https://orcid.org/0000-0003-3880-8446
Figures
Abstract
Chikungunya virus (CHIKV) is an arthropod-borne virus transmitted by mosquitoes of the genus Aedes. CHIKV infection causes various rheumatic symptoms, including enthesitis; however, these effects are rarely investigated. The aim of this study was to describe the rheumatic manifestations in CHIKV infection, estimate the prevalence of enthesitis in CHIKV-infected patients, and determine the factors associated with CHIKV-induced enthesitis. We conducted a prospective, observational study in patients with CHIKV infection confirmed by positive RT-PCR or IgM assay from October 2019 to March 2020. Patients with pre-existing inflammatory rheumatic diseases were excluded. A rheumatologist evaluated the demographic and clinical characteristics of the patients, including the number of inflamed joints, enthesitis sites, tendinitis, and tenosynovitis. The Leeds enthesitis index (LEI) and the Maastricht ankylosing spondylitis enthesis score (MASES) were used to evaluate enthesitis sites. Factors associated with enthesitis were determined using logistic regression analysis. One hundred and sixty-four participants diagnosed with CHIKV infection were enrolled. The mean (SD) age of the patients was 48.2 (14) years. The most common pattern of rheumatic manifestations was polyarthritis with or without enthesitis. Enthesitis was observed in 63 patients (38.4%). The most common site of enthesitis was the left lateral epicondyle as assessed by LEI and the posterior superior iliac spine as assessed by MASES. Multivariate analysis indicated that the number of actively inflamed joints and Thai-HAQ score at the initial evaluation were significantly associated with the presence of enthesitis. The main rheumatic manifestations of CHIKV infection were arthritis/arthralgia, with enthesitis as a prominent extraarticular feature. CHIKV infection can cause enthesitis at peripheral and axial sites. We found that enthesitis was associated with a high number of inflamed joints and reduced physical function. These results indicate that the assessment of enthesitis should be considered when monitoring disease activity and as a treatment response parameter in CHIKV-infected patients.
Citation: Benjamanukul S, Osiri M, Chansaenroj J, Chirathaworn C, Poovorawan Y (2021) Rheumatic manifestations of Chikungunya virus infection: Prevalence, patterns, and enthesitis. PLoS ONE 16(4): e0249867. https://doi.org/10.1371/journal.pone.0249867
Editor: Pierre Roques, CEA, FRANCE
Received: January 17, 2021; Accepted: March 15, 2021; Published: April 22, 2021
Copyright: © 2021 Benjamanukul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: YP; P-15-50004, The Research Chair Grant from the National Science and Technology Development Agency. YP; GCE 59-009-30-005, The Center of Excellence in Clinical Virology, Chulalongkorn University. JC; the Second Century Fund (C2F), Chulalongkorn University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Chikungunya virus (CHIKV) is an arthropod-borne virus transmitted by mosquitoes of the genus Aedes (A. albopictus and A. aegypti) [1]. “Chikungunya” is a Makonde phrase meaning “that which bends up” and refers to the stooping posture displayed by CHIKV-infected patients as a result of excruciating joint pain [2]. The classic symptoms of CHIKV infection include an abrupt onset of fever, rash, and incapacitating joint pain. Clinically, CHIKV infection may lead to a broad spectrum of chronic rheumatic symptoms similar to rheumatoid arthritis (RA), spondyloarthritis (SpA), undifferentiated arthritis (UA), psoriatic arthritis, and soft-tissue rheumatism [3–5]. In individual patients, arthralgia or arthritis may persist for months or years. Persistent symptoms can significantly impair the quality of life of patients [6]. In addition to arthritis, the reported rheumatic manifestations for CHIKV infection include tendinitis, tenosynovitis, neuropathic pain, and, rarely, enthesitis.
The first CHIKV outbreak in Thailand was reported in 1958 [7]. The second was in 2008–2009 and affected mainly the southern region of the country [8, 9]. However, in 2018, a large-scale outbreak occurred in different parts of Thailand. Although the clinical manifestations and cytokine profiles of CHIKV infection have been reported [10–13], no study has investigated the rheumatic manifestations associated with infection by this virus. The objectives of our study were to describe the rheumatic manifestations of CHIKV infection, estimate the prevalence of enthesitis in CHIKV-infected patients, and determine the factors associated with the presence of CHIKV infection-induced enthesitis.
Materials and methods
This study was conducted according to the principles expressed in the Declaration of Helsinki and Good Clinical Practice (ICH-GCP) guidelines. The proposal was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB No. 798/62). All the study participants were informed of the study objectives and provided written consent.
Study area and populations
Banphaeo is a district of Samutsakhon province, located approximately 70 km southwest of Bangkok, Thailand. The average population density is 410 people per square kilometer, and most are agriculturists. The 2019–2020 CHIKV outbreak began at the end of the rainy season in 2019 (October) and lasted until the end of the winter in 2020 (March). At the onset of illness, adult patients suspected of being infected with CHIKV were routinely assessed by general practitioners. These patients were later referred to a rheumatologist (SB) for the evaluation of rheumatologic conditions and further management. Adult patients (≥18) with rheumatic symptoms and with CHIKV infection confirmed by positive real-time RT-PCR or IgM results were included in this study. Real-time RT-PCR and IgM testing for CHIKV diagnosis have been described elsewhere [14]. Patients who were unable to give consent or those with pre-existing inflammatory rheumatic diseases were excluded.
