Since 2003, the tropical arthritogenic chikungunya (CHIK) virus has become an increasingly medical and economic burden in affected areas as it can often result in long-term disabilities. The clinical spectrum of post-CHIK (pCHIK) rheumatic disorders is wide. Evidence-based recommendations are needed to help physicians manage the treatment of afflicted patients. We conducted a 6-year case series retrospective study in Reunion Island of patients referred to a rheumatologist due to continuous rheumatic or musculoskeletal pains that persisted following CHIK infection. These various disorders were documented in terms of their clinical and therapeutic courses. Post-CHIK de novo chronic inflammatory rheumatisms (CIRs) were identified according to validated criteria. We reviewed 159 patient medical files. Ninety-four patients (59%) who were free of any articular disorder prior to CHIK met the CIR criteria: rheumatoid arthritis (n=40), spondyloarthritis (n=33), undifferentiated polyarthritis (n=21). Bone lesions detectable by radiography occurred in half of the patients (median time: 3. 5 years pCHIK). A positive therapeutic response was achieved in 54 out of the 72 patients (75%) who were treated with methotrexate (MTX). Twelve out of the 92 patients (13%) received immunomodulatory biologic agents due to failure of contra-indication of MTX treatment. Other patients mainly presented with mechanical shoulder or knee disorders, bilateral distal polyarthralgia that was frequently associated with oedema at the extremities and tunnel syndromes. These pCHIK musculoskeletal disorders (MSDs) were managed with pain-killers, local and/or general anti-inflammatory drugs, and physiotherapy. Rheumatologists in Reunion Island managed CHIK rheumatic disorders in a pragmatic manner following the outbreak in 2006. This retrospective study describes the common mechanical and inflammatory pCHIK disorders. We provide a diagnostic and therapeutic algorithm to help physicians deal with chronic patients, and to limit both functional and economic impacts. The therapeutic indication of MTX in pCHIK CIR could be approved in future efficacy trials.
Fifty years after its first tropical description in the Newala district of Tanganyika [1,2], chikungunya (CHIK) has re-emerged extensively, resulting in 1. 4 to 6. 5 million infected individuals between 2004 and 2014 in Africa, as well as regions within the Indian Ocean, Southeast Asia, the Pacific Islands and Europe [3]. Its first autochthonous transmission in the intertropical Americas was identified at the end of 2013 [4], and six months later this turned into a large outbreak in most of the Caribbean Islands that has now reached northern South America [5] and the United States [6]. Currently, this arboviral disease represents a pressing threat to public health in large areas of the American and European continents that are colonized by the primary disease vector: the Aedes mosquito [4,7]. CHIK is usually characterized by an acute febrile and sometimes eruptive polyarthritis, commonly followed by persistent rheumatologic and general disabling symptoms [8]. Historically, post-CHIK (pCHIK) rheumatic disorders were first described in South Africa after a local outbreak at the end of the 1970s. In 1979, Fourie and Morrison first reported a pCHIK rheumatoid arthritic syndrome [9], and in 1983 Brighton et al. highlighted a high prevalence of chronic polyarthralgia or stiffness occurring three years after disease onset [10], with one case of destructive pCHIK polyarthritis [11]. After minimal exposure in the literature over the last 20 years, the wide clinical spectrum of pCHIK rheumatic disorders has been rediscovered [12–22]. During its re-emergence in the past 10 years, 92 published articles related to chronic pCHIK status have been indexed in PubMed [keywords: “chikungunya” and “chronic”, last search on October 24th, 2014], but there are no available evidence-based guidelines with standardized definitions and treatment recommendations. While the overall proportion of patients with chronic symptoms diminishes over time after CHIK onset (from 100 to 88% during the first 6 weeks, to less than 50% after 3–5 years, with variable results depending on the study), the time required to return to pre-CHIK status is still uncertain, as some infected individuals remain symptomatic for 6 to 8 years post-infection [23,24]. Simple analgesics and/or non-steroidal anti-inflammatory drugs (NSAIDs) provide relief in most patients [25], but better-targeted drugs are clearly needed to treat inflammatory rheumatic disorders. Hydroxychloroquine and ribavirin were not effective [26–28], but methotrexate (MTX) was of benefit in pCHIK inflammatory polyarthritis [29–31]. MTX efficacy is supported by scientific data that indicates active monocyte/macrophage trafficking into the synovial tissue of chronic patients, possibly maintained by a local viral persistence [32]. Thus, the current challenge for physicians in epidemic areas is to identify and diagnose pCHIK rheumatic disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course. To answer this real-world need, we retrospectively documented the clinical and therapeutic courses of rheumatic and musculoskeletal pCHIK disorders (pCHIK-RMSD) that were referred to rheumatologists in Reunion Island over a 6-year period following the 2005–2006 epidemic. We have summarized this practical experience in an algorithm for disease management purposes.
