Viral arthritides

Abstract

Viral infections may manifest as acute or chronic arthritis. Joint involvement arises from either direct infection of the joint, through an immunological response directed towards the virus or autoimmunity. Epidemiological clues to the diagnosis include geographic location and exposure to vector-borne, blood-borne or sexually transmitted viruses. Although not always possible, it is important to diagnose the pathogenic virus, usually by serology, nucleic acid tests or rarely, viral culture. In general, viral arthritides are self-limiting and treatment is targeted at symptomatic relief. This article focuses on the causes, clinical features, diagnosis and treatment of viral arthritides.

Figure 1. Aedes albopictus , the Asian tiger mosquito. Photograph courtesy of James Gathany, CDC Public Health Image Library.
(Figure omitted. See article PDF.)

Figure 2. Rash associated with B19 virus infection in an older child. Photograph taken from the CDC Public Health Image Library.
(Figure omitted. See article PDF.)

Infectious arthritis may be caused by multiple pathogens including bacteria, viruses and fungi. Although most bacterial and viral infections produce an acute arthritis, while mycobacterial and fungal infections typically follow a more indolent course, determining the etiology of infectious arthritis can be challenging. There is considerable overlap and variability in the presentation of disease and noninfectious causes can complicate the diagnostic process.

Common causes of viral arthritis include Togaviridae (Ross River virus, Barmah Forest virus, Chikungunya virus, O'nyong-nyong virus and rubella virus), Parvoviridae (B19 virus), Flaviviridae (dengue and HCV), Hepadnaviridae (HBV) and Retroviridae (HIV and human T-cell lymphotropic virus type 1 [HTLV-1]). These pathogens can also be grouped into three epidemiologic categories: arboviruses, endemic or childhood viruses and blood-borne viruses.

A thorough history including contact history, geographic location, travel history, sexual history and intravenous drug use should be sought to help determine the underlying viral etiology. It can be difficult to distinguish the responsible virus on clinical examination alone, as the pattern of joint involvement is usually not specific to a particular virus. Arthritis may be the predominant feature in a viral infection, or occur as part of a syndrome that may include fever, rash, myalgia or hepatitis. Some viruses are location specific due to the associated vectors responsible for transmission of infection. Knowing the current local epidemiology of potential viral agents is also useful when differentiating sporadic from epidemic cases of viral arthritis.

In this article, we first describe the epidemiology and pathogenesis of each virus, followed by the clinical features and diagnostic modalities currently employed, and finally discuss some treatment options for viral arthritides.

Togaviridae

The members of the Togaviridae family associated with arthritides include the Alphavirus species Chikungunya, Ross River, Barmah Forest, O'nyong-nyong, Mayaro and Sindbis viruses and the Rubivirus species rubella virus. These viruses are enveloped and all possess a single-stranded, positive-sense RNA genome of 9-12 kb.

Viruses of the genus Alphavirus cause zoonotic infections and are transmitted by arthropod vectors (usually mosquitoes). Incidence often varies with season and is related to the vector density, nonhuman vertebrate reservoirs of infection and number of susceptible people. Incubation periods for the arthritogenic alphaviruses are similar, typically 1-12 days for Chikungunya virus and 5-15 days for Ross River and Barmah Forest viruses. Subclinical or asymptomatic infection is common [1].

The alphaviruses associated with arthritis are capable of causing productive infection of macrophages and also synovial cells [1]. Cell entry occurs via receptor-mediated endocytosis followed by envelope fusion within the endosome. Envelope glycoprotein E2 binds to cell-surface receptors such as α1β1 integrin, DC-SIGN and L-SIGN [2]. Under the acidic conditions of the maturing endosome, envelope glycoprotein E1 forms homotrimers that trigger membrane fusion [3,4]. The pathogenesis of arthritis in alphavirus infection is not fully understood. It is possible that direct infection of synovial cells produces tissue damage, but the predominant mechanism may be inflammatory effects associated with infection of, or persistence of viral particles within, joint macrophages.