Data collection and clinical evaluation
In this observational prospective cohort study, we collected disease symptom data (fever, rash onset, pain score, and joint pain locations) of the patients at their first visit to a general practitioner. All the participants were followed up by a rheumatologist (SB) every one-to-two months, depending on the severity of the pain or arthritic symptoms. They were assessed for their personal history, body mass index (BMI), underlying diseases, pre-existing joint diseases, pain score, tender and/or swollen joint count (66/68), and presence and sites of tendinitis, enthesitis, dactylitis, and tenosynovitis. The pain score was assessed using a verbal numeric scale in which patients were asked to verbally state a number between 0 (no pain) and 10 (worst possible pain) that corresponded to their present pain intensity. Enthesitis was defined as the presence of at least one tender entheseal site using the Leeds enthesitis index (LEI) and the Maastricht ankylosing spondylitis enthesis score (MASES). Neuropathic pain was assessed using the Thai version of the Douleur Neuropathique 4 questions (DN4) questionnaire [15], and the presence of neuropathic pain was defined as a score ≥4. Other rheumatic symptom data collected included back pain and myalgia. At the first visit, the rheumatologist performed a functional evaluation using the Thai version of the Health Assessment Questionnaire (Thai-HAQ) [16] and a quality-of-life evaluation using the Thai version of the standardized EQ-5D-5L questionnaire [17] at the onset of symptoms. The acute phase of CHIKV infection was defined as having symptoms for less than or equal to three weeks; the post-acute phase as having symptoms for between three weeks and three months; and the chronic phase as having symptoms for more than three months [18]. Patients who progressed to the chronic stage were classified as having post-CHIKV chronic inflammatory rheumatism (pCHIK-CIR) and post-CHIKV musculoskeletal disorder (pCHIK-MSD) [3]. pCHIK-CIR was classified into the following three categories: 1) RA, based on the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria [19]; 2) SpA, as defined by the European Spondyloarthropathy Study Group (ESSG) [20]; and 3) UA, when none of the existing classification criteria for definitive diagnoses were fulfilled [21]. pCHIK-MSD was categorized as locoregional or diffuse (i.e., at least 4 painful areas) [3]. Data regarding the medication prescribed at the acute, post-acute, and chronic phases were also collected.
Statistical analysis
Categorical variables were summarized using percentages. Continuous variables were shown as means ± standard deviation (SD) and/or medians with interquartile range (IQR) as appropriate. The demographic and clinical parameters associated with enthesitis were analyzed using logistic regression. Associations between LEI and MASES scores were expressed using Spearman’s rank correlation coefficient. Data were analyzed using Stata statistical software version 15.1 (StataCorp, College Station, TX, USA).
Results
A total of 209 patients were assessed by general practitioners as fulfilling the diagnosis criteria for acute CHIKV infection. Forty-two patients were lost to follow-up before assessment by a rheumatologist. Three patients were excluded because of pre-existing inflammatory rheumatic disorders, i.e., RA in 2 cases and SpA in 1. Consequently, this study reported the data for 164 patients.
CHIKV diagnosis was confirmed by RT-PCR in 92 patients (56%) and by IgM antibody assay in 72 patients (44%). The demographic and clinical data of the enrolled patients are presented in Table 1. The mean (SD) age of the patients was 48.2 (14) years, with a female to male patient ratio of 2.8:1. Sixty-eight patients (41.4%) had comorbid diseases, including hypertension in 35 patients (21.3%), diabetes mellitus in 16 patients (9.8%), and asthma in 11 patients (6.7%). Sixteen patients (9.8%) were hospitalized for severe pain. No deaths were reported in our study. The median (IQR) duration of work absenteeism was 7 days (4–10).
The information of the clinical features at the onset of CHIK infection as assessed by general practitioners showed that rashes were reported in 136 patients (82.9%), and the mean (SD) duration of fever before the occurrence of rash was 2 (2.6) days (median [IQR] 1 [0–3]). Rheumatic manifestations occurred within two weeks of fever onset with a mean (SD) of 0 (2.6) days (median [IQR] 0 [0–0]). Based on the general practitioners’ examinations, the most common pattern of articular involvement was a polyarticular form in 152 patients (92.7%), followed by an oligoarticular form in 10 patients (6.1%) and a monoarticular form in 2 (1.2%). Joint pain affected both the upper and lower extremities in 129 patients (79%). Symmetrical joint pain was observed in 155 patients (94.5%), and both small and large joints were involved in 150 patients (91.5%). The most common site of joint pain was the ankle (n = 133, 81.1%), the proximal interphalangeal (PIP) joint of the finger (n = 125, 76.2%), the wrist (n = 118, 72%), and the knee (n = 112, 68.3%). The mean (SD) pain score was 8.1 (1.8). The mean (SD) number of actively inflamed joints (tender and/or swollen) at the acute stage was 21.0 (14.1). Nonsteroidal anti-inflammatory drugs (NSAIDs) were prescribed for 51 patients (31.1%); combination treatment with NSAIDs and/or muscle relaxant and/or tramadol and/or paracetamol was prescribed for 48 patients (29%). Paracetamol alone was prescribed for 30 patients (18.3%), muscle relaxant alone for 9 patients (5.5%), prednisolone alone for 3 patients (1.8%), and tramadol alone for 12 patients (1.3%). The medication prescribed for 8 patients (4.9%) was unknown because they received treatment from private clinics. Three patients were not prescribed any medication.