Data were anonymously analyzed and reported. The study was approved by the research ethical committee of Laveran Military Teaching hospital (registration n° 2014-PRSimon). This retrospective study was carried out at two referring rheumatologic practices: University Hospital (“CHU”) Félix Guyon and the private office of a rheumatologist in Saint-Denis, the capital of Reunion Island, which was affected by a massive CHIK outbreak in 2005–2006. All eligible participants were older than 16 years of age and had been referred to the specialist for joint pain that persisted for more than 4 months following typical clinical acute CHIK infection [33], which was assumed to be related to CHIK-RMSD. Biological confirmation of CHIK infection was obtained for all patients, either by detection of CHIK virus RNA in the blood during the acute stage by reverse-transcriptase polymerase chain reaction (RT-PCR), or the presence of anti-CHIK virus-specific immunoglobulin M and/or G (depending on the delay relative to the acute CHIK infection) as detected by enzyme-linked immunosorbent assay (ELISA) using CHIK virus antigens produced by the French Referent National Centre for Arbovirus, Marseille, IRBA, France. Data were collected anonymously and retrospectively from January to May of 2012, based on patient medical files using a structured questionnaire developed for the purposes of this study. Patient details were recorded, including factors considered to be predictors of non-recovery after CHIK according to the literature: age (>45 year), female gender, previous history of an osteoarthritic event, and severe acute CHIK [12,13,18,22,29,34]. Details on CHIK-RMSD included the date of the first visit to the rheumatologist, the clinical and biological histories, imaging features, and treatments since the acute CHIK infection. We recorded the following clinical data: i) joint involvement: small joints (metacarpophalangeal, proximal and distal interphalangeal, metatarsophalangeal, thumb interphalangeal joints and wrists), large joints (shoulders, elbows, hips, knees and ankles), vertebral, sacroiliac, temporomandibular and sternocostoclavicular areas; ii) joint count: polyarticular if more than 4 (oligoarticular if 4 or less); iii) articular inflammatory signs or symptoms defining arthritis: synovitis, warmth and/or redness over the joint (“hot” joint), prolonged morning stiffness (> 30 minutes), inflammatory pain (which improved with exercise, or worsened after rest or during the night), or arthritis that was clinically distinguished from oedema without join effusion; iv) periarticular involvement: enthesitis (inflammation of the tendon or ligament insertion into bone: Achilles tendonitis, plantar fasciitis), tenosynovitis, periostitis (tibial and ischial tuberosities inflammation), tendinopathy, bursitis, myalgia and neural tunnel syndrome. Hyperuricemia and vitamin D deficiency were determined using standard biological assays, as were the elevated erythrocyte sedimentation rate (ESR), and the levels of C-reactive protein (CRP), antinuclear antibodies (ANA), rheumatoid factor (RF), anti-citrullinated peptide autoantibodies 2 (ACPA2) and HLA B27 positive status, when required for scoring. The treatments were classified as follows: painkillers; oral or topical non-steroidal anti-inflammatory drugs (NSAIDs); oral or intra-articular corticosteroids; conventional disease-modifying anti-rheumatic drugs (DMARDs) including MTX (7. 5–25 mg/week), hydroxychloroquine (200 mg/day), leflunomide (10–20 mg/day), sulfasalazine (1. 5–3 g/day); immune-modulating biologic agents including anti-TNF, a B-lymphocyte depletion agent (rituximab), and an interleukin-6 receptor inhibitor (tocilizumab) for indications and at dosages recommended by national guidlines (former and revised text) [35,36]; physiotherapy; orthopaedic braces; complementary therapeutics such as vitamin D supplementation or gout treatment using colchicine with a urate-lowering diet, such as a xanthine oxidase inhibitor (allopurinol) or uricosurics. Patients without previously defined arthritis were classified as pCHIK musculoskeletal disorders (pCHIK-MSD) that were either loco-regional or diffuse (if > 4 painful areas). For patients with arthritis, we separated crystalline and non-crystalline rheumatic disorders. Crystalline arthritis was defined as a convincing clinical presentation associated with hyperuricemia that improved after gout treatment. Patients presenting non-crystalline polyarthritis were classified as chronic inflammatory rheumatism (CIR). CIRs were categorized into 3 groups (Table 1) [37,38]. Patients who had not previously displayed rheumatic symptoms and developed CIR immediately after CHIK were classified as de novo pCHIK-CIR. We measured the median period from acute CHIK to the first rheumatology consultation