Joint manifestations typically begin early in the course of Alphavirus infections, usually soon after the onset of fever and coincident with the onset of rash. Arthritis is usually symmetrical, polyarticular and involves small joints of the wrists, hands, ankles and feet, although large joints can also be involved [1,5,6]. In some cases the arthritis is migratory. The duration of joint symptoms is variable, but is often weeks to months.

Chikungunya virus is an Alphavirus that has caused the greatest burden of disease in recent years. In 2005-2007, a major epidemic of Chikungunya commenced on the islands of the Indian Ocean, subsequently causing 255,000 cases on the island of Réunion and an estimated 1.3 million cases in India [7]. Although epidemics of Chikungunya have been attributed to transmission by sylvatic mosquitoes of the Aedes furcifer-taylori group or by Aedes aegypti historically, the 2005-2007 epidemic was enhanced through transmission by Aedes albopictus in addition to A. aegypti (Figure 1). A single amino acid substitution may have been responsible for the ability of the epidemic strain of Chikungunya virus to infect A. albopictus [8].

The distributions of the other arthritogenic alphaviruses are also determined by their vectors. O'nyong-nyong virus is transmitted by Anopheles mosquitoes found in tropical Africa and causes a similar disease to Chikungunya virus. An estimated 2 million cases occurred during a major outbreak in Central and East Africa from 1959 to 1962 [9]. Mayaro virus is transmitted by Haemagogus mosquitoes found in tropical South America. Sindbis virus is transmitted by Culex mosquitoes and causes disease in Africa, the Middle East, Finland, the Philippines and parts of Australia. Epidemic polyarthritis in Australia is caused by Ross River and Barmah Forest viruses and both are transmitted by Culex and Aedes mosquitoes [5].

In the future, climate change may increase the distribution and activity of mosquito vectors capable of transmitting these viruses [10]. In addition, high-volume air travel facilitates the introduction of arboviruses into new areas where competent vectors, such as the widespread mosquito A. albopictus , are present. An autochthonous outbreak in Italy with more than 200 cases of Chikungunya infection may be a harbinger of future disease patterns [11]. A. albopictus was the likely vector in that outbreak.

Although there are subtle differences between the diseases caused by the arthritogenic alphaviruses, distinction on clinical grounds alone is difficult. For example, Barmah Forest virus typically causes a more extensive rash than Ross River virus, while lymphadenopathy is a frequent feature of Chikungunya and O'nyong-nyong, but not Ross River virus infections [1]. The typical rash in Chikungunya infection is widespread, nonpruritic and morbilliform [7]. Chikungunya can lead to a seronegative chronic erosive inflammatory arthritis, with associated synovial thickening, marrow edema and tenosynovitis [12]. Table 1 compares the clinical features of arboviruses from the genera Alphavirus and Flavivirus that are associated with arthritis.

Rubella virus, unlike the alphaviruses, is directly transmitted between humans by droplet or aerosol via the respiratory tract. The incubation period is 15-20 days [13]. Although uncommon in childhood infection, up to 60% of adults with rubella develop joint symptoms and a true arthritis develops in up to 50% of adult females. Pathogenesis of arthritis is unclear, but may involve immune complex deposition or the presence of virus in synovial cells or joint macrophages. The joints most commonly affected are the fingers, knees, wrists, elbows and ankles [14]. The duration of rubella-associated arthritis is typically 1-3 weeks [6].

Parvoviridae (parvovirus)

Parvovirus B19 is a member of the genus Erythrovirus and is a nonencapsulated virus with a 5600-nucleotide ssDNA genome. It is transmitted between humans via respiratory tract droplets. The incubation period is 13-18 days [13].

The cell receptor for B19 is globoside, a glycosphingolipid, with the cofactors α5β1 integrin and Ku80 [15-17]. The distribution of globoside includes red blood cells, erythroblasts, endothelial cells and fibroblasts [18]. α5β1 integrin is a fibronectin receptor with wide tissue distribution that includes joint cartilage [19]. Ku80 is a nuclear membrane protein that can also function as a fibronectin receptor [17]. It is expressed on cell surfaces in a number of marrow cell lines and also by other tissues in response to hypoxia. The presence of these receptors and the capacity of B19 virus to undergo efficient replication determine the cellular distribution and affected tissues in clinical B19 infection. Although B19 virus DNA has been found in synovial biopsies and can persist for years after initial infection, it remains unclear if the pathogenesis of B19-associated arthritis is due to viral replication or to immune complex deposition [6,20-22].

