Successful Methotrexate Treatment of Chronic Chikungunya Arthritis

J. Kennedy Amaral, MD; Clifton O. Bingham, III, MD; Robert T. Schoen, MD, MBA


J Clin Rheumatol. 2020;26(3):119-124. 

In This Article


Since 2004, explosive CHIK epidemics have occurred throughout the tropical and subtropicaI world—in Africa, South Asia, the Far East, southern Europe, and, most recently, the Americas, with millions of cases reported.[1,4–6] In the majority of patients, CHIKF is followed by chronic CHIK arthritis and musculoskeletal illness. In a recent meta-analysis, the prevalence of "chronic inflammatory rheumatism" among 5702 CHIK-infected individuals was 40.22%.[13] In another study, more than 60% of CHIK patients continued to have arthralgia 36 months after acute infection.[22] In an outbreak on La Reunion Island, 83% of the patients had joint pain at a mean of 32 months' follow-up,[23] and 59% were symptomatic for more than 6 years.[13,20]

Brazil is a tropical and subtropical country with 210 million people.[21] Because of the tropical climate, urban crowding, and challenges in vector control, every Brazilian state is infested with Aedes mosquitoes, the vectors responsible for dengue and Zika virus as well as CHIK.[24] In Brazil, the first locally transmitted CHIK infection occurred in September 2014 in the state of Amapá, near the state of Pernambuco where our patients live. By 2016, Brazil had 263,598 suspected and 145,059 confirmed CHIKF cases.[21] Given this massive epidemic of inflammatory arthritis, our experience caring for a large cohort of chronically ill, disabled Brazilian CHIK rheumatology patients is not surprising. As elsewhere, the Brazilian arthritis epidemic has strained available resources. In addition, the lack of evidence as to how these patients should be treated increases the challenges faced by rheumatologists.

Our patients experienced chronic pain and disability prior to their self-referral to our clinic. In the group of individuals reported here, the mean time between the onset of CHIKF and the first rheumatology consultation was 14.2 months. Our experience was similar to delays of 8 months to 2 years in treatment of chronic CHIK arthritis reported elsewhere.[7,20,25] Failure to treat chronic CHIK arthritis promptly burdens the individual patient with pain and disability and the community with economic loss.[15] In addition, treatment delay increases the risk of bone erosions and permanent joint deformities.[16,26,27]

In this cohort of 50 CHIK arthritis patients, we assessed joints affected to look for patterns of arthritis (Figure 1). We determined that the most frequently affected joints were hands, wrists, and shoulders and hands, similar to other reports. For example, Borgherini et al.[7] reported joints affected such as hands (57.1%), knees (57.1%), wrists (50%), ankles (46.4%), and shoulders (44.6%). Mathew et al.[28] reported involvement of knees (83.3%), ankles (62.3%), and elbows (59%). As in our study, other studies generally report a pattern of symmetric polyarthralgia/polyarthritis of large and small joints, especially hands, knees, shoulders, wrists, and ankles.[14,29–33]

We evaluated whether preexisting rheumatic disease impacts the subsequent clinical expression of chronic CHIK arthritis. Among 159 cases of "postchikungunya rheumatic disorders" analyzed by Javelle et al.,[20] 50 (31%) had previous "rheumatic and musculoskeletal disorders,", including 6 with "chronic inflammatory rheumatism." Sissoko et al.[34] observed osteoarthritis in 38 (26%) of 147 patients followed for 15 months. In a small study, Zeana et al.[35] reported preexisting rheumatic disease, including osteoarthritis, carpal tunnel syndrome, retrocalcaneal bursitis, and lateral epicondylitis. Essackjee et al.[36] found that among 173 patients followed for more than 2 years after CHIKV infection 27 (15.6%) had some preexisting musculoskeletal disease. Questioning our patients carefully, we observed that 22 (44%) had rheumatic disease prior to CHIKV infection, but there was no relationship between these conditions and clinical expression of CHIK arthritis or response to treatment.

