Chikungunya Virus Infection: An Update on Joint Manifestations and Management

The advent of sophisticated diagnostics has enabled the discovery of previously unknown arthropod-borne viruses like Chikungunya. This infection has become increasingly prevalent in the last 10 years across the Indian Ocean and has been brought to media attention by a recent outbreak in the Caribbean. The outbreak has been aided by a drastic rise in air travel, allowing infected individuals to transport the virus to previously unaffected regions. In addition, a recently documented viral mutation has allowed its transmission by the Aedes albopictus mosquito, therefore facilitating outbreaks in Southern Europe and the USA. The duration and extent of the arthritis seen peri- and post infection has become a topic of academic interest. Although published data are largely observational, there has been a definite increase in original research focusing on this. Symptoms can persist for years, particularly in older patients with pre-existing medical conditions. The etiology is still not fully understood, but viral persistence and immune activation within synovial fluid have been shown in mouse models. There have been no prospective clinical trials of treatment in humans; however, animal trials are in process. The mainstay of treatment remains anti-inflammatories and steroids where necessary. The clinical presentation seems to mimic common rheumatological conditions like rheumatoid arthritis; therefore recent recommendations suggest the use disease-modifying agents as a common practice for the specific syndrome. This review uses recent published data and draws on our own clinical experience to provide an overview of joint complications of Chikungunya infection.


INT RODUCTION
Chikunguny a v irus (CHIKV) is a mosquito -borne alpha v irus that has precipitated several large outbreaks across the southern hemisphere in the last decade. First described in Tanzania in the 1 950s, Chikunguny a, also known as break-bone fev er, means "that which bends up" in the Makonde language. Following a few outbreaks in the 1 960s and 1 97 0s in Asia and Africa, the v irus re-emerged in 2005 and spread across the Indian Ocean. Since 201 4, over a million cases have been reported in the Americas and the Caribbean, with declining case numbers in 201 6. Much of what we currently know about the disease was first published following a large outbreak on the island of La Réunion, affecting 37 % of the entire population. 1 The v irus causes a self-limiting acute illness comprising of fev er, rash, arthralgia, and my algia.
Other complications, like multi-organ failure and neurological manifestations, hav e been described but are ex tremely rare. The most notable long-term complication is a chronic debilitating arthritis that causes considerable disability in certain groups. As we gain more ex perience with this disease, published literature describing this manifestation has become more plentiful; however, little is understood about the pathophy siology and optimal management of this condition. This review will provide an update of current data and recommendations on Chikunguny a-related arthralgia.

T HE VECTOR
Chikunguny a is a zoonotic arbovirus that is transmitted by the Aedes mosquito. These are day-biting arthropods that breed in open water and can be found across Africa and Asia. Epidemics occur through human-mosquito transmission made possible by high-circulating viremia during acute infection. Between epidemics, the life cy cle is maintained through primates and mainly Aedes aegypti mosquito. The genetic v ariation seen in this RNA v irus has allowed mutation of the v irus to enable transmission by the Aedes albopictus, an arthropod that is well established in the Americas and Europe. 2 This has facilitated the outbreaks of the last 1 0 y ears, around the Indian Ocean and across the Caribbean, with an outbreak in Italy in 2 007 and cases in other parts of Europe. 3 Subsequently, there are concerns that the v irus may , in time, cause further outbreaks across Europe and Northern America.

DIAGNOST ICS
Diagnostic techniques have improved significantly in recent y ears and can be grouped into molecular and serological tests.
Molecular tests are most useful in the acute phase of illness. These use reverse transcriptase PCR assays to amplify fragments of the CHIKV genome and can be used to quantify fragments in real time. 4 A dev elopment in recent y ears has been the multiplex assay on a chip that can simultaneously detect 26 tropical pathogens including CHIKV and dengue. 5 Serological assay s can be used to determine whether the patient has been previously infected. These use enzy me-linked immunosorbent assay s (ELISAs) that capture IgM and IgG. Other tests include immunofluorescence and immunoblot assays for CHIKV proteins. 4 More recently a rapid immunochromatographic test has been developed that can detect CHIKV , best used in the first 5 days of illness, with a sensitiv ity of 89.4% and specificity of 94.4%. 6 This would allow rapid diagnosis at the point of care, therefore precluding the need for further inv estigations.