The classical presentation of B19 infection is 'fifth disease'in childhood, with fever and 'slapped cheek'facial rash. In older patients, the rash may instead have a glove-and-stocking distribution (Figure 2). Temporary arrest of erythropoiesis is common. The prevalence of arthritis in B19 infection increases with age, from approximately 10% in children [23] to approximately 50% in adults [24]. Joint involvement is usually acute-onset, symmetrical and polyarticular, typically involving small joints of the hands such as the proximal interphalangeal and metacarpophalangeal joints, although in children asymmetrical pauciarticular arthritis, often involving the knees, has also been described [21].

Dengue virus

The four genetically related but serologically distinct dengue viruses (DENV-1-4) are RNA viruses belonging to the family Flaviviridae . It is estimated that over 50 million dengue infections occur annually, of which 500,000 cases result in dengue hemorrhagic fever (DHF) [101]. A. aegypti is the main mosquito vector responsible for transmission, but as with Chikungunya virus, A. albopictus has emerged as another competent and widespread vector. Areas affected by dengue mirror the distribution of these vectors. Ecological expansion of Aedes vectors has led to dengue occurring in areas previously free of disease. Transmission has also been described following blood transfusions from viremic patients, by needle-stick injuries [25] and perinatally.

Dengue infection can involve muscle, tendons, joints and bone [26]. The arthritis in dengue occurs as part of a syndrome that includes fever, headache and a faint macular rash that spares the palms and soles. This typically occurs after a short incubation period of 4-7 days following exposure to the virus and a second wave of symptoms can recur after a period of convalescence. Unlike DHF, the pathogenesis of arthritis in dengue has not been fully elucidated [27].

As dengue and Chikungunya virus share common vectors for transmission, coinfections can occur and both infections should be considered in the differential diagnosis of polyarthritis in a patient presenting from an endemic area. While thrombocytopenia and bleeding tendencies are more common with dengue infection, acute arthritis is more pronounced in Chikungunya. Both viruses can lead to disability from chronic arthritis [28].

HCV

HCV is a single-strand positive sense RNA virus 30-60 nm in diameter also within the Flaviviridae family. An estimated 170 million people are infected with HCV worldwide [29]. Transmission mainly occurs through intravenous drug use and unsafe healthcare practices (e.g., blood transfusions prior to universal screening, or reuse of nonsterile needles). Percutaneous, mucous membrane and sexual exposures are less frequent modes of transmission.

Extrahepatic manifestations are not uncommon with HCV infection. Indeed, symptomatic arthralgia has been estimated to occur in 6.5-19% of patients [30-32]. Hepatitis C can cause two distinct types of arthritic symptoms: the more common rheumatoid arthritis-like polyarthritis of the small joints but without erosions in general; and a mono- or oligo-arthritis associated with type II or type III cryoglobulinemia [33-35]. Associated features of cryoglobulinemia include palpable purpura, rash, peripheral neuropathy and glomerulonephritis [36].

It is unclear if the underlying pathogenesis of HCV-induced arthritis is part of the mixed cryoglobulinemia syndrome, or is due to direct invasion of the synovium by virus, cytokine-induced disease or immune complex disease [37]. Arthritis is also more common in HCV/HIV coinfection, although HIV itself is an independent risk factor for arthralgia.

HBV

HBV is a partially dsDNA virus in the Hepadnaviridae family. An estimated 350 million people are infected with HBV worldwide [38], with transmission occurring vertically, sexually or through blood-borne exposure (intravenous drug use and blood transfusions).

The pathogenesis of arthritis in acute HBV infection is secondary to deposition of immune complexes containing hepatitis B antigens such as surface antigen or e antigen together with associated antibodies in the synovial tissue [39]. The classical and alternate complement pathways are also activated, leading to low serum complement levels (C3, C4 and CH50) and detection of complement in the synovial fluid of affected joints during the active arthritic phase, which then normalize on resolution of the arthritis [40].

