From the Journals

Chikungunya virus goes undetected despite chronic arthritis in 25% of patients after 20 months



Up to a quarter of patients infected with chikungunya virus who reported joint pain as one of their initial symptoms continue to have joint pain after 20 months of follow-up, and evidence suggests that the persistent joint symptoms are not related to the continued presence of the virus in synovial fluid, according to two studies of patients infected during the 2014-2015 Colombian epidemic.

In the first large-scale, cross-sectional follow-up of a prospective cohort from the Colombian epidemic, Aileen Chang, MD, of George Washington University, Washington, and her colleagues at multiple other institutions reported persistent joint pain and multiple swollen and/or tender joints after 20 months in 123 of 485 Colombian patients who initially had joint pain with their Chikungunya virus infection (CHIKV) diagnosis. In their report in Arthritis & Rheumatology, they said that increased initial viral load and severe initial joint pain were predictors of persistent arthritis, which is consistent with the work of other researchers.

Shown is the Chikungunya virus. CDC/Cynthia Goldsmith

Shown is the Chikungunya virus.

In another study reported separately in Arthritis & Rheumatology from the same population of CHIKV patients with chronic arthritis, synovial fluid and blood plasma samples obtained from 38 patients at a median of 22 months of follow-up showed no signs of CHIKV RNA.

Dr. Chang worked with a variety of coinvestigators, some of whom were also involved in the larger symptom follow-up study, to conduct this Study of Chikungunya Arthritis Mechanisms in the Americas (CAMA). They collected synovial fluid and blood plasma from these 38 patients as well as 10 healthy controls who were serologically negative for CHIKV and never had arthritis, and analyzed the fluid and plasma for signs of CHIKV. They assessed viral RNA via quantitative reverse transcription polymerase chain reaction (qRT-PCR) testing, looked at viral proteins via mass spectrometry, and did viral cultures.

All samples from the 38 patients in the study were negative for CHIKV in two separate qRT-PCR assays. To determine if low-level viremia was present in synovial fluid samples, the samples were added to cell cultures to expand viral replication. No viral growth was found after three attempts and 10 days of culture. Conversely, controls with low quantities of virus (about 1 plaque-forming unit per well) yielded growth and detection of the virus.

Patients with CHIKV-associated arthritis also had no significant increase in rheumatoid arthritis markers or C-reactive protein. In fact, plasma markers for rheumatoid arthritis were found in only a fraction of patients with CHIKV arthritis: rheumatoid factor (RF) IgM antibody in 9%, RF IgG antibody in 12%, and anti–cyclic citrullinated peptide in 0%.

The more probable potential mechanisms through which CHIKV could cause persistent arthritis symptoms is through the presence of persistent CHIKV or viral antigens at low enough levels in the synovial tissue that it is undetectable in the synovial fluid, Dr. Chang and her associates suggested. There is also a possibility of epigenetic changes to the host DNA, altering host gene transcription. Other epigenetic changes, like epigenetic imprinting, could be possible in macrophages, leading to more aggressive cell behavior, they said. Unlikelier scenarios would be the presence of seronegative RA in these patients or, alternatively, the presence of seronegative RA indicating prior infection with CHIKV or other arthritogenic viruses.

Whatever mechanisms are causing CHIKV-associated arthritis, “these study findings may have important clinical relevance for CHIKV in the Americas. Since there is no current standard of care guidance for the treatment of CHIKV arthritis, some patients are currently being treated with immunosuppressant medications such as methotrexate, hydroxychloroquine, etanercept, adalimumab, sulfasalazine, fingolimod, abatacept, and tofacitinib,” Dr. Chang and her colleagues wrote. “This practice could be potentially harmful in the setting of replicating virus in the synovium as it could permit reemergence of a systemic viral infection.”

The CAMA study has several important limitations , the investigators said, the first being that during collection of synovial fluid, 0-20 mL of saline solution were used to flush the joints, which could have affected the ability to detect virus in the samples. In an attempt to mitigate this, the researchers cultured 0.5-1.5 mL of sampled synovial fluid to expand any replication-competent virus present in the sample, used two complementary PCR assays to detect nucleic acids, and a proteomic approach to look for viral proteins.

The researchers acknowledged that despite these measures, “proving the absence of a target is difficult, and we recognize that it is possible that our approach failed to detect low-level viral antigen; however, our orthogonal approach clearly demonstrates that if viral antigen exists in the synovial fluid, it is at extremely low levels.” They advised that future studies may want to use synovial biopsies rather than extracted fluid.

The investigators also did not include patients who had previously been infected by CHIKV without chronic arthritis. This issue was compounded by the lack of age- and sex-matched healthy controls.

All researchers involved in the studies reported no financial conflicts of interest. The studies were supported by various grants from the National Institutes of Health and the Rheumatology Research Foundation.

SOURCE: Chang A et al. Arthritis Rheumatol. 2017 Dec 20. doi: 10.1002/art.40383 and Chang A et al. Arthritis Rheumatol. 2017 Dec 20. doi: 10.1002/art.40384

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