The median (IQR) duration from a general practitioner’s visit to a rheumatologist consultation was 21 days (12–39) (with a mean [SD] of 28.6 [23] days). Eighty-three patients (50.6%) were in the acute phase when they were assessed by a rheumatologist, 78 (47.6%) in the post-acute phase, and 3 (1.8%) in the chronic phase. The patterns of joint and/or enthesis involvement at the rheumatologist’s first assessment are shown in Table 2. Isolated joint involvement was the most common form of rheumatic manifestation with CHIKV infection, affecting 86 patients (52.4%). Polyarthritis was predominant in 36 patients (22%). Fifty-seven patients (34.8%) displayed both joint and enthesis involvement, while 16 patients (9.8%) presented with polyarthritis and enthesitis in at least three sites. The median (IQR) number of actively inflamed joints (tender and/or swollen joint count) examined by the rheumatologist at the first appointment was 4 (1–12) (mean ± SD: 7.8 ± 8.9 joints). The median (IQR) tender joint count was 4 (1–10) (mean ± SD: 7.1 ± 9 joints), while the median (IQR) swollen joint count was 2 (0–6) (mean ± SD: 4.1 ± 5.7 joints). The most frequently affected joint examined by the rheumatologist was the PIP joint of the finger (n = 89, 54.3%), followed by the ankle (n = 72, 43.9%), wrist (n = 68, 41.5%), metacarpophalangeal (MCP) joint (n = 51, 31.1%), and knee (n = 27, 16.5%). Uncommon sites of joint involvement included the acromioclavicular joint in 22 patients (13.4%), sternoclavicular joint in 9 patients (5.5%), and temporomandibular joint in 5 patients (3%).
At the first assessment by a rheumatologist, joint pain due to acute CHIKV infection had intrinsic joint and/or tendon and/or tenosynovial and/or enthesis involvement in 97 patients (59%). Joint involvement only was reported in 62 patients (38%), while tendinitis and/or tenosynovitis and/or enthesitis only was reported in 5 patients (3%). Tendinitis was detected in 54 patients (32.9%) and tenosynovitis in 5 (3%). Achilles tendinitis was predominant in patients with tendinitis (48 patients; 88.9%).
The prevalence of chronic CHIKV infection in our cohort was 55.5% (91 out of 164 patients). The rheumatologic manifestations in these patients are shown in Fig 1. Forty-eight patients (52.7%) had pCHIK-CIR, including 7 (14.6%), 11 (22.9%), and 30 (62.5%) who were classified as having RA, SpA, and UA, respectively. Forty-three patients (47.3%) had pCHIK-MSD. Of these, 14 (32.6%) displayed diffuse symptoms (polyarthralgia in 12 patients and polyenthesitis in 2). Twenty-nine (67.4%) patients had locoregional symptoms (monoarthralgia/oligoarthralgia in 18 patients, neuropathic pain in 6, enthesitis in 4, and tendinitis in 1).
CHIKV, Chikungunya virus; pCHIK-CIR, post-chikungunya chronic inflammatory rheumatism; pCHIK-MSD, post-chikungunya musculoskeletal disorder; RA, rheumatoid arthritis; SpA, spondyloarthritis; UA, undifferentiated arthritis.
Enthesitis was observed in 63 patients (38.4%). Thirty-seven (58.7%), 25 (39.7%), and 1 (1.6%) patients presented with enthesitis in the acute, post-acute, and chronic phases, respectively, at the first assessment by a rheumatologist. LEI values and MASESs are presented in Tables 3 and 4. The mean (SD) LEI value was 1.6 (1.4). The most common enthesitis site as assessed by the LEI was the left lateral epicondyle (42.9%), and the left medial femoral condyle (38.1%) was the second. The mean (SD) MASES was 1.8 (2.2). The most common sites determined using the MASES were the posterior superior iliac spine (PSIS; 38.1% of patients) and fifth lumbar spinous process (17.5% of patients). The LEI was shown to be poorly associated with the MASES (r = 0.14).
Back pain was detected in 72 patients (43.9%) and myalgia in 118 (72%). Diffuse myalgia was the major complaint for 70% of patients, and local myalgia in the calf muscle was found in 3%. Fifty-six patients (34.1%) in all phases reported having neuropathic pain as assessed by the DN4 score. The characteristics of neuropathic pain included tingling in 52.9% of patients, pins and needles in 50.6%, electric shock in 31%, itching in 31%, burning in 27.7%, numbness in 18.7%, hypoesthesia to touch in 23.3%, hypoesthesia to pinprick in 18.7%, and increased pain by brushing in 5.8%. Neuropathic pain in the hands was found in 85.7% of patients, 25% reported neuropathic pain in the feet, and 17.9% reported neuropathic pain in both hands and feet. Neuropathic pain displayed a glove- and/or stocking-like pattern in 96.4% of our patients, and presented as carpal tunnel syndrome in 3.6%. Two-thirds (32/48) of patients with neuropathic pain reported a greater than 50% improvement after taking 300 mg of gabapentin per day. Physical function and quality of life at illness onset were moderately impaired, with a mean (SD) Thai-HAQ score of 2.01 (0.84) and a mean (SD) value for the Thai version of the EQ-5D-5L utility of 0.27 (0.32) (median [IQR] 0.23 [0.01–0.54]).