Polyarthritis involving the small joints of the hands, wrists, elbows, knees and ankles may be a feature during the prodromal phase of acute HBV infection. The arthritis is typically self-limiting and generally begins a few weeks prior to and subsides at the onset of jaundice. It may be the predominant or only symptom of acute HBV infection [41]. On the other hand, polyarthritis is an uncommon manifestation of chronic HBV infection and its presence should raise the suspicion of associated polyarteritis nodosa (PAN). Most cases of HBV-associated PAN occur during the first 6 months of infection and can cause arthralgia, myalgia or frank large joint polyarthritis of the wrists, knees and ankles [39]. Other manifestations such as rash, peripheral neuropathy and glomerulonephritis may also be present in PAN.

HIV

HIV is an enveloped, plus-stranded RNA retrovirus measuring 100-150 nm in diameter. An estimated 33 million people live with HIV worldwide and 25 million people have died from the infection [102]. Rheumatic conditions associated with HIV have differed following the introduction of HAART, with HIV-associated arthritis, arthralgia, myalgia, septic arthritis, enthesitis, the Sjögren's syndrome-like diffuse infiltrative lymphocytosis syndrome and spondyloarthropathies (reactive arthritis, psoriatic arthritis and undifferentiated spondyloarthropathy) being described prior to HAART; and immune reconstitution inflammatory syndrome (IRIS), pyogenic septic arthritis, malignancies (multifocal bone non-Hodgkin's lymphoma and Kaposi's sarcoma), hyperuricemia, rhabdomyolysis and osteonecrosis (particularly affecting the hip joints) described in the post-HAART era [42-47]. IRIS that occurs following HAART results from the restoration of dysregulated immune response to pathogen-specific antigens or autoimmune disorders [48].

There remains considerable debate as to whether HIV infection is the cause of, or a coincidental finding in, all the associated rheumatological conditions. Findings to support a causative role of HIV include the detection of p24 antigen and HIV DNA in the synovium and the epidemiological observation of increased prevalence of rheumatic conditions in HIV-infected individuals [49-52]. On the other hand, HIV has not been isolated from the synovial fluid of affected joints and post-mortem studies of AIDS patients with arthritis demonstrate ischemic changes within the joints [53]. There have been many postulated pathogenetic mechanisms of HIV-associated rheumatological conditions including direct CD4 ⁺ T-lymphocyte destruction by HIV, B-cell proliferation, molecular mimicry and abnormal T-lymphocyte responses -reflecting the heterogeneity of the rheumatological conditions observed [46].

While arthralgia is common in acute HIV infection, arthritis can present at any stage of HIV infection. HIV-associated arthritis typically causes a nonerosive oligoarthritis of the lower extremities [42], although monoarticular or polyarticular involvement of other joints in a symmetrical or asymmetrical pattern has also been described [54]. HIV-associated arthritis is usually self-limiting and generally resolves within 6 weeks [42].

Human T-cell lymphotropic virus type 1

HTLV-1 is a delta retrovirus with a genome comprising two positive ssRNA molecules that are converted to DNA once the virus infects human cells. HTLV-1 infects 15-20 million people worldwide, with a focus of endemicity in Japan (seroprevalence up to 25%), the Caribbean, sub-Saharan Africa, and Central and South America. Like HIV, HBV and HCV, HTLV-1 is also a blood-borne virus, being transmitted sexually, through blood transfusions, sharing of needles in intravenous drug users, vertically and postnatally via breast milk. HTLV-1 is associated with adult T-cell leukemia (ATL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), infective dermatitis, polymyositis, uveitis and an erosive polyarthritis. HTLV-1-associated arthritis (HAA) can be associated with, but can also be independent of, ATL and HAM/TSP.

