INTRODUCTION — Arthritis and arthralgias are well-recognized and relatively common accompaniments to viral infections. The viral infections that most commonly have arthritis and/or arthralgias as a manifestation include parvovirus, hepatitis B, hepatitis C, rubella, Epstein-Barr virus (EBV), the alphaviruses, and Zika virus. Joint complaints are also observed less commonly in association with a wide variety of other viral infections (eg, mumps, enteroviruses, and herpes viruses), although the enteroviruses may be the most common causes of nonspecific self-limited viral arthritis syndromes [1-3] (table 1).
This topic will provide a general overview of the pathogenesis and presentation of viral arthritis and the approach to evaluation, diagnosis, and management of these disorders. Specific viruses that cause arthritis and the evaluation of polyarticular pain in adults are discussed separately. (See "Viruses that cause arthritis" and "Evaluation of the adult with polyarticular pain".)
PATHOGENESIS — Viruses can initiate joint and other rheumatologic symptoms by a variety of mechanisms, including direct invasion of the joint cells or tissues, immune complex formation, and by directly or indirectly causing immune dysregulation. These mechanisms depend upon host factors, including age, sex, genetics, infectious history, and the immune response [4-8]. Despite these many effects, no viruses have been convincingly implicated as a cause of any of the common forms of chronic inflammatory arthritis such as rheumatoid arthritis or systemic lupus erythematosus.
Major mechanisms of viral arthritis include:
●Direct invasion – Viruses may directly invade the joint, resulting in infection of the synovium or other joint tissues. This may be the mechanism utilized by rubella and rubella vaccine virus despite the fact that viral isolation from a joint is a rare occurrence [9-14]. In vivo data support the tropism of these viruses for synovial tissue and their potential for both lytic and persistent infection. Other viruses that may be arthrotropic include parvoviruses [15], enteroviruses [1], and chikungunya virus, which can cause an autoimmune reaction in the synovia [16]; both parvovirus and enteroviruses have been isolated from joint fluid. (See "Viruses that cause arthritis", section on 'Rubella and rubella vaccine virus' and "Viruses that cause arthritis", section on 'Parvovirus' and "Viruses that cause arthritis", section on 'Enterovirus infections: Coxsackie virus and echovirus' and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
Alphavirus infections may cause joint symptoms mainly by virus persisting in synovial macrophages, with the host's inflammatory antiviral immune response giving rise to the arthritic symptoms [17]. As an example, virus has been detected in the joint effusions of Ross River virus patients, and Ross River virus can establish in vitro persistent productive infection in macrophages [18,19]. These macrophage cultures also secrete inflammatory mediators associated with macrophage recruitment and activation, including chemokines, interleukin (IL)-8, and the antiviral cytokine interferon [19-21]. Similar findings to those with Ross River virus have been found in Barmah Forest virus, chikungunya, Semliki Forest, and Sindbis viruses. T-cell derived interferon gamma is also involved in Ross River and other alphavirus diseases. Interferon gamma has been detected in the synovial exudate from Ross River virus patients, and interferon gamma-secreting Ross River virus-specific T cells from humans and mice have been isolated [22]. (See "Viruses that cause arthritis", section on 'Alphaviruses'.)
●Immune complex formation – Viral particles (either whole virions or viral antigens) may act as the antigenic component of immune complexes formed by the humoral response to viral infection [4,5,15,23]. These immune complexes may be preferentially deposited in the joints and skin, leading to arthralgias, arthritis, and rash. This type of presentation is common and has been well documented in the cases of hepatitis B infection, alphaviruses, hepatitis C (often via the formation of cryoglobulins), and parvovirus. Antibodies directed against viral antigens also may crossreact with tissue antigens, a process called molecular mimicry [6,7]. (See "Viruses that cause arthritis", section on 'Hepatitis B virus' and "Viruses that cause arthritis", section on 'Alphaviruses' and "Viruses that cause arthritis", section on 'Hepatitis C virus' and "Viruses that cause arthritis", section on 'Parvovirus'.)