CLINICAL COURSE OF T HE DISEASE
The clinical illness has a relatively sho rt incubation period-ty pically 2-1 0 day s. Sudden-onset high fev er is usually the first symptom and can last up to a week and can follow a biphasic course. Fever often precedes a maculo-papular rash over the trunk and ex tremities, headache, my algia, and arthralgia. Ocular disease has been described in Malaysia from a few cases of anterior uveitis. 7 More severe complications include nephritis, my ocarditis, meningoencephalitis, Guillain-Barré syndrome, and cranial nerv e palsies that can occur during the acute illness or in subsequent months. 4 It can be difficult to differentiate acute CHIKV infection from dengue; howev er, it has been suggested that thrombocy topenia is more indicativ e of dengue, whereas rash and arthralgia suggest CHIKV . 8 It has also been noted that pregnant women infected with the virus in the last few day s of pregnancy are able to transmit the v irus to the baby, which can lead to sev ere encephalopathy in the neonate and subsequent neurodisability, as demonstrated in a recent cohort study from La Réunion. 9 After the acute illness, which can last from 7 to 1 0 day s, rheumatic sequelae can persist for months to y ears. These can have broad clinical presentations and an, as y et, unclear etiology .

CHIKUNGUNY A RHEUMAT ISM
Musculoskeletal manifestations of disease have been shown to affect 4%-7 5% of those infected with CHIKV. 4 These figures v ary widely depending on baseline genetic susceptibility of populations, cultural perceptions, and quality of study .
Arthralgia usually affects more than one joint, particularly knees, ankles, hands, and wrists in a bilateral and sy mmetric distribution. 10 In some cohorts, ov er 50% of patients had arthralgia and clinically detectable joint swelling at 3 y ears after their acute infection. 11,12 A 6-year retrospective study in La Réunion by Jav elle et al. looked at patients referred to a rheumatologist due to rheumatic sy mptoms lasting more than 4 months following CHIKV infection. Out of 1 59 cases, they found that 59% met the criteria for de novo chronic inflammatory rheumatism (CIR) like rheumatoid arthritis, spondy larthropathy, and undifferentiated polyarthritis, and 31 % had pre-existing rheumatic musculoskeletal disorders. Amongst those with de novo rheumatoid arthritis, 80% dev eloped joint damage within 3-4 y ears. They found that some patients remained sy mptomatic for 6-8 y ears. Patients that did not fit the CIR criteria presented most commonly with bilateral distal poly arthralgia, fibromy algia, edema, and carpal tunnel syndrome. 13 This finding was mirrored in a study from Sri Lanka from 2006 where 21 % of the total number of infected indiv iduals ex hibited carpal tunnel sy ndrome. 14 There hav e also been recent cases of patients presenting with catastrophic antiphospholipid sy ndrome and adult-onset Still's disease. 15 Plasma markers of inflammation such as ESR and CRP are unreliable in predicting the severity of joint inv olvement. Javelle et al. found that only 2 out of 1 5 patients with spondylarthropathies were HLA-B27 positive, both of whom had psoriasis. Rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) positiv ity was found in 30% of patients, which was similar to other studies. 13 Radiological imaging of affected joints showed erosions and joint space narrowing in a small cohort in La Réunion. 16 Destructive lesions were more commonly seen in those with an rheumatoid arthritislike presentation, with up to 80% affected in some cohorts. 13 By contrast, in our London cohort of CHIKV -infected returning travelers, we found pre-dominantly joint effusions rather than synovitis on ultrasound examination (unpublished data). Magnetic resonance imaging has similar findings to ultrasound with predominant joint effusion, sy nov ial thickening, tendonitis, and tenosy nov itis. 17 Risk factors for prolonged disease are age greater than 50 y ears, longer acute stage of illness (more than 1 5 days), and presence of other comorbidities. 18 A study looking at predictors of rheumatism in the TELECHIK cohort of patients in La Réunion performed a multinomial logistic regression on the 346 patients with declared rheumatic musculoskeletal pain. They found age greater than 45, severe rheumatic involvement at presentation (fever, more than six joints affected, and four other rheumatic sy mptoms), and CHIKV -specific IgG titers were strong determinants of persistent musculoskeletal pain. The CHIKV -specific IgG titers were correlated to age, female gender, and severity of initial rheumatic sy mptoms. They concluded that the humoral immune response has a significant prognostic value; howev er, the adaptive immune response play s an important role in chronic manifestations. 10 The etiology of the arthralgia is not fully understood. Research from mouse models comparing wild-ty pe and Rag1-deficient mice that lack T and B cells inoculated with CHIKV shows higher v iral lev els in Rag1-deficient mice. This suggests the role of the adaptive immune system in host response and persistence of infection. In addition, tissues with high CHIKV RNA lev els in these mice histologically ex hibited synovitis, arthritis, and tendonitis, suggesting that the arthritis is not mediated by the adaptiv e immune system. The persistence of CHIKV was tissue-specific as sampling of other organs showed rapid clearance of the virus when compared with joints and skeletal muscle, in which it persisted for at least 1 6 weeks. 19 Samples from a human sy nov ial biopsy taken from an affected indiv idual with chronic joint disease showed joint infiltration with natural killer cells, CD4 cells, and CHIKV RNA in macrophages. Histologically there was sy novial hypertrophy, vascular proliferation, and perivascular macrophage infiltration similar to that seen in rheumatoid arthritis. 20 This suggests that the CHIKV arthralgia is etiologically similar to other inflammatory arthropathies and, as such, a similar treatment approach can be adopted.
As disease can last for y ears, there is ev idence that quality of life of indiv iduals is adversely affect-ed. A study by Couturier et al. followed up CHIKVinfected individuals for 2 y ears following diagnosis. Of the 391 patients that answered the survey, 55% of patients considered themselv es to hav e not recovered from CHIKV at a median of 23.4 months post diagnosis. Assessments of quality of life using well-known tools like SF-36 (short term health surv ey), GHQ-1 2 (general health questionnaire), and AIMS2-SF (arthritis impact measurement scale) were performed at regular intervals and compared with age-and gender-matched scores. Those who considered themselves as unrecov ered had much lower scores than recov ered participants. 18 In addition, there is ev idence of the financial burden that this can hav e-a study from La Réunion has estimated the annual cost at €34 million. 12