The treatments administered to patients in the post-acute and chronic phases are shown in Table 5. The treatments for the post-acute phase of CHIKV infection with which the patients showed a greater than 50% improvement in pain score at one-month follow-up included NSAIDs only (90%; 44/49), low-dose (10 mg or less per day) prednisolone (84.4%; 27/32), chloroquine (71.1%; 27/38), and conventional synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs; 50% [2/4]). Patients who received chloroquine, prednisolone, or DMARDs were also prescribed NSAIDs for pain relief. The treatment response assessment for the chronic phase after three months of infection has yet to be determined.
Table 6 shows the univariate and multivariate logistic regression analysis for factors associated with the presence of enthesitis. In the univariate analysis, three factors were significantly associated with enthesitis, including neuropathic pain, the number of actively inflamed joints as assessed by a rheumatologist, and the Thai-HAQ score at disease onset. However, in the multivariate analysis, only the number of actively inflamed joints (odds ratio [OR] 1.11, 95% CI 1.05–1.16, p<0.001) and the Thai-HAQ score at illness onset (OR 1.71, 95% CI 1.06–2.76, p = 0.03) were significantly associated with the presence of enthesitis.
Discussion
This is the first study to report the rheumatic manifestations associated with confirmed cases of CHIKV infection in Thailand, including detailed data on enthesitis.
In the acute phase, joint involvement was mostly symmetric, involving both small and large joints of the upper and lower limbs. Polyarthritis was the most common manifestation of articular involvement, which was in agreement with that reported in several studies [22–25], but different from the results obtained in another study [26], in which oligoarticular involvement was predominant. The affected joints examined by general practitioners at the acute stage were different from those assessed by the rheumatologists, which might be explained by the different assessment times or differences in the ability to discriminate between articular and periarticular involvement.
In the acute phase of the disease, CHIKV replicates in the target tissues, especially the synovium, periosteum, and skin, all of which contain fibroblasts [2, 27]. Innate and adaptive immune responses contribute to the occurrence of CHIKV infection-induced arthritis [1]. Monocytes and macrophages play a significant role in the immunopathology of CHIKV-related arthritis, and both are important for efferocytosis and the resolution of inflammation [28]. Several cytokines and chemokines induced by inflammation are associated with the severity and/or persistence of CHIKV infection-related symptoms [29]. The cytokine profile in CHIKV infection is similar to that in inflammatory arthritis [1, 30, 31], which may explain the similarities between the pathogenesis and clinical features of CHIKV-associated arthropathy and those of RA and SpA. Proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1 beta (IL-1β), IL-6, and IL-17 also mediate pain by directly acting on the nociceptive system [32]. TNF and IL-6 can also function as mediators of neuropathic pain [33–35].
The prevalence of chronic CHIKV infection varies between 5.9% and 84.3%, with the time at the assessment ranging from 3 to 81 months [5, 25, 36–44]. This variation depends on the definition of chronic CHIKV, the assessor’s specialty, and the assessment time. The prevalence of chronic CHIKV in our cohort was 55.5% at three-month evaluation, which was higher than that reported in previous studies with a similar time of assessment (27.5%–40.2%) [5, 45].
Few studies have reported on enthesitis in CHIKV infection [46]. Enthesis is defined as the area where a tendon, ligament, or joint capsule inserts into the bone and acts to transmit the tensile load from soft tissues to the bone. The tissue in this transitional zone is composed of fibrocartilage, and is populated by fibroblasts [47]. The prevalence of enthesitis in our study was 38.4%, which was higher than that reported in other studies [3, 5]. A prevalence of 2.7% was reported for the acute to subacute phases [5] and between10.1% and 19.4% for the chronic phase. However, these studies did not provide detail on the anatomical sites of enthesitis [3, 5], with only one case report having described the presence of enthesitis at the insertions of both Achilles tendons in CHIKV infection [46]. Additionally, entheseal sites in CHIKV infection, as assessed by LEI or MASES, have never been reported. The LEI, which was developed specifically for psoriatic arthritis, is simple to use as only six sites are assessed. However, because it lacks discriminative power as only peripheral entheseal sites are evaluated, we also used the MASES, which is suitable for use with ankylosing spondylitis (AS) and axial SpA [48, 49]. As assessed by MASES, the most frequent entheseal site in our study was the PSIS, which was different from that assessed in a study on psoriatic arthritis, where the most commonly reported site was Achilles insertion [50]. LEI values showed only a very weak association with MASES in our research, suggesting that CHIKV infection involved both peripheral and axial entheseal sites. Both the LEI and MASES should be used for evaluating entheseal sites in CHIKV-infected patients. Other entheseal score indices may be further validated in CHIKV-infected patients.
The involvement of acromioclavicular, sternoclavicular, and temporomandibular joints was also observed in our study, as well as in a previous report [37, 51]. These joints are also involved early in AS [52] and psoriatic arthritis [50]. These synovial joints are lined with fibrocartilage rather than hyaline cartilage [53], and entheseal compartments are dominant within these joints [47].
Studies have reported that approximately 15%–23% of CHIKV-infected patients present with neuropathic pain [5, 26, 54]. In contrast, the prevalence of neuropathic pain in our patients was higher, at 34.1%. Peripheral axonal polyneuropathy was confirmed by nerve conduction studies in one report [55]. In another study, meanwhile, ultrasound examination indicated that only 14% of patients with hand paresthesia showed thickened median nerves [56]. Other mechanisms might explain neuropathic pain in CHIKV-infected patients, such as small nerve fiber involvement. Neuropathic pain in our patients displayed a glove- and/or stocking-like pattern, which was consistent with peripheral neuropathy rather than nerve entrapment syndrome. However, we did not perform nerve conduction velocity (NCV) tests or skin biopsies in our patients, and the mechanisms underlying the neuropathic pain were therefore not elucidated. Nevertheless, more than half of our patients who reported neuropathic pain showed an improvement of at least 50% with 300 mg per day of gabapentin treatment within one month of follow-up. Neuropathic pain in CHIKV-infected patients may be managed successfully with medications such as gabapentin, opioids (such as tramadol), or tricyclic antidepressants. Physicians should be aware if joint pain in CHIKV-infected patients does not respond well to the usual analgesics as the pain may be either nociceptive or neuropathic.