●Latent viruses and immune dysregulation – Viruses may establish persistent infections in which the host cells remain metabolically active, expressing viral antigens on their cell surfaces [24,25]. These antigens become a target for the immune system, resulting in the development of chronic inflammatory reactions. This situation has not been documented to occur in synovial tissues in humans but has been seen with lentivirus infection in animals, in which it gives rise to a chronic form of caprine arthritis [26].
In addition, the direct viral infection of elements of the immune system can lead to a primary immunologic derangement, which could eventually produce signs or symptoms of autoimmunity and rheumatic disease [27].
In patients with autoimmune disease, a potential complication of immunosuppressive therapy is reactivation of pathogenic viruses that have remained latent. The most commonly encountered are varicella-zoster virus, hepatitis B and C, Epstein-Barr virus (EBV), and polyoma John Cunningham (JC) virus [28]. Many cases of reactivation of Epstein-Barr infections have been seen in patients with rheumatoid arthritis or juvenile idiopathic arthritis on biologics such as the tumor necrosis factor (TNF) inhibitors or rituximab. (See "Viruses that cause arthritis", section on 'Varicella' and "Viruses that cause arthritis", section on 'Hepatitis B virus' and "Viruses that cause arthritis", section on 'Hepatitis C virus' and "Viruses that cause arthritis", section on 'Epstein-Barr virus' and "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections".)
CLINICAL PRESENTATION
History and physical findings — Patients with viral arthritis tend to present with symmetric polyarticular disease that may consist of arthralgias alone or a true arthritis that can mimic a rheumatic disease. In general, the musculoskeletal signs and symptoms are seen during the prodrome of, or coincident with, the clinical onset of infection. Joint involvement tends to be of sudden onset and of relatively short duration and may be accompanied by a rash. The clinical manifestations of each of the major causes of viral arthritis are described in detail separately. (See "Viruses that cause arthritis".)
Arthralgias and arthritis generally do not persist or recur in the vast majority of cases of viral arthritis; exceptions include infections due to rubella virus, parvovirus, Epstein-Barr virus (EBV), and chikungunya and other alphaviruses [12-16,29,30]. Even in instances of persistent or recurrent symptoms, however, viral arthritis has typically not been shown to lead to persistent chronic arthritis and destructive joint disease, except in some cases of chikungunya. (See "Viruses that cause arthritis", section on 'Rubella and rubella vaccine virus' and "Viruses that cause arthritis", section on 'Parvovirus' and "Viruses that cause arthritis", section on 'Alphaviruses' and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)
In some patients, a specific viral etiology may be strongly suspected clinically because of particular features, such a classic rash (eg, rubella), particular facial rash (eg, parvovirus B19), specific physical finding (eg, parotid enlargement in mumps, jaundice in hepatitis B, or hepatitis C virus infection), or historical feature (eg, onset after rubella vaccination, recent travel to an endemic area).
Laboratory findings — Laboratory findings are typically nonspecific and may be normal. Such testing is generally of little value in differentiating viral arthritis from other musculoskeletal conditions, unless characteristic findings of another disorder are present (see 'Differential diagnosis' below):
●There is usually little change in the peripheral white blood cell count, although some viral infections are associated with either a mild leukocytosis or lymphopenia.
●Liver function tests may be elevated with infections due to viruses that have tropism for the liver (eg, hepatitis B and C viruses, parvovirus, and EBV).
●Complement levels are not of diagnostic utility, although low levels may be seen with immune complex deposition diseases. As an example, essential mixed cryoglobulinemia, which is associated with both arthritis and hypocomplementemia, is most often due to hepatitis C virus infection. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)
●Synovial fluid findings are typically nonspecific, except for those selected patients in whom a viral culture has been performed and a positive result obtained (see 'Viral isolation from the joint' below). The synovial leukocyte counts may be elevated, occasionally to quite high levels; however, normal cell counts are not uncommon. There may be a predominance of polymorphonuclear leukocytes or lymphocytes, depending upon the viral etiology and other factors, including acuity and severity.
DIAGNOSIS — A possible viral etiology for joint symptoms should be suspected in patients with synovitis of less than six weeks' duration and in those with polyarthralgia without synovitis. The approach to establishing the diagnosis of viral arthritis varies with the clinical setting (see 'History and physical findings' above). There are usually two components to the diagnostic approach to viral arthritis: establishing the diagnosis when it is suspected (which usually begins with serologic testing) and evaluating the patient with polyarticular joint pain when a specific viral infection is not suspected. (See 'Approach to diagnosis' below and 'Differential diagnosis' below.)