for the pCHIK-CIR and pCHIK-MSD patient groups. The severity of all CHIK-RMSDs was evaluated based on the level of joint destruction or deformation (chondrolysis, joint space reduction, juxta-articular osteopenia, subluxation, bony erosion or destruction, sacroiliitis) detected in the imaging tests, and based on the need for an internal or external orthopaedic brace. The functional burden was estimated based on a history of being unable to work or requiring adjustment, self-estimated significant reduction of daily activities (as a percentage of reduction) [13] and initiation of psychological follow-up or antidepressant medical treatment since 2006 due to CHIK. For each patient, we recorded the therapeutic strategy, including corticotherapy, and the outcome after complete drug withdrawal (the type of response at 3 and 6 months following therapeutic interruption). Rheumatologists treated pCHIK-CIR patients with MTX at the recommended dosage and routes of administration based upon the 2008 ACR Recommendations for Rheumatoid Arthritis Treatments [39] and French national guidelines [35,36]. We defined a positive response to MTX if there was no further need for a drug switch or escalation (treatment in association with other DMARDs). Recovery after MTX was defined as the absence of relapse more than 6 months after MTX withdrawal. We documented the DMARDs that were received by patients other than MTX, including hydroxychloroquine and immune-modulating biologic agents. Descriptive results were expressed as the median value and the distribution or the number (percentage) of patients according to the category of the variable (quantitative or qualitative).
A total of 159 patients with persistent pCHIK-RMSD were included in this study. The population was predominantly female (75%) and the median age was 51 years-old, ranging from 16 to 80 years-old. Repartition of pCHIK-RMSD is detailed in Fig. 1. Demographic characteristics and comorbidities are presented in Table 2, according to the patients’ CHIK-RMSD categories. There was no significant difference between these groups. In the entire cohort, 66% of patients reported a prolonged acute CHIK infection (fever> 10 days or symptoms> 3 weeks). The median time elapsed between CHIK infection and the first consultation with a rheumatologist was 2 years (median delay: 15. 0 months for the MSD-group and 38. 5 months for the CIR group) (Fig. 2); 80% of patients with pCHIK-MSD were referred within the first two years, whereas patients with pCHIK-CIR were regularly referred throughout the 6-year period, independent of the type of CIR. All patients received painkillers as a first-line treatment, and 20% received vitamin D supplementation. The treatment history and medical features according to the different pCHIK-RMSD are summarized in Tables 3 and 4. The characteristics and specific management of the 43 cases of pCHIK-MSD are shown in Table 5. Only seven patients (15%) responded to the optimal painkiller treatment (using a second- or third-step analgesic if necessary, with the additional availability of a painkiller in the case of a painful episode). Among the 28 diffuse pCHIK-MSD, 22 consisted of distal polyarthralgia involving the hands (18 out of 22) and/or the feet (17 out of 22), typically associated with bilateral oedema of the extremities (about 50% of cases). This feature was frequently complicated by carpal or tarsal tunnel syndromes and paraesthesia that responded to a short course of corticotherapy (oral and/or injected into the joint) and sometimes improved with neuropathic pain medication, when indicated. Five patients with diffuse pCHIK-MSD (18%) received hydroxychloroquine without a self-reported benefit, while 20 out of 28 (70%) were efficiently treated with oral corticosteroids (16 out of 20 had a successful withdrawal of systemic corticotherapy without clinical relapse). Loco-regional pCHIK-MSD primarily involved proximal joints. In 11 cases, pCHIK-MSD presented as exacerbated pain in previously involved joints: arthrosis (n = 8) and injured areas (n = 3). Thirteen shoulder capsulitis or tendinitis required physiotherapy to limit stiffness and amyotrophy. Loco-regional CHIK-MSD mainly benefited from joint injections, physiotherapy and/or NSAIDs. Two of the 9 patients presenting with carpal tunnel syndromes developed algodystrophy (complex regional pain syndrome) after early surgery. Among the patients with inflammatory arthritis, 4 were diagnosed as early-onset crystalline polyarthritis, and they responded to gout treatment. One hundred twelve patients met the criteria for CIR. Eighteen patients had pre-existing CIR (diagnosed or suspected) that was exacerbated immediately after CHIK infection, and the other 94 patients were considered pCHIK-CIR. Twenty-seven percent of patients with pCHIK-CIR reported the