Pain improvement in the post-acute phase varied considerably with each treatment option. However, we could not compare the effectiveness of the different treatments owing to different baseline severity and the different types of rheumatic manifestations. A few studies have reported the medications prescribed in the post-acute phase of CHIKV infection, including NSAIDs, chloroquine, prednisolone, and DMARDs [57–59]. Ninety percent of our patients in the post-acute phase showed a good response to NSAIDs, which was consistent with the results of a previous study [57]. We recommend NSAIDs as the first-line treatment for CHIKV-infected patients without contraindications. Approximately 80% of our patients who were prescribed low-dose prednisolone experienced an improvement in pain score of at least 50% after one-month follow-up. We recommend using low-dose prednisolone with slow tapering for patients who do not respond well to NSAIDs or those who have a high arthritis or enthesitis severity score. French and Brazilian guidelines recommend that low-dose prednisolone, with slow and gradual reduction, can be used for intractable synovitis and tenosynovitis [18, 60]. Among the patients who were prescribed chloroquine, three-quarters exhibited an improvement in the pain score of at least 50% after one-month follow-up. It was not clear whether or not the rapid response to chloroquine in our patients was primarily due to the NSAIDs prescribed alongside chloroquine. The evidence for chloroquine efficacy in relieving pain in the post-acute phase was also inconclusive [59]. The Brazilian guidelines recommend using hydroxychloroquine for joint pain in the subacute phase [60]. These observations highlight that the efficacy of chloroquine requires further assessment. For the effectiveness of DMARDs in CHIKV-associated arthritis, half of our patients responded to DMARDs in the post-acute phase. These results corroborated those reported in a previous study, in which early methotrexate administration was not effective in improving outcomes in patients with post-CHIKV-infection arthritis [58]. However, a one-month follow-up is not long enough to evaluate the responses to DMARDs.
We found that approximately 83% of our patients developed skin rashes in the acute phase of the disease, which was higher than that reported in previous studies [26, 42, 61]. A high percentage of patients (82.9%) presenting with rashes were also diagnosed with painkiller allergies. To avoid misdiagnosis, physicians should be cautious when prescribing medications for patients with suspicion of CHIKV infection as the rashes could be either a manifestation of CHIKV infection or a drug allergy.
In terms of physical function and quality of life, the Thai-HAQ scores at the initial evaluation indicated moderate functional impairment, consistent with that previously reported [37]. The EQ-5D-5L index scores at the onset of symptoms were low, indicating that CHIKV infection impaired the quality of life of the patients. As the patients completed both questionnaires at the first visit to a rheumatologist and not when visiting a general practitioner, the Thai-HAQ and EQ-5D-5L scores at the onset of symptoms might be affected by recall bias.
Multivariate logistic regression analysis showed that the number of actively inflamed joints assessed by a rheumatologist and the Thai-HAQ score at the onset of symptoms were significantly associated with enthesitis. Highly active CHIKV-related disease was associated with enthesitis, similar to that found in psoriatic arthritis [62]. Enthesitis might be a sign of increased burden as it is associated with disease severity and poor function, which is consistent with that seen in SpA patients who also have enthesitis [63]. One study reported that the presence of at least one site of enthesitis increased the risk of developing chronic CHIKV-related arthritis [5]. To confirm this finding, enthesitis found in our patients should be followed up in the longer term, i.e., from three months onwards.
This study had some limitations. First, selection bias might have occurred because we only included CHIKV-infected patients seen at our hospital, and patients with mild, self-limited disease might not seek treatment or the disease may resolve before assessment by a rheumatologist. Therefore, our patients might not be representative of the entire CHIKV-infected population. Secondly, enthesitis was evaluated by clinical examination only, and its prevalence might have been underestimated owing to a lack of imaging confirmation.
In conclusion, rheumatic manifestations resulting from CHIKV infection comprise a broad spectrum of articular features mimicking several forms of chronic inflammatory arthritis, as well as enthesitis. Enthesitis usually occurs together with polyarthritis and is associated with increased arthritic severity and poorer physical function. Thus, enthesitis should be evaluated and followed up in all CHIKV-infected patients.
Acknowledgments
We are grateful to Assistant Professor Sithichai Ukritchon for reviewing the manuscript and the staff of the Center of Excellence in Clinical Virology for their technical and administrative assistance.
References
- 1. Amdekar S, Parashar D, Alagarasu K. Chikungunya Virus-Induced Arthritis: Role of Host and Viral Factors in the Pathogenesis. Viral immunology. 2017;30(10):691–702. pmid:28910194.
- 2. Schwartz O, Albert ML. Biology and pathogenesis of chikungunya virus. Nature reviews Microbiology. 2010;8(7):491–500. pmid:20551973.