In many cases the diagnosis of viral arthritis is made difficult by the following general features of viral arthritis:
●There is no single presentation that is typical of viral arthritides
●Many of the signs and symptoms are nonspecific (eg, fever, arthralgia, rash) and can be seen in more than several different disorders
●Arthritis may occur before the onset of the major signs of the viral infection (eg, before icterus in hepatitis B virus infection)
●Evidence of viral infection (viral isolation or serologic evidence of recent infection) is frequently difficult to document
Approach to diagnosis — We take the following approach:
●In patients suspected of a particular infection based upon the clinical presentation or epidemiologic features (eg, residence in or travel to an endemic area or other potential exposures to one of these pathogenic agents, such as human immunodeficiency virus (HIV), Epstein-Barr virus [EBV], or a hepatitis virus), we perform serologic testing and limit initial testing to the virus(es) of interest. (See 'Principles of serologic testing' below and 'Diagnosis' above.)
When viral infection is suspected, serum should be collected immediately and then approximately two to three weeks later to detect the immunoglobulin M (IgM) antibody response seen with exposure to the agent and the switch to an increasing IgG response.
●All patients with arthritis should undergo arthrocentesis and synovial fluid analysis, including white blood cell count and differential, crystal search, Gram stain, and routine culture. Findings with viral arthritis are nonspecific, but this serves to exclude bacterial infection and some other conditions that may mimic viral arthritis, including crystal disease.
●To evaluate inflammatory arthritis of unknown etiology and for the initial exclusion of new-onset rheumatoid arthritis or a systemic autoimmune rheumatic disease, we obtain a complete blood count (CBC), urinalysis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and chemistry panel including liver function tests and muscle enzymes, along with testing for rheumatoid factor, anti-citrullinated peptide antibodies, and antinuclear antibodies. Such testing may also point to a viral etiology, such as hepatitis. (See 'Differential diagnosis' below.)
●In the absence of features to suggest a specific viral etiology and negative testing for a suspected nonviral rheumatologic cause, we obtain serologic testing for the following agents (see 'Principles of serologic testing' below):
•Hepatitis B
•Hepatitis C
•EBV
•Parvovirus B19
The diagnoses of specific viral infections and several caveats regarding the diagnoses of these disorders are described here and separately. (See 'Diagnosis of specific viral infections' below.)
●In patients in whom no etiology is found and the clinical manifestations have resolved after a typical two- to six-week clinical course, we generally do not pursue further testing.
●In patients with persistent synovitis of unknown etiology that has not responded to medical therapy, synovial biopsy for possible viral isolation should be performed when serologic studies and cultures have not been helpful.
●In routine clinical practice, synovial fluid is usually not sent for viral isolation due to cost, insurance approval, and difficulty isolating the virus. However, in selected cases, if symptoms persist and a definitive diagnosis is needed, synovial fluid can be sent for attempted isolation of rubella, rubella vaccine virus, parvovirus, and enteroviruses and for viral testing by polymerase chain reaction (PCR) techniques. Care must be exercised, however, not to culture blood elements as a consequence of a traumatic aspiration or as part of the synovial material that is biopsied.
Principles of serologic testing — Serologic testing is the most common means of establishing a viral etiology for a clinical condition. Serologic diagnosis is based upon two facets of the immune system's response to viral infections: the first exposure to an agent results in the development of an initial IgM response, and the IgM response is followed by isotype switching and by the appearance of IgG antibodies. Thus, if viral infection is suspected, serum should be collected immediately and then approximately two to three weeks later. Serologic testing must be directed against the specific viruses suspected to be involved based upon both epidemiologic and clinical data.
●An acute IgM antibody response followed by the presence of IgG antibodies against the suspected agent confirms a viral etiology.
●A significant (greater than fourfold) time-related increase in IgG also suggests a recent infection in which the initial sample was obtained too late to detect the IgM response. Alternatively, this serologic pattern could represent reinfection with a particular virus or recrudescence of infection.