HAA is thought to arise from direct infection of joints by HTLV-1, as evidenced by the detection of ATL-like T lymphocytes and HTLV-1 proviral DNA in the synovial fluid and synovial tissue, and higher titers of IgM antibodies against HTLV-1 in the synovial fluid [55-57]. HTLV-1 Env and Tax proteins play a crucial role in the development of HAA by acting as major antigens in inflamed synovium and are recognized by T cells infiltrating the joints [58].

Clinically, the polyarthritis of HAA is similar to that of rheumatoid arthritis, with symmetrical involvement of the small joints of the hand [36]. Arthroscopic and synovial biopsy reveals proliferative synovitis and T-cell infiltration of the joint. Mild erosive changes may be seen on x-rays, and rheumatoid factor and antinuclear antibodies are frequently present. Although epidemiological studies in Japan have suggested HTLV-1 as a possible trigger for rheumatoid arthritis [59], these findings have not been replicated in Africa, Europe or USA [60].

Diagnosis of viral arthritides

Determining the etiology of viral arthritides is important for individual patient management and epidemiological surveillance. A thorough history including contact history, geographic location, travel history, sexual history and intravenous drug use should be sought to help diagnose the underlying viral infection. Arthritis may be the presenting feature of an acute or a previously undiagnosed chronic viral infection and may be accompanied by fever, rash, hepatitis or other systemic manifestations.

Serology is the most frequently used method to diagnose viral infections that cause arthritides. The advantages of serology include its noninvasive nature and minimal sample degradation if transported and stored appropriately. The availability of stored samples also presents an opportunity to test acute and convalescent samples in parallel to determine seroconversion, which provides greater confidence in the diagnosis of an infection rather than a single positive or negative result on an acute-phase sample. However, the need for convalescent sampling means laboratory confirmation is slow. Serological diagnosis can also be complicated by cross-reacting antibodies, leading to confusion over the true infecting agent. Pathogen-specific IgM and IgG can be measured; a positive pathogen-specific IgM gives a presumptive diagnosis, whereas IgG seroconversion (or a fourfold or greater rise in antibody titers) of acute and convalescent sera is usually regarded as definitive evidence of infection. When only a single serum sample is available, measuring IgG avidity to determine the maturity of the IgG response may differentiate acute from previous infection. High IgG avidity is indicative of previous infection, but low IgG avidity is not necessarily suggestive of an acute infection as high avidity can take years to develop.

Other methods of diagnosis include nucleic acid tests (NATs) and viral cultures of synovial fluid. Specimen quality, storage and transport conditions can affect NAT and viral culture results, hence laboratory advice should be sought to determine optimal methods to increase the diagnostic yield of these tests. Synovial fluid examination is not always helpful in the diagnosis of viral arthritides, although it should be performed when arthritis due to other pathogens such as bacteria or fungi, or noninfective causes of arthritis such as crystal deposition disease, cannot be excluded.

Imaging with ultrasound or magnetic resonance rather than x-rays of the affected joints delineates the presence of effusions and synovitis [61]. Ultrasound imaging may also be used to guide arthrocentesis. The radiological findings in viral arthritides can be variable and are generally nonspecific. The spectrum of changes may range from joint swelling to rheumatoid arthritis-like erosions. Indeed, it can be difficult to diagnose rheumatoid arthritis in the presence of viral infections and vice-versa on serological or radiological grounds alone.

Alphavirus infections should be considered in patients presenting with fever and arthropathy with or without rash who have been exposed to the appropriate vector. A presumptive diagnosis can be confirmed by detection of IgM antibodies directed against the virus E1 envelope protein [5,62]; a fourfold or greater rise in total or IgG antibody titers between acute and convalescent sera is definitive. There is potential for antibody cross-reaction between the alphaviruses and conversely, sequence variation in viral antigens can lead to false-negative results [62]. NAT for Chikungunya and other alphaviruses are available, but the period of viremia is brief, so specimens should be collected soon after symptom onset [63,64].

The diagnosis of rubella and parvovirus is generally made on clinical grounds, followed by serological confirmation. A positive rubella-specific or parvovirus-specific IgM result is suggestive of recent infection, but false-positive assays and persistence for long periods after initial infection or immunization is well described [65,66]. Rubella IgM serology may cross-react with parvovirus, in addition to cytomegalovirus and Epstein-Barr virus [67]. In such instances, rubella and/or parvovirus IgG avidity testing may be helpful in excluding a previous infection [68,69].