- 3. Javelle E, Ribera A, Degasne I, Gauzere BA, Marimoutou C, Simon F. Specific management of post-chikungunya rheumatic disorders: a retrospective study of 159 cases in Reunion Island from 2006–2012. PLoS neglected tropical diseases. 2015;9(3):e0003603. pmid:25760632
- 4. Bouquillard E, Fianu A, Bangil M, Charlette N, Ribera A, Michault A, et al. Rheumatic manifestations associated with Chikungunya virus infection: A study of 307 patients with 32-month follow-up (RHUMATOCHIK study). Joint bone spine. 2018;85(2):207–10. pmid:28238882
- 5. Bertolotti A, Thioune M, Abel S, Belrose G, Calmont I, Césaire R, et al. Prevalence of chronic chikungunya and associated risks factors in the French West Indies (La Martinique): A prospective cohort study. PLoS neglected tropical diseases. 2020;14(3):e0007327. pmid:32163420.
- 6. Couturier E, Guillemin F, Mura M, Leon L, Virion JM, Letort MJ, et al. Impaired quality of life after chikungunya virus infection: a 2-year follow-up study. Rheumatology (Oxford, England). 2012;51(7):1315–22. pmid:22427407.
- 7. Sudeep AB, Parashar D. Chikungunya: an overview. Journal of biosciences. 2008;33(4):443–9. pmid:19208970.
- 8. Chusri S, Siripaitoon P, Silpapojakul K, Hortiwakul T, Charernmak B, Chinnawirotpisan P, et al. Kinetics of chikungunya infections during an outbreak in Southern Thailand, 2008–2009. The American journal of tropical medicine and hygiene. 2014;90(3):410–7. pmid:24493674.
- 9. Rianthavorn P, Prianantathavorn K, Wuttirattanakowit N, Theamboonlers A, Poovorawan Y. An outbreak of chikungunya in southern Thailand from 2008 to 2009 caused by African strains with A226V mutation. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases. 2010;14 Suppl 3:e161–5. pmid:20417142.
- 10. Chirathaworn C, Rianthavorn P, Wuttirattanakowit N, Poovorawan Y. Serum IL-18 and IL-18BP levels in patients with Chikungunya virus infection. Viral immunology. 2010;23(1):113–7. pmid:20121409.
- 11. Chirathaworn C, Poovorawan Y, Lertmaharit S, Wuttirattanakowit N. Cytokine levels in patients with chikungunya virus infection. Asian Pacific journal of tropical medicine. 2013;6(8):631–4. pmid:23790334.
- 12. Thaikruea L, Charearnsook O, Reanphumkarnkit S, Dissomboon P, Phonjan R, Ratchbud S, et al. Chikungunya in Thailand: a re-emerging disease? The Southeast Asian journal of tropical medicine and public health. 1997;28(2):359–64. pmid:9444021.
- 13. Chirathaworn C, Chansaenroj J, Pongsuchart P, Poovorawan Y. IL-18: a suggested target for immunomodulation in chikungunya virus infection. Archives of virology. 2020. pmid:33073324.
- 14. Chansaenroj J, Wanlapakorn N, Ngamsaithong C, Thongmee T, Na Nakorn N, Siriyasatien P, et al. Genome sequences of chikungunya virus isolates from an outbreak in southwest Bangkok in 2018. Archives of virology. 2020;165(2):445–50. pmid:31834526.
- 15. Chaudakshetrin P, Prateepavanich P, Chira-Adisai W, Tassanawipas W, Leechavengvongs S, Kitisomprayoonkul W. Cross-cultural adaptation to the Thai language of the neuropathic pain diagnostic questionnaire (DN4). Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2007;90(9):1860–5. pmid:17957931.
- 16. Osiri M, Wongchinsri J, Ukritchon S, Hanvivadhanakul P, Kasitanon N, Siripaitoon B. Comprehensibility, reliability, validity, and responsiveness of the Thai version of the Health Assessment Questionnaire in Thai patients with rheumatoid arthritis. Arthritis research & therapy. 2009;11(4):R129. pmid:19709443.
- 17. Pattanaphesaj J, Thavorncharoensap M, Ramos-Goni JM, Tongsiri S, Ingsrisawang L, Teerawattananon Y. The EQ-5D-5L Valuation study in Thailand. Expert review of pharmacoeconomics & outcomes research. 2018;18(5):551–8. pmid:29958008.
- 18. Simon F, Javelle E, Cabie A, Bouquillard E, Troisgros O, Gentile G, et al. French guidelines for the management of chikungunya (acute and persistent presentations). November 2014. Medecine et maladies infectieuses. 2015;45(7):243–63. pmid:26119684.
- 19. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis and rheumatism. 2010;62(9):2569–81. pmid:20872595.
- 20. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis and rheumatism. 1991;34(10):1218–27. pmid:1930310.
- 21. Krabben A, Huizinga TW, van der Helm-van Mil AH. Undifferentiated arthritis characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid arthritis. Annals of the rheumatic diseases. 2012;71(2):238–41. pmid:21953339.
- 22. Bouquillard E, Combe B. A report of 21 cases of rheumatoid arthritis following Chikungunya fever. A mean follow-up of two years. Joint bone spine. 2009;76(6):654–7. pmid:19945329.
- 23. Miner JJ, Aw-Yeang HX, Fox JM, Taffner S, Malkova ON, Oh ST, et al. Diamond MS, Lenschow DJ, Yokoyama WM. Chikungunya viral arthritis in the United States: a mimic of seronegative rheumatoid arthritis. Arthritis Rheumatol. 2015; 67(5):1214–1220. pmid:25605621.