●The presence of a stable level of IgG antibody is not diagnostic of recent infection since it may represent a viral infection that significantly antedated the onset of arthritis.
Immunoassays for both IgM and IgG antibodies to a variety of viral components have replaced the older classical means of serologic diagnosis. Direct testing of serum for viral-specific nucleic acid by PCR can also be performed.
Diagnosis of specific viral infections — The approaches to the diagnosis of specific viral infections are described separately:
●Hepatitis A – (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Overview of hepatitis A virus infection in children", section on 'Diagnosis'.)
●Hepatitis B – (See "Hepatitis B virus: Screening and diagnosis".)
●Hepatitis C – (See "Screening and diagnosis of chronic hepatitis C virus infection" and "Hepatitis C virus infection in children", section on 'Diagnosis'.)
●Parvovirus B19 – It is important to note that IgG antibody is evidence of a preexisting infection and may be found in a substantial proportion of the normal population [15,31]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Diagnosis'.)
●Rubella – The diagnosis of rubella-associated arthropathy must be substantiated by either viral isolation from the nasopharynx or joint tissues or serologic evidence of an acute viral infection with an IgM response. (See "Rubella", section on 'Diagnosis'.)
●Alphavirus infection – IgG seropositive results should be interpreted with caution, especially for individuals who live or have lived in endemic areas and who may be IgG seropositive because of previous infections. The diagnosis for these diseases varies. In Australia, commercial serodiagnostic tests based on enzyme-linked immunoassays (ELISA) for Barmah Forest and Ross River virus infections are available (see "Ross River virus infection", section on 'Diagnosis'). The laboratory-based tests for chikungunya, Mayaro, and Sindbis virus infections are available in several countries and are usually based on ELISA, hemagglutination inhibition, or indirect immunofluorescent assays [32]. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)
●Flaviviruses (Dengue and Zika) – (See "Dengue virus infection: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Zika virus infection: An overview", section on 'Diagnosis'.)
●Mumps – (See "Mumps", section on 'Diagnosis'.)
●Enterovirus and echovirus – Establishing the specific diagnoses of these diseases is frequently difficult because of the endemic nature of these viruses in most populations, and such confirmation is generally not required in clinical practice. For research purposes, proving a causal role requires culture from an involved tissue [1] or convincing epidemiologic evidence of a simultaneous epidemic in the geographic area of interest [33]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Laboratory diagnosis'.)
●Adenovirus – (See "Diagnosis, treatment, and prevention of adenovirus infection".)
●Herpesviruses – (See "Diagnosis of varicella-zoster virus infection" and "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Diagnosis' and "Infectious mononucleosis", section on 'Diagnosis' and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis' and "Approach to the diagnosis of cytomegalovirus infection".)
●HIV - (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Screening and diagnostic testing for HIV infection".)
●Coronavirus disease 2019 – Coronavirus disease 2019 (COVID-19) is not usually associated with rheumatologic symptoms; however, with the epidemic, post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been noted in two pediatric cases as a post-reactive arthritis. Both responded well to naproxen 250 mg twice daily [34]. Also, arthralgias have been noted in children with multisystem inflammatory syndrome (MIS-C). All responded well to treatment of MIS-C with no residuals [35]. The rheumatologic manifestations of COVID-19 and other issues related to the care of patients with rheumatologic disease during the pandemic are described in detail separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease".)
Viral isolation
Viral isolation from the joint — Only a small number of viruses directly infect the joint, and viral isolation in these cases is accomplished infrequently, but in some patients in whom serologic studies have been unrevealing, such studies may permit a diagnosis. However, strict confirmation of a viral etiology of an arthritic condition requires isolation of the etiologic agent from the site of musculoskeletal symptoms (joint fluid or synovium). Any isolate from the joint can be considered pathogenic since the joint does not harbor known persistent viruses. In routine clinical practice, synovial fluid is usually not sent for viral isolation due to cost, insurance approval, and difficulty isolating the virus.
Synovial biopsy for possible viral isolation should be performed in clinical practice in patients with persistent synovitis of unknown etiology that has not responded to medical therapy. Synovial biopsy is only indicated in such patients when serologic studies are not helpful. The common isolates for which samples could be evaluated are hepatitis B and C, parvovirus, and the alphaviruses.