Dengue is typically confirmed by serology, although NAT such as reverse-transcriptase PCR (RT-PCR) has the advantages of high sensitivity (in the acute phase of infection) and relatively rapid turnaround times [70]. The detection of dengue IgM is indicative of acute infection, but it usually takes 5 days from the onset of symptoms for antibodies to appear. A positive dengue IgG indicates past exposure and may predispose the affected individual to develop dengue hemorrhagic fever during a secondary dengue infection. Unfortunately, dengue serology is not specific and cross-reactivity with other flaviviruses can be problematic. The detection of dengue virus NS1 antigen by ELISA or the rapid, lateral flow immunochromatographic test may provide an early diagnosis of primary or secondary dengue infection when dengue IgM is undetectable. However, both tests are relatively insensitive in detecting NS1 antigen (64% for ELISA and 55.1-89.5% for immunochromatographic test) [71-73] and are affected by the time of specimen collection post-onset of illness and whether the dengue is a primary or secondary infection.

Dengue RT-PCR is useful for diagnosing the early stages of dengue infection when serology may be negative. Dengue RT-PCR can serotype the four different dengue viruses and can also be multiplexed for simultaneous detection of Chikungunya and West Nile viruses [74]. Dengue may also be isolated by viral culture in cell lines, although this method is slow, labor-intensive and requires specialized laboratory equipment and personnel.

The diagnosis of both HBV and HCV is usually made on serological grounds. The detection of HBV core IgM (particularly in the presence of HBV surface antigen) is suggestive of acute hepatitis B infection. Anti-HCV antibodies may take several months to develop, hence negative HCV serology does not exclude an acute infection. This has improved with the availability of HCV antigen-antibody combination assays, which can detect anti-HCV antibodies 4-6 weeks after infection. NAT techniques including RT-PCR, branched DNA and transcription-mediated amplification are used to diagnose acute HCV infection [75]. Replication of HBV and HCV can also be quantified by measuring viral loads using NAT.

Typical serological markers of HCV arthritis associated with cryoglobulinemia include the detection of cryoglobulins and low C4. Leukocytoclastic vasculitis may be demonstrable in skin biopsies of rash. The diagnosis of rheumatoid arthritis in the presence of HCV can be confusing as rheumatoid factor is often present in HCV (and HBV) infection, but anticyclic citrullinated peptide antibodies may help distinguish between them [76,77]. Although current evidence does not support the routine screening for HCV in patients from low- or high-prevalence populations presenting with polyarthritis in the absence of risk factors for HCV infection [78,79], screening for HBV, HCV and other latent or chronic infections is recommended prior to commencing immunosuppressive therapy.

HIV screening is usually performed using an antigen/antibody combination or antibody enzyme immunoassays, with confirmatory testing performed using western blot or p24 antigen detection. Western blots may be indeterminate during the early phase of infection and patients with such results should have their serology repeated. HIV viral load is used for monitoring of disease activity and should not be used to diagnose early infection in general. CD4 ⁺ T-lymphocyte count is indicative of the level of immunosuppression. Serum antinuclear antibody (ANA), rheumatoid factor and HLA-B27 are characteristically negative in HIV-associated arthritis [42].

HTLV-1 infection can be confirmed by serology (ELISA or western blot) or NAT. Simultaneous genotyping and proviral load quantification to determine the type of HTLV and measure disease activity, respectively, can be performed by multiplex, real-time PCR assays [80,81]. Radiological findings in HTLV-1-associated arthritis may be normal, although tissue swelling and erosions similar to that of rheumatoid arthritis may be present [55].

The initial approach to investigation of the arthritogenic arbovirus infections is outlined in Table 1, while Table 2 summarizes the risk factors, associated clinical features and initial investigation of common endemic and blood-borne viruses that can cause arthritis.

Treatment

The treatment for viral arthritides is generally targeted at symptomatic relief, with no specific treatment for most infections. NSAIDs, glucocorticoids (systemic or intra-articular), DMARDs and antivirals are used in specific instances.