- 24. Manimunda SP, Vijayachari P, Uppoor R, Sugunan AP, Singh SS, Rai SK, et al. Clinical progression of chikungunya fever during acute and chronic arthritic stages and the changes in joint morphology as revealed by imaging. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2010;104(6):392–9. pmid:20171708.
- 25. Borgherini G, Poubeau P, Jossaume A, Gouix A, Cotte L, Michault A, et al. Persistent arthralgia associated with chikungunya virus: a study of 88 adult patients on reunion island. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2008;47(4):469–75. pmid:18611153.
- 26. Rahman MM, Been Sayed SJ, Moniruzzaman M, Kabir A, Mallik MU, Hasan MR, et al. Clinical and Laboratory Characteristics of an Acute Chikungunya Outbreak in Bangladesh in 2017. The American journal of tropical medicine and hygiene. 2019;100(2):405–10. pmid:30526743.
- 27. Couderc T, Chrétien F, Schilte C, Disson O, Brigitte M, Guivel-Benhassine F, et al. A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease. PLoS pathogens. 2008;4(2):e29 pmid:18282093.
- 28. Suhrbier A. Rheumatic manifestations of chikungunya: emerging concepts and interventions. Nature reviews Rheumatology. 2019;15(10):597–611. pmid:31481759.
- 29. Chirathaworn C, Chansaenroj J, Poovorawan Y. Cytokines and Chemokines in Chikungunya Virus Infection: Protection or Induction of Pathology. Pathogens (Basel, Switzerland). 2020;9(6). pmid:32471152.
- 30. Coates LC, FitzGerald O, Helliwell PS, Paul C. Psoriasis, psoriatic arthritis, and rheumatoid arthritis: Is all inflammation the same? Seminars in arthritis and rheumatism. 2016;46(3):291–304. pmid:27388027
- 31. Teng TS, Kam YW, Lee B, Hapuarachchi HC, Wimal A, Ng LC, et al. A Systematic Meta-analysis of Immune Signatures in Patients With Acute Chikungunya Virus Infection. The Journal of infectious diseases. 2015;211(12):1925–35. pmid:25635123.
- 32. Schaible HG. Nociceptive neurons detect cytokines in arthritis. Arthritis research & therapy. 2014;16(5):470. pmid:25606597.
- 33. Sommer C, Schmidt C, George A. Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Experimental neurology. 1998;151(1):138–42. pmid:9582261.
- 34. DeLeo JA, Colburn RW, Nichols M, Malhotra A. Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research. 1996;16(9):695–700. pmid:8887053.
- 35. Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neuroscience letters. 2004;361(1–3):184–7. pmid:15135924.
- 36. Sissoko D, Malvy D, Ezzedine K, Renault P, Moscetti F, Ledrans M, et al. Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS neglected tropical diseases. 2009;3(3):e389. pmid:19274071.
- 37. Ganu MA, Ganu AS. Post-chikungunya chronic arthritis—our experience with DMARDs over two year follow up. The Journal of the Association of Physicians of India. 2011;59:83–6. pmid:21751641.
- 38. Couzigou B, Criquet-Hayot A, Javelle E, Tignac S, Mota E, Rigaud F, et al. Occurrence of Chronic Stage Chikungunya in the General Population of Martinique during the First 2014 Epidemic: A Prospective Epidemiological Study. The American journal of tropical medicine and hygiene. 2018;99(1):182–90. pmid:29848408.
- 39. Rahim AA, Thekkekara RJ, Bina T, Paul BJ. Disability with Persistent Pain Following an Epidemic of Chikungunya in Rural South India. The Journal of rheumatology. 2016;43(2):440–4. pmid:26669921.
- 40. Mathew AJ, Goyal V, George E, Thekkemuriyil DV, Jayakumar B, Chopra A. Rheumatic-musculoskeletal pain and disorders in a naïve group of individuals 15 months following a Chikungunya viral epidemic in south India: a population based observational study. International journal of clinical practice. 2011;65(12):1306–12. pmid:22093538.
- 41. Rodríguez-Morales AJ, Cardona-Ospina JA, Fernanda Urbano-Garzón S, Sebastian Hurtado-Zapata J. Prevalence of Post-Chikungunya Infection Chronic Inflammatory Arthritis: A Systematic Review and Meta-Analysis. Arthritis care & research. 2016;68(12):1849–58. pmid:27015439.
- 42. Huits R, De Kort J, Van Den Berg R, Chong L, Tsoumanis A, Eggermont K, et al. Chikungunya virus infection in Aruba: Diagnosis, clinical features and predictors of post-chikungunya chronic polyarthralgia. PloS one. 2018;13(4):e0196630. pmid:29709007.
- 43. Essackjee K, Goorah S, Ramchurn SK, Cheeneebash J, Walker-Bone K. Prevalence of and risk factors for chronic arthralgia and rheumatoid-like polyarthritis more than 2 years after infection with chikungunya virus. Postgraduate medical journal. 2013;89(1054):440–7. pmid:23645664.
- 44. Chang AY, Encinales L, Porras A, Pacheco N, Reid SP, Martins KAO, et al. Frequency of Chronic Joint Pain Following Chikungunya Virus Infection: A Colombian Cohort Study. Arthritis Rheumatol. 2018;70(4):578–584. Epub 2018 Mar 2. pmid:29266783.