The following viruses have been isolated from joint fluid or synovium in individuals with clinical signs of arthritis: rubella virus, rubella vaccine virus, parvovirus, enterovirus, vaccinia virus, and herpes family viruses [4,14,26] (see "Viruses that cause arthritis"). In addition to isolation of the virus, identification of viral nucleic acid by PCR techniques is another method to confirm viral infection of the joint. PCR may be helpful in selected cases but is difficult to use as a screening tool.
In selected cases, if definitive diagnosis is needed because of persistent disease of uncertain etiology, synovial fluid can be sent for attempted isolation of rubella, rubella vaccine virus, parvovirus, and enteroviruses; to check the synovial fluid white blood cell count; and for viral testing by PCR techniques. Care must be exercised, however, not to culture blood elements as a consequence of a traumatic aspiration or as part of the synovial material that is biopsied.
Viral isolation from other tissues — In patients with persistently active disease of unknown etiology despite serologic and molecular techniques and efforts at viral isolation from synovial fluid and tissues, viral cultures from other parts of the body can be attempted. For cases in which viral isolation is unequivocally pathogenic (eg, rubella and arthropod-borne alphaviruses), identification of the virus represents strong presumptive evidence for the etiology of the associated joint symptoms. By contrast, one cannot unequivocally relate joint symptoms with the isolation of commonly found organisms (eg, enteroviruses from the stool or EBV from the blood or saliva).
Role of viral DNA detection — Detection of viral deoxyribonucleic acid (DNA) in synovium or synovial fluid is generally not indicated in routine clinical practice. There are high rates of detection of viral DNA sequences in controls (eg, 50 and 21 percent for parvovirus B19 in synovium and synovial fluid, respectively, of controls with osteoarthritis [36]), which have limited usefulness of PCR techniques for this purpose in clinical practice. Nonetheless, PCR may be helpful in selected cases but is difficult for these reasons to use as a screening tool.
DIFFERENTIAL DIAGNOSIS — Patients in whom there is no obvious association with a particular viral infection should undergo an evaluation to identify one of the multiple other causes of polyarticular joint pain, particularly rheumatoid arthritis, systemic lupus erythematosus, and juvenile idiopathic arthritis (JIA) (table 2). Oligoarticular-onset JIA may also be difficult to distinguish clinically from viral arthritis, especially early in its presentation, and is another diagnosis to consider. The differential diagnosis and evaluation of polyarticular pain and polyarthritis are reviewed in detail separately. (See "Evaluation of the adult with polyarticular pain" and "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Oligoarticular juvenile idiopathic arthritis" and "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications" and "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)
A possible viral etiology is more likely in patients with synovitis of less than six weeks' duration and in those with polyarthralgia without synovitis. Routine laboratory testing and serologic studies for rheumatoid arthritis and systemic lupus erythematosus will help to distinguish a nonspecific viral arthritis from a major rheumatologic disorder (see 'Approach to diagnosis' above). Mycoplasma infection should also be considered in the differential diagnosis if such testing is unrevealing and persistent leukopenia is present.
TREATMENT — Therapy in viral arthritis is generally directed at relief of symptoms and at maintenance of function. Patients should be treated with analgesic agents (eg, acetaminophen) and nonsteroidal antiinflammatory drugs (NSAIDs) in doses typically used in any inflammatory arthropathy (table 3), such as rheumatoid arthritis (see "Initial treatment of rheumatoid arthritis in adults", section on 'NSAIDs'). Physical and occupational therapy can be initiated if required to maintain or improve function.
The use of glucocorticoids, either orally or by intraarticular injection, should be discouraged since they are of limited utility in most viral arthritis. Use of glucocorticoids may mask the disease and the correct diagnosis. Intravenous immune globulin therapy has been used in selected patients with certain conditions, such as chronic parvovirus infection complicated by anemia, for measles postexposure prophylaxis if the patient is immunocompromised or nonimmune, and in some enteroviral infections. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Uses for IVIG'.)