No specific antiviral treatment is available for Togavirus , Parvovirus , dengue virus or HTLV-1. The mainstay of therapy for joint manifestations of these infections is symptomatic relief with anti-inflammatory agents.

For HCV infection, treatment providing symptomatic relief should be balanced against potential hepatotoxicity. In addition to NSAIDs and glucocorticoids, combination antiviral therapy with pegylated IFN-α and ribavirin has been shown to improve arthritic symptoms, although interferon therapy can induce or worsen autoimmune disorders [82]. HCV patients with arthritis also reported symptomatic relief following treatment with biologic agents including etanercept without decompensation of chronic liver disease [83], although these agents are usually reserved for severe refractory cases.

Mixed cryoglobulinemia associated with HCV infection remains difficult to manage, owing to the potential promotion of viral replication by therapeutic immunosuppression. The objective is to reduce viral replication and reduce cryoglobulin generation by B lymphocytes using combination therapy with pegylated interferon alpha and antiviral agents, together with corticosteroids, plasma exchange, mycophenolate, ciclosporin or rituximab [84].

Arthritis during the prodrome of acute HBV infection is self-limiting and management comprises symptomatic relief [41]. HBV-associated PAN has been successfully managed with corticosteroids, plasma exchange and antiviral agents [85].

The use of DMARDs including methotrexate and leflunomide has been associated with a high risk of hepatotoxicity [86,103]. Risk factors for hepatotoxicity include the use of methotrexate and leflunomide in combination, concurrent NSAID use, previous alcohol abuse or pre-existing viral and autoimmune hepatitis. Indeed, reactivation of chronic HBV infection (particularly precore mutant HBV infection or hepatitis B surface antigen negative disease) can result in hepatic failure in patients given corticosteroids, DMARDs, leflunomide, anti-TNF-α agents or chemotherapeutic agents [87-90]. Current recommendations are for preventive antiviral therapy against HBV prior to starting and upon withdrawal of immunosuppressive medications [91,92]. There is evidence that with appropriate antiviral therapy, anti-TNF-α agents can be used safely in patients with concomitant HBV or HCV infection [93,94]. Further caution should be exercised in patients with HBV/HCV coinfection and close monitoring of clinical and virologic parameters while on immunosuppressive therapy is essential.

The first line of treatment for HIV-associated arthritis is symptomatic relief with NSAIDs. Sulfasalazine, hydroxychloroquine, methotrexate and anti-TNF-α agents have been used in spondyloarthropathies not responding to NSAIDs. Indomethacin and hydroxychloroquine have been shown to reduce replication of HIV in vitro and in vivo , respectively [95,96]. Methotrexate can be used in HIV-infected individuals on HAART with psoriatic arthropathy if CD4⁺ T cells and HIV viral loads are adequately monitored [43,97]. The introduction of HAART has reduced the prevalence of HIV-associated rheumatic syndromes with the exception of HIV-associated arthritis and IRIS [42,43,98,99]. Treatment of IRIS includes careful monitoring and ongoing exclusion of occult infection, temporary interruption of HAART or a short course of corticosteroid therapy [99].

Expert commentary & conclusion

The epidemiology of some of the viral arthritides has changed in recent years. Chikungunya virus has emerged as a widespread and prevalent arboviral pathogen in the tropics and must also be considered in the diagnosis of febrile returned travelers with joint symptoms. Rubella infections have declined in many developed countries due to immunization, but susceptible cohorts that have not received 'catch-up'immunization remain at risk of infection. While HBV is also declining in some countries as a result of immunization, together with HCV and HIV it remains common on a global scale.

Epidemiologic clues are essential for the diagnosis of viral arthritides. The viral causes of arthritis may be categorized as arboviruses, endemic childhood viruses and blood-borne viruses. These three categories are helpful in forming a differential diagnosis and selecting appropriate diagnostic tests, as outlined in Table 1 and Table 2. Treatment of the arboviruses and endemic childhood viruses remains largely confined to supportive care, but there are specific treatments for many of the blood-borne viruses that can cause arthritis. Therapeutic options for HBV, HCV and HIV remain under active research and, in most cases, patients should be managed in consultation with a specialist in that field.

