Arthritis in Chikungunya Patients Not Due to Persistent Virus

Janis C. Kelly

December 29, 2017

Chikungunya virus (CHIKV) infection, a mosquito-borne disease reported in the Americas in 2013, leaves about one quarter of those infected with persistent arthritis, according to data from the Chikungunya Arthritis Mechanisms in the Americas (CAMA) study. The joint symptoms, however, do not appear to be associated with persistent infection, suggesting it is safe to treat patients with regimens used for other types of inflammatory arthritis.

Chronic joint pain after CHIKV infection has been reported previously in prior studies, but the frequency was unclear, with estimates ranging from 30% to 70%. Therefore, Aileen Y. Chang, MD, MSPH, from the Department of Medicine at George Washington University in Washington, DC, and colleagues conducted a cross-sectional follow-up of a prospective cohort of 500 patients who had been clinically diagnosed during the 2014 to 2015 Columbian epidemic.

The patients, referred for the study by primary care providers, had clinically suspected CHIKV, defined as fever greater than 38°C, severe joint pain or arthritis, acute onset of erythema, and residing or having visited an area with evidence of CHIKV transmission.

Of these subjects, 485 were serologically confirmed as having CHIKV and responded to baseline questions regarding joint pain. The most commonly affected joints were wrists, ankles, and fingers, and initial joint pain had lasted a median of 4 days. The authors note there were no significant increases in rheumatoid arthritis-associated markers or in C-reactive protein in subjects with CHIKV-associated arthritis.

With a median follow-up of 20 months, 25.4% of participants reported in a telephone interview that they had persistent joint pain. Factors associated with persistent pain included initial symptoms of headache or joint pain, 4 or more days of initial symptom, 4 or more weeks of initial pain, missed work, missed normal activities, and college graduate status. At follow-up, most patients had only one swollen joint, but also had tenderness in three more joints, with a mean global pain score of 47.

"The finding of chronic joint pain in one fourth of the patients infected with CHIKV approximately 2 years after initial infection has important implications for prediction of the magnitude of disability and health system costs after the Latin American epidemic," the authors write in an article published online December 20 in Arthritis & Rheumatology. "Prior predictions had over-estimated the expected frequency of CHIKV-related joint pain in Latin America indicating 48% of CHIKV-infected people were predicted to have chronic chikungunya arthritis 20 months after acute infection."

The authors explain in an accompanying article published at the same time that although small studies have shown apparent benefit from treating CHIKV with antivirals such as ribavirin or immunosuppressants such as methotrexate, hydroxychloroquine, etanercept, adalimumab, or sulfasalazine, large-scale clinical studies will require deeper understanding of CHIKV pathophysiology. "If persistent CHIKV infection is responsible for ongoing arthritis, immunocompromising disease modifying agents may be improper and potentially dangerous treatments. Alternatively, if CHIKV does not persist in the joint, then evaluation of immunomodulating arthritis agents could be useful," they write.

To address that question, the researchers also performed a cross-sectional analysis of synovial fluid from 38 CHIKV-infected subjects with chronic arthritis and 10 location-matched control patients who were CHIKV-negative and did not have arthritis. The researchers tested the synovial fluid for CHIKV, viral RNA, and viral proteins, using viral culture, quantitative reverse transcription polymerase chain reaction, and mass spectrometry, respectively. All three assays were negative, indicating that the joint pain is not a result of persistent viral infection.

Furthermore, plasma cytokine/chemokine concentrations did not differ significantly between cases and controls, which also supports that conclusion.

The researchers conclude, "This finding suggests that CHIKV may cause arthritis through induction of potential host autoimmunity suggesting a role for immunomodulating medications in the treatment of CHIKV arthritis or that low-level viral persistence exists in synovial tissue only that is undetectable in synovial fluid."

The authors have disclosed no relevant financial relationships.

Arthritis Rheum. Published online December 20, 2017. Chronic joint pain abstract, Arthritis abstract

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