inability to work, and 77% reported a significant reduction in their daily activities. Half of the patients with pCHIK-CIR presented radiographical osteoarticular destructions or misalignments, mostly occurring in pCHIK-rheumatoid arthritis (RA) (83% of the cases). The median time from acute CHIK to the diagnosis of radiographical damage was 45 months (range 3–76). Thirteen patients (40%) with pCHIK-spondyloarthroarthritis (SA) had radiographical chondrolysis, 4 of these with sacroiliitis and 3 with bone erosions. Six other patients with SA had non-destructive arthritis with periosteal appositions and reconstructions. Systemic corticotherapy was deemed necessary in 70% (13 out of 18) of pre-existing CIR, but complete withdrawal was achieved in only half of the cases. MTX was started in 8 patients with pre-existing CIR (3 RA, 4 SA and one systemic lupus previously under hydroxychloroquine), and it failed in 6 cases (3 RA, 3 SA), thereby leading to a switch to biologic DMARDs. A therapeutic escalation with immune-modulating biologic agents was required for 3 erosive RA previously controlled with MTX, and this appeared to have a beneficial effect; one patient with RA treated with infliximab was switched to etanercept, but remission occurred only after appropriate urate-lowering therapy, as the final diagnosis for their worsening condition was gout. For the 2 patients with untreated chronic viral hepatitis (B and C, one case each), hydroxychloroquine was ineffective in relieving joint inflammation, and consequently, sequential short courses of oral corticotherapy were given. Lastly, among the 4 patients who started hydroxychloroquine, 3 had to complete their treatment with immune-modulating biologic agents. RA was the most common CIR in this cohort (16% pre-existing RA and 36% de novo pCHIK-RA) and was associated with the highest prevalence of osteoarticular damage, requirement for braces, and functional consequences (Table 4). Among the 41 SA, we noticed a difference in clinical features: the 8 pre-existing SA presented as mostly ankylosing spondylitis with peripheral involvement (arthritis and/or enthesitis) triggered by CHIK, while the 33 de novo pCHIK-SA consisted of 15 cases of psoriatic polyarthritis (including 6 first occurrences of psoriasis) and 16 polyenthesitis (only two cases were HLA B27+). About one-third of patients with de novo pCHIK-CIR (14 RA, 11 SA and 3 UP) presented tenosynovitis of the wrist, hands and/or Achilles tendon, resulting in tunnel syndromes in 16 patients (17%). Seventy-two pCHIK-CIR (77% with 100% of RA, 78% of SA and 30% of UP) received MTX at a mean weekly dose of 15 mg. Thirty six patients (50%) already had varying degrees of radiographical damage at the start of MTX treatment. With a median follow-up time of 21 months (a mean of 25 months), MTX led to a positive clinical response in 54 out of 72 patients (75% with 67% in RA, 80% in SA, 100% in UP); 7 cases developed bone destruction while undergoing MTX treatment, whereas recovery was achieved for 6 patients (3 RA and 3 SA). Nine patients had to promptly stop taking MTX due to side effects, which included 4 significant increases in transaminases, 2 digestive intolerances, one hair loss, one depression, one rash and cough); only 3 patients fully stopped MTX treatment due to a complete inefficacy. A total of 26 out of 94 patients received other DMARDs as a consequence of MTX contraindication or failure; 12 of these (9 RA, 3 SA) required immune-modulating biologic agents. Finally, algodystrophy after early carpal tunnel surgery was also reported in 3 more cases.
CHIK virus is currently generating an epidemic of chronic rheumatism worldwide. Using a 6-year insight, this rheumatology case series from Reunion Island broadly describes clinical and therapeutic approaches to pCHIK’s long-lasting rheumatic disorders. We highlight the destructive pCHIK-CIR that affects a minority of patients, and we emphasize the importance of reducing the time necessary for the initiation of disease management by a medical specialist. Studies aimed at validating the efficacy of early use of MTX to prevent joint damage and long-term corticotherapy should be conducted in the future. Physiotherapy should also be evaluated in CHIK-MSD. Official guidelines for clinicians are necessary.
With a 6-year insight, we extensively and retrospectively describe clinical profiles and specific treatments of mechanical and inflammatory post-chikungunya rheumatic disorders. In the current context of chikungunya’s global spread, we provide the first diagnostic and therapeutic algorithm to guide physicians according to the amount of time that has elapsed since the acute CHIK infection.
Specific Management of Post-Chikungunya Rheumatic Disorders: A Retrospective Study of 159 Cases in Reunion Island from 2006-2012