Five-year view

The expansion of the ecological niche of vectors capable of transmitting alphaviruses or flaviviruses (e.g., due to climate change) will lead to increased prevalence of infection in areas previously free of disease. Vector control will remain a key method for the prevention of arboviral arthritides, but barriers to comprehensive implementation, including resource and infrastructure limitations in developing countries, will persist. Clinical trials of vaccines for some of the Alphavirus (Chikungunya) and Flavivirus (dengue and HCV) causes of viral arthritis will proceed, but widespread availability of these vaccines in the next 5 years is unlikely. Increased iatrogenic immunosuppression and new immunosuppressive agents may lead to atypical or previously unrecognized presentations of known infectious agents.

Table 1.

Arthritogenic arboviruses transmitted by mosquito vectors.
ICT: Immunochromatographic test; RT-PCR: Reverse-transcription PCR.

Arthritogenic arbovirus		Geographic location		Mosquito vector		Incubation period (days)		Distinguishing clinical features		Laboratory diagnosis
Chikungunya		Africa, Indian Ocean, South and Southeast Asia		Aedes spp.		1-12		Arthritis predominant, lymphadenopathy		Serology, RT-PCR
Dengue		Asia, Central and South America		Aedes spp.		4-7		Dengue hemorrhagic fever in secondary infections		ICT, serology, RT-PCR, viral culture
Ross River		Australia		Aedes spp. and Culex spp.		5-15		Epidemic polyarthritis, chronic arthralgia, glomerulonephritis		Serology
Barmah Forest		Australia		Aedes spp. and Culex spp.		5-15		Epidemic polyarthritis, rash more prominent than Ross River virus, myalgia		Serology
O'nyong-nyong		Africa		Anopheles spp.		≥8		Sporadic epidemics, chronic arthritis/arthralgia, rash, hemorrhagic symptoms		Serology
Sindbis		Europe, Africa, Asia, Australia		Culex spp.		<7		Rash, paraesthesiae		Serology
Mayaro		Tropical South America		Haemagogus spp.		3-11		Small sporadic epidemics, chronic arthralgias, hemorrhagic symptoms		Serology

Table 2.

Initial diagnostic tests for endemic and blood-borne viral causes of arthropathy.
ATL: Adult T-cell leukemia; HAM/TSP: HTLV-1-associated myelopathy/tropical spastic paraparesis; HTLV: Human T-cell lymphotropic virus; IVDU: Intravenous drug use; NA: Not applicable; NAT: Nucleic acid test.

Suspected viral pathogen		Risk factors		Associated clinical features		Initial tests
Rubella		NA		Rash, congenital rubella syndrome		Serology
B19 virus		NA		Rash, arrest of erythropoiesis, hydrops foetalis		Serology
HBV		Residence in high-prevalence country, unsafe injection or IVDU, unscreened transfusion, sexual transmission		Hepatitis		Serology
HCV		Unsafe injection or IVDU, unscreened transfusion of blood products		Hepatitis		Serology, quantitative NAT, cryoglobulin
HIV		Residence in high-prevalence country, unsafe injection or IVDU, unscreened transfusion, sexual transmission		AIDS		Serology, quantitative NAT, CD4 count
HTLV-1		Residence in high-prevalence country, unsafe injection or IVDU, unscreened transfusion, sexual transmission		HAM/TSP, ATL		Serology

Key issues

* Epidemiological clues are helpful in determining the etiology of viral arthritis as it is difficult to distinguish the different causes on clinical grounds alone.

* Viral arthritides can be considered in three broad epidemiological groups: arboviral infections; endemic viral infections of childhood; and blood-borne viruses.

* Acute and convalescent pathogen-specific serology and nucleic acid tests remain the cornerstone to diagnosis.

* Most cases of viral arthritis are self-limiting and require symptomatic treatment only.

* Follow up is critical to ensure that a chronic rheumatological disease is not missed.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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