Collaborative management together with an expert in infectious disease is of particular importance in patients with chronic viral infections. However, generally, there is no need for specific antiviral therapy since most viral arthritides are of short duration and are self-limited, although no specific antiviral therapy exists for most of the agents implicated in causing rheumatic disease. Exceptions include hepatitis B and C and HIV, for which highly effective therapies are available. (See "Hepatitis B virus: Overview of management" and "Overview of the management of chronic hepatitis C virus infection" and "Overview of antiretroviral agents used to treat HIV" and "When to initiate antiretroviral therapy in persons with HIV".)
Additional issues are relevant to the management of particular viral infections. These include:
●Hepatitis B – In those individuals with chronic hepatitis B virus infection and clinical syndromes such as polyarteritis nodosa, glomerulonephritis [37,38], and mixed cryoglobulinemia syndrome [39], treatment of the immune syndrome may be required in addition to treatment for the hepatitis B infection. (See "Treatment and prognosis of polyarteritis nodosa", section on 'Associated hepatitis B or C infection' and "Kidney disease associated with hepatitis B virus infection", section on 'Treatment' and "Mixed cryoglobulinemia syndrome: Treatment and prognosis", section on 'Hepatitis B infection'.)
●Hepatitis C – Patients with chronic hepatitis C infection may develop systemic disease, including mixed cryoglobulinemia syndrome, with vasculitis, arthritis, renal disease, and other manifestations [40-43] (see "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis"). Treatment of these manifestations can be necessary in addition to the therapy directed against the hepatitis C virus. NSAIDs and hydroxychloroquine may be helpful for the joint manifestations, but conventional treatment of arthritis may be problematic in the context of viral hepatic arthropathy. Tumor necrosis factor (TNF)-alpha inhibitors appear relatively safe when used to treat patients with hepatitis C virus and an associated rheumatoid arthritis-like disorder, although data are limited [44,45]. Glucocorticoids should be avoided if possible in these patients. Therapies with a high potential for being curative are available for hepatitis C infection. The treatment of hepatitis C infection and of mixed cryoglobulinemia syndrome are discussed in detail separately. (See "Overview of the management of chronic hepatitis C virus infection" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)
●Dengue virus and suspected alphavirus infections in dengue-endemic regions – In the patient who may have dengue, aspirin and other NSAIDs should not be used until the patient is afebrile ≥48 hours and there are no warning signs for severe dengue (severe abdominal pain, persistent vomiting, mucosal bleeding, pleural effusion or ascites, lethargy, enlarged liver, and increased hematocrit with decrease in platelet count); this is important given the risk of bleeding complications associated with dengue infection and because of the potential risk of Reye syndrome in children. (See "Dengue virus infection: Clinical manifestations and diagnosis".)
●HIV – Patients with HIV require treatment for their primary viral infection. In addition, treatment may be needed for arthritis and other rheumatic disease manifestations that can occur in this population. Most available information is from case reports and small case series [46,47]. Treatment of systemic rheumatic diseases co-occurring in patients with HIV may require certain adjustments, and there is limited experience with biologic agents. In patients with HIV arthritis, those with mild to moderate symptoms of arthritis may respond to NSAIDs. Low-dose glucocorticoids, hydroxychloroquine, or sulfasalazine may be used for those with more severe or prolonged arthritis but are rarely necessary [48].
Treatment of reactive arthritis in the setting of HIV infection is similar to that in non-HIV-infected individuals. Some of the agents that are used to treat reactive arthritis and enthesitis, including indomethacin, sulfasalazine, and hydroxychloroquine, have been suggested to have some antiviral activity. This has been suggested for indomethacin, sulfasalazine, and hydroxychloroquine [49-52]. Methotrexate may be used cautiously in HIV patients for both reactive and psoriatic arthritis (PsA) [48,53,54]. There is at least one case report of improvement in a patient with reactive arthritis following use of the anti-TNF therapy infliximab [55]. (See "Reactive arthritis".)