- 45. Bonifay T, Lienne JF, Bagoée C, Santa F, Vesin G, Walter G, et al. Prevalence and risk factors of post chikungunya rheumatic musculoskeletal disorders: a prospective follow-up study in French Guiana. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 2018;37(11):2159–64. pmid:30120648.
- 46. Carmona RJ, Shaikh S, Khalidi NA. Chikungunya viral polyarthritis. The Journal of rheumatology. 2008;35(5):935–6. pmid:18412299.
- 47. Schett G, Lories RJ, D’Agostino MA, Elewaut D, Kirkham B, Soriano ER, et al. Enthesitis: from pathophysiology to treatment. Nature reviews Rheumatology. 2017;13(12):731–41. pmid:29158573.
- 48. Mease P. Enthesitis in psoriatic arthritis (Part 3): clinical assessment and management. Rheumatology (Oxford, England). 2020;59(Supplement_1):i21–i8. pmid:32159795.
- 49. Mease PJ. Measures of psoriatic arthritis: Tender and Swollen Joint Assessment, Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Modified Nail Psoriasis Severity Index (mNAPSI), Mander/Newcastle Enthesitis Index (MEI), Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht Ankylosing Spondylitis Enthesis Score (MASES), Leeds Dactylitis Index (LDI), Patient Global for Psoriatic Arthritis, Dermatology Life Quality Index (DLQI), Psoriatic Arthritis Quality of Life (PsAQOL), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Joint Activity Index (PsAJAI), Disease Activity in Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Arthritis care & research. 2011;63 Suppl 11:S64–85. pmid:22588772.
- 50. Sunar I, Ataman S, Nas K, Kilic E, Sargin B, Kasman SA, et al. Enthesitis and its relationship with disease activity, functional status, and quality of life in psoriatic arthritis: a multi-center study. Rheumatology international. 2020;40(2):283–94. pmid:31773391.
- 51. Staikowsky F, Talarmin F, Grivard P, Souab A, Schuffenecker I, Le Roux K, et al. Prospective study of Chikungunya virus acute infection in the Island of La Reunion during the 2005–2006 outbreak. PloS one. 2009;4(10):e7603. pmid:19893613.
- 52. Watad A, Bridgewood C, Russell T, Marzo-Ortega H, Cuthbert R, McGonagle D. The Early Phases of Ankylosing Spondylitis: Emerging Insights From Clinical and Basic Science. Frontiers in immunology. 2018;9:2668. pmid:30505307.
- 53. Benjamin M, McGonagle D. The anatomical basis for disease localisation in seronegative spondyloarthropathy at entheses and related sites. Journal of anatomy. 2001;199(Pt 5):503–26. pmid:11760883.
- 54. de Andrade DC, Jean S, Clavelou P, Dallel R, Bouhassira D. Chronic pain associated with the Chikungunya Fever: long lasting burden of an acute illness. BMC infectious diseases. 2010;10:31. pmid:20170492.
- 55. Silva VP, Costa DS, Carvalho V, Garces T, Barros ELT, Oliveira JS, et al. Peripheral polyneuropathy associated with Chikungunya virus infection. Journal of neurovirology. 2020;26(1):122–6. pmid:31428990.
- 56. Mogami R, Pereira Vaz JL, de Fatima Barcelos Chagas Y, de Abreu MM, Torezani RS, de Almeida Vieira A, et al. Ultrasonography of Hands and Wrists in the Diagnosis of Complications of Chikungunya Fever. Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine. 2018;37(2):511–20. pmid:28786505.
- 57. Rosario V, Munoz-Louis R, Valdez T, Adames S, Medrano J, Paulino I, et al. Chikungunya infection in the general population and in patients with rheumatoid arthritis on biological therapy. Clinical rheumatology. 2015;34(7):1285–7. pmid:26017232.
- 58. Adarsh MB, Sharma SK, Dwivedi P, Singh MP, Dhir V, Jain S. Methotrexate in Early Chikungunya Arthritis: A 6 Month Randomized Controlled Open-label Trial. Curr Rheumatol Rev. 2020;16(4):319–323. pmid:31858912.
- 59. Chopra A, Saluja M, Venugopalan A. Effectiveness of chloroquine and inflammatory cytokine response in patients with early persistent musculoskeletal pain and arthritis following chikungunya virus infection. Arthritis Rheumatol. 2014 Feb;66(2):319–26. pmid:24504804.
- 60. Marques CDL, Duarte A, Ranzolin A, Dantas AT, Cavalcanti NG, Gonçalves RSG, et al. Recommendations of the Brazilian Society of Rheumatology for the diagnosis and treatment of chikungunya fever. Part 2—Treatment. Revista brasileira de reumatologia. 2017;57 Suppl 2:438–51. pmid:28739354.
- 61. Chopra A, Anuradha V, Ghorpade R, Saluja M. Acute Chikungunya and persistent musculoskeletal pain following the 2006 Indian epidemic: a 2-year prospective rural community study. Epidemiology and infection. 2012;140(5):842–50. pmid:21767452.
- 62. Polachek A, Li S, Chandran V, Gladman DD. Clinical Enthesitis in a Prospective Longitudinal Psoriatic Arthritis Cohort: Incidence, Prevalence, Characteristics, and Outcome. Arthritis care & research. 2017;69(11):1685–91. pmid:27998023.
- 63. Mease PJ, Liu M, Rebello S, Hua W, McLean RR, Yi E, et al. Characterization of Patients With Axial Spondyloarthritis by Enthesitis Presence: Data from the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. ACR Open Rheumatol. 2020;2(7):449–56 pmid:32627974.