There is a lack of consensus as to how chronic CHIK arthritis symptoms should be treated[37] in part because the pathogenesis is uncertain, specifically whether chronic CHIK arthritis results from a persistent viral infection or from postinfectious immune-mediated factors.[2,12] In a recent Colombian study of 22 chronic arthritis patients, synovial fluid analysis did not detect CHIKV by culture, by quantitative polymerase chain reaction, or by mass spectrophotometry for CHIK viral proteins. The authors concluded that CHIK arthritis may therefore represent a postinfectious, immune-mediated process and that CHIKV infection may no longer present in the arthritic phase of the disease. But that study did not include synovial biopsies and therefore could not exclude the presence of residual CHIKV in synovial tissue.[38]

Various treatments, including MTX and other DMARDs, have been used to treat chronic CHIK arthritis. These have included NSAIDs, corticosteroids, HCQ, SSZ, and MTX alone or in combination, and in some cases, with biological agents.[20,34,37,39] In our study, we treated 48 patients with used MTX for several reasons.[40] As discussed, we considered the concept of a postinfectious inflammatory pathogenesis for chronic CHIK arthritis. We also noted the clinical similarities between chronic CHIK arthritis and RA, the risk of irreversible joint deformity, and the mechanism of action of MTX in RA and other inflammatory rheumatic diseases. In addition, given the widespread availability and relative cost-effectiveness of MTX and familiarity with its use in the treatment of inflammatory arthritis, we believe that if MTX is effective and safe it could become the drug of choice in chronic CHIK arthritis.[40–42]

In our study, the pain VAS was considered a good parameter in the evaluation of pain and disability. Because all our patients had pain, but not all patients had demonstrablesynovitis, but all had persistent pain. Pain VAS was used as the outcome measure in 72 patients with persistent CHIKF arthritis evaluated by Ravindran and Alias[41] in a 24-week randomized clinical trial. In that study, one group received triple combination therapy (fixed dose of MTX 15 mg/wk, SSZ 1 g/d, and HCQ 400 mg/d), and the other group received HCQ monotherapy (400 mg/d). Both European League Against Rheumatism response and pain VAS were significantly better in patients with combined therapy (85% vs. 14% and 46 ± 6.13 vs. 60.8 ± 11.6, p < 0.0001, respectively). In another prospective study by Pandya,[42] most of the 305 subjects with chronic inflammatory polyarthritis (>5 swollen and painful joints for >3 months) were treated with a combination of MTX (15 mg/wk) and HCQ (400 mg/d). Visual analog scale was used in the evaluation results along with ACR 20, ACR 50, ACR 70, 28-joint Disease Activity Score, erythrocyte sedimentation rate, and Health Assessment Questionnaire. Approximately 48.8% and 18.8% of the patients completed the 16 weeks of treatment and achieved ACR 20 and ACR 50 responses, respectively. However, none of the studies described the outcome of the treatment using pain VAS alone. Importantly, in the studies cited, patients all had baseline arthritis, whereas in our study the majority had arthralgia without arthritis.

Ahmed et al.[43] also used VAS to evaluate treatment with chloroquine or paracetamol in 86 participants in the post–acute stage of CHIKV. In this randomized study, at 8 days, the chloroquine group had better pain relief compared with those who received paracetamol (relative risk, 1.52; 95% confidence interval, 1.20–1.93). Similarly, Padmakumar et al.[44] and Chopra et al.[45] also used VAS as an outcome measure for the treatment of CHIKF arthritis.

The pain VAS responses to MTX therapy in our study are notable. There was a rapid reduction in pain in most patients that began to plateau by 4 weeks. This is shorter than is typical for such low-dose MTX in RA and other forms of inflammatory arthritis, with current treatment recommendations for rapid dose escalation to 20 to 25 mg/wk, with clinical responses occurring over a longer period.[46] Among the patients with frank arthritis, we also observed significant improvement in swollen and tender joints.

Limitations of our study include its retrospective nature, being historical, and the lack of a control group. In the patients with arthritis, there was no specified documentation of swollen or tender joints or patient global assessment to enable the calculation of composite disease outcome measures such as ACR or European League Against Rheumatism responses, or Clinical Disease Activity Index or Simplified Disease Activity Index calculations. The results nonetheless demonstrate a rapid and robust improvement in pain in these MTX-treated chronic CHIK arthritis patients, documented by VAS, a widely validated outcome measure. Methotrexate therapy was well tolerated without evidence of drug toxicity or recurrence of CHIK infection. We believe that this study informs practitioners of the possible benefit of low-dose MTX to treat both arthralgia and arthritis in chronic CHIK arthritis. Our study also supports further evaluation of MTX in chronic CHIK arthritis in a larger, prospective, randomized, placebo-controlled trial.