In HIV-associated PsA, treatment is the same as in non-HIV-infected patients with PsA, although in both rheumatoid arthritis and PsA use of these drugs has generally been reported in patients with CD4 lymphocyte counts of at least 100 to 200 cells per microL and low or undetectable viral load, which has become feasible with highly active antiretroviral therapies. Though NSAIDs are generally used as initial treatment for HIV-associated PsA, these agents are often ineffective in controlling the disease, and disease-modifying antirheumatic drugs (eg, methotrexate [5 to 10 mg once weekly], azathioprine, sulfasalazine [1 to 2 g daily]) have been used with success [47,53]. Use of mycophenolate mofetil and ustekinumab have been described in case reports in HIV-associated PsA [47,56]. Psoralen and pulsed ultraviolet light therapy may be effective for both the skin and joint manifestations.
Anti-TNF agents may be beneficial in PsA and in patients with rheumatoid arthritis. One study evaluated eight HIV patients with various rheumatic diseases, including three with PsA and two with rheumatoid arthritis, who received anti-TNF agents, all of whom had CD4 counts over 200 cells per microL [57]. The side effect profile was overall good, except one patient had transient elevation of the viral ribonucleic acid (RNA).
SUMMARY AND RECOMMENDATIONS
●The viral infections in which arthritis and/or arthralgias are most common include parvovirus, hepatitis B, hepatitis C, rubella, Epstein-Barr virus (EBV), the alphaviruses, and Zika virus. Joint complaints are also observed in association with a variety of other viral infections (eg, mumps, enteroviruses, and herpes viruses), although the enteroviruses may be the most common causes of nonspecific self-limited viral arthritis syndromes (table 1). (See 'Introduction' above and "Viruses that cause arthritis".)
●Viruses can initiate rheumatic symptoms by a number of mechanisms that depend upon host factors, including age, sex, genetics, infectious history, and immune response. Major mechanisms include the direct invasion of the joint (eg, rubella and enteroviruses) and immune complex formation, which may occur both in the joints and in the skin (eg, hepatitis B and C, alphaviruses). Parvovirus may use both of these mechanisms. Molecular mimicry may also occur. (See 'Pathogenesis' above.)
●The usual presentation includes the sudden onset of symmetric polyarticular arthralgias or arthritis, sometimes associated with a rash. The musculoskeletal manifestations are typically seen during the prodrome of, or coincident with, the clinical onset of infection. Articular manifestations generally do not persist or recur, except with infections due to rubella virus, parvovirus, and alphaviruses. Signs and symptoms are usually nonspecific, and clinical evidence of a specific viral etiology on exam may occur but is uncommon. Viral arthritis has not been shown to lead to persistent chronic arthritis and destructive joint disease, even when symptoms persist or recur, except in rare cases. Laboratory findings are typically nonspecific. (See 'Clinical presentation' above.)
●The two components to the diagnostic approach to viral arthritis are establishing the diagnosis when it is suspected (which usually begins with serologic testing) and evaluating the patient with polyarticular joint pain when a specific viral infection is not suspected. A history of recent travel to or residence in endemic areas is important to ascertain. Thus, if viral infection is suspected, serum should be collected immediately and then approximately two to three weeks later to detect the immunoglobulin M (IgM) antibody response seen with exposure to the agent and the switch to an increasing IgG response. Serologic testing must be directed against the specific viruses suspected to be involved based upon both epidemiologic and clinical data. (See 'Approach to diagnosis' above and 'Diagnosis' above and 'Principles of serologic testing' above.)
●We suspect a possible viral etiology in patients with synovitis of less than six weeks' duration and in those with polyarthralgia without synovitis. The initial evaluation in all such patients includes a complete blood count (CBC), urinalysis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and blood chemistries including liver function tests and muscle enzymes, and testing for rheumatoid factor, anti-citrullinated peptide antibodies, and antinuclear antibodies should be performed to help exclude rheumatoid arthritis or another systemic autoimmune rheumatic disease. Serologic testing for hepatitis B and C virus, parvovirus, and EBV infection should be performed if the etiology is not established with routine testing. (See 'Approach to diagnosis' above and 'Differential diagnosis' above.)
●Therapy is generally directed at relief of symptoms and at maintenance of function by use of analgesic agents (eg, acetaminophen) and nonsteroidal antiinflammatory drugs (NSAIDs) in antiinflammatory doses; physical and occupational therapy can be initiated if required to maintain or improve function. We generally avoid the use of either oral or intraarticular glucocorticoids. (See 'Treatment' above.)