T REATMENT AND PREVENTION OF INFECTION
There are currently no licensed tre atments for CHIKV infection. Several drugs have been found to hav e modest effect by targeting viral replication or host cellular components. Although these mainly target acute v iral infection, little is known of the effect of antiv iral treatments on chronic infection.
Drugs that inhibit v iral entry include chloroquine and arbidol. Chloroquine, historically an antimalarial drug, has been thought to be effectiv e against chronic CHIKV since the early 1 980s; howev er, a recent trial using it as treatment in acute infection has shown it to be ineffective. 21,22 Arbidol is a licensed antiv iral in Russia, and arbidol analogues hav e been found to hav e anti-CHIKV activ ity . 23 A potent inhibitor of viral protein translation has been found to be harringtonine and its mor e stable analogue, homoharringtonine. This drug has minimal cy totoxic effects and has recently been licensed in the USA for treatment of acute my eloid leukemia. 24 Most effectiv e of the antiv iral drugs are those that target v iral genome replication. Ribavirin has been used most widely as it is licensed for treatment of respiratory syncytial v irus in infants. Ribavirin in combination with interferon has been shown to act sy nergistically in preventing CHIKV replication. 25 My cophenolic acid appears to be more effective than ribav irin in vitro as described by Khan et al. in 201 1. 26 Another anti-metabolite that is effectiv e in vitro is 6-azauridine as it inhibits sy nthesis of py rimidines. 22,25 Favipiravir has been shown to protect mice against CHIKV -caused disease as a potent poly merase inhibitor. 27 Although these drugs have displayed some efficacy , they can only reduce viral replication by 50% in mouse models and have not yet moved to more relev ant testing platforms for chronic CHIKV infection.
An alternative to these antiviral drugs is human poly -or monoclonal antibodies. The use of human poly v alent antibodies taken from human plasma donors in the convalescent phase of CHIKV infection showed full protectiv e efficacy in mouse models. This effect was completely therapeutic 8 hours post infection and reduced as time passed. 27 Prophy lactic administration of neutralizing monoclonal antibodies to Rag1 -deficient mice prevented them from dev eloping persistent infection and was ev en effective in clearing CHIKV from tissues when administered later on in infection. 19 This work suggests the potential for monoclonal neutralizing antibodies in prev ention of CHIKV -associated arthralgia in endemic areas.
Further preventive measures such as v accines against CHIKV have not y et been licensed but hav e been a goal since the 1960s. The CHIK-IRES vaccine is an attenuated vaccine derived from a strain of virus from La Réunion in 2006. This has been engineered to prevent it from replicating in the Aedes mosquito and, following recent trials in non-human primates, is planned for phase I trials. Another promising v accine has implemented induced neutralizing antibodies and v irus-like particles (V LPs) which are immunogenic in non-human primates and has entered into phase II trials (NCT02562482). 27 It will be important to show that these vaccines can hav e long-lasting protection against the v irus and are robust against wild-type v irus and different v ectors.
The release of a genetically engineered mosquito carry ing lethal genes (Rele ase of Insects with Dominant Lethal Gene [RIDL]) has also been inv estigated for prevention of infection. Howev er, there have been concerns that this measure in Aedes aegypti in Panama has allowed the mutation of CHIKV to be transmitted by the Aedes albopictus. 28 In addition, it may ev en driv e selection of more v irulent and severe v iruses. 2 Another approach has been to infect mosquitoes with the Wolbachia bacterium, which is thought to interfere with mosquito replication.

