritis, however, which led the researchers to test whether adding a
human antibody against chikungunya virus could improve the
As before, the researchers infected mice with the virus and three
days later dosed them with the arthritis drug abatacept, the antiviral
drug or both. Each drug individually reduced joint swelling a week after
infection. But when abatacept and the antiviral drug were used
together, the joint swelling and the infectious virus in the animals’
joints were eliminated.
“We saw real improvement in the acute phase, but unfortunately, the
drug interventions we tried failed to correct the chronic phase,”
In humans, the chronic phase of chikungunya arthritis starts three
weeks after initial infection and lasts as long as the patient continues
to experience joint pain, which can be three or four years. During the
chronic phase, infectious virus is no longer detectable in the joints,
but viral genetic material persists and may be sufficient to trigger an
ongoing immune response, causing the tissue damage that patients
perceive as arthritis.
The researchers found a similar pattern in the mice treated with the
drug combination: By four weeks after infection, live virus was no
longer present in the animals’ joints, but viral genetic material
remained, suggesting that the drugs had not eliminated the chronic phase
of the disease.
It is possible that a treatment that reduces arthritis symptoms in
the first weeks after infection could lower the chance that the disease
becomes chronic, but no data has yet been published for or against the
possibility. Still, any effective treatment, even if short-lived, would
be a boon for chikungunya patients, who currently have no proven
treatment options. Lenschow has discussed beginning a human study with
colleagues in Brazil, but plans are not yet finalized.
“In those first weeks, people are really very sick with a high fever
and a lot of pain, so if further studies show that this combination
treatment is effective in humans, that will have real benefits for
patients,” Diamond said. “As for the chronic phase, we’re going to
continue looking for other treatment strategies.”