MANAGEMENT OF CHIKV RHEUMAT ISM
Management of CHIKV rheumatic disease has traditionally used a generic approach to this diverse group of clinical presentations. Javelle et al. recently suggested grouping patients according to their clinical sy ndrome and tailoring treatment accordingly. 13 The mainstay of treatment has been with antiinflammatory drugs, phy siotherapy , and short courses of oral steroids; however, clinical withdrawal of these treatments can be difficult. Evidence from La Réunion suggested that loco -regional disease responded well to physiotherapy and to localized joint injections. Carpal tunnel syndrome was treated with NSAIDs and with phy siotherapy . Uratelowering drugs can be effectiv e, as can bonestrengthening measures such as v itamin D. 13 In those with persistent symptoms, there is little ev idence on effectiv e therapies. Sev eral diseasemodify ing drugs (DMARDs) hav e been trialed with v ary ing success. Chloroquine has some antiv iral effect but has not been found to be more effectiv e than other anti-inflammatories like melox icam in acute and chronic CHIKV arthralgia. 29 Methotrexate has been widely used, particularly in patients who present with a systemic polyarthritis. A recent study showed that 7 5% of patients had a positive clinical response to this. 13 Sulfasalazine has been shown to hav e good clinical efficacy , particularly when combined with methotrex ate. 30 There are no good-quality trials assessing the use of biologic drugs in CHIKV rheumatic disease. There are data to suggest that serum cytokines are raised in patients with persistent symptoms, including IL-6 and IL-8. 31 In addition, a number of cases report successful use of biologic immuno modulatory agents such as inflix imab or etanercept in patients with sev ere disease. 32 Bindarit is a small-molecule indazolic derivative that has anti-inflammatory properties through inhibiting chemokine sy nthesis. This has been trialed in CHIKV mouse studies to reduce joint damage and inflammation and improve bone health. 33,34 These studies showed reduced macrophage infiltration of joints and therefore reduced tissue damage and disease sy mptoms and also reduced osteoclastic activity. As it is less immunosuppressive than more widely used biologic agents such as anti-TNF drugs, it has the potential to be a safe treatment to prev ent v iral-induced joint damage and bone loss.

CONCLUSION
Since its initial description in the 1 950s, there have been multiple large Chikungunya outbreaks worldwide. Mutation of the v irus to allow carriage by Aedes albopictus has enabled transmission of the v irus in prev iously unexposed areas, substantially increasing the at-risk population. The recent warnings in relation to Zika v irus have emphasized the increasing risk from Aedes-borne v iruses to the general population.
The growing body of ev idence regarding th e debilitating chronic arthritis following Chikungunya infection has illustrated trends in presentation. It has also allowed certain conclusions to be drawn regarding treatment strategies from the experience of clinicians worldwide. As the arthritis often has a strong semblance to well-described rheumatic presentations, it has often been treated as such, with reasonable outcomes. The importance of maintaining a holistic approach and considering quality of life is ev ident, particularly as long-term sequelae are more frequently seen in older patients with preex isting medical comorbidities. Although the mortality associated with this infection is small, the morbidity and burden of disease is large, affecting sev eral million people worldwide. With a rapidly ex panding area of endemicity , rheumatologists should be prepared to see more chronic arbov iral arthritides in their day-to-day clinics. More research and awareness is necessary in order to dev elop better treatment strategies for such patients.