INTRODUCTION — Arthralgia and/or arthritis are well-recognized and relatively common occurrences with a variety of viral infections [1]. For many patients, the episode of viral arthritis is self-limiting and does not cause permanent joint injury, while other patients may experience significant systemic disease and disabling joint symptoms.
This topic will review the more common and other important viral infections that can cause arthralgia, arthritis, and related symptoms. An overview of the approach to evaluation and management of viral arthritis and the pathogenesis of these conditions is presented separately. (See "Viral arthritis: Approach to evaluation and management".)
ENTEROVIRUS INFECTIONS: COXSACKIE VIRUS AND ECHOVIRUS — Enterovirus infections cause the majority of cases of nonspecific viral polyarthritis. Both large and small joints may be involved. Although arthritis is an uncommon manifestation of enterovirus infections, affecting approximately 0.1 percent of patients, with a large number of patients with these illnesses, it can represent a substantial number of cases of nonspecific self-limited arthritis [2-4]. Joint symptoms commonly accompany some episodes of illness and are typically associated with the other symptoms of the acute viral infection, including fever, sore throat, pleuritic pain, myocarditis, and rash. Routine laboratory findings are nonspecific and include leukocytosis, elevated erythrocyte sedimentation rate (ESR), and joint fluids with white counts ranging from 2000 to >10,000/mm3.
The incubation period for viral infection is short, three to five days, and is followed by the abrupt onset of fever, headache, and other nonspecific constitutional signs and symptoms. There may be associated maculopapular rash, pharyngitis, conjunctivitis, myalgias, nausea, vomiting, diarrhea, and abdominal pain. Symptoms are generally short-lived (two to four days), although they may recur [5]. (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)
Enteroviruses are endemic throughout the world. The peak incidence of disease is in the summer and fall in temperate climates. Prevalence is inversely correlated with socioeconomic status [5]. The mechanism by which enteroviruses cause arthritis is not known. Virus has occasionally been isolated from involved joints, but immune complexes have not been reported [2]. Isolated outbreaks of disease to specific enterovirus immunotypes are not uncommon.
HEPATITIS VIRUSES
Hepatitis A virus — In patients with hepatitis A virus (HAV) infections, arthralgias and rash occur in 10 to 14 percent of patients, but arthritis is extremely rare. Patients with joint manifestations usually present with knee and ankle arthralgias with accompanying rash. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Extrahepatic manifestations' and "Overview of hepatitis A virus infection in children", section on 'Clinical manifestations'.)
True arthritis, rather than arthralgias alone, has been described in case reports primarily in patients with vasculitis who had a chronic relapsing form of hepatitis A and also high titer of polyclonal immunoglobulin G (IgG)- and IgM-circulating cryoglobulins (type III cryoglobulinemia) [6].
Hepatitis A is usually a self-limited illness that does not become chronic and is typically transmitted by a fecal-oral route. Overviews of HAV infection are presented separately. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Overview of hepatitis A virus infection in children".)
Hepatitis B virus — Arthritis and skin manifestations can be the presenting features of acute hepatitis B virus (HBV) infection, as well as a feature of chronic infection with the virus. Ten to 25 percent of patients with HBV develop joint symptoms and arthritis [7]. Joint symptoms can be symmetric, migratory, or additive, and arthritis usually occurs in the prodromal stage of the disease at a time when there may be no other clinical manifestations of hepatitis. Women have a higher incidence of joint disease than men. The joints of the hands and knees are most often affected, but wrists, ankles, elbows, shoulders, and other large joints can also be affected and morning stiffness is common [7-9]. Joint symptoms tend to persist for days to weeks and commonly resolve with the onset of jaundice [7,9].
Skin involvement is a common accompaniment of HBV-associated arthritis and often appears coincident with the joint symptoms [7,9]. Urticarial and maculopapular eruptions primarily involving the lower extremities are most typical. The joint disease is always self-limited, with no reports of progression to chronic arthritis or evidence of joint damage [10,11].
Patients with acute hepatitis B-associated arthritis may have abnormal liver function tests with transient decreases in complement levels and increasing levels of circulating immune complexes. The laboratory evaluation will distinguish hepatitis B from other potential underlying causes of the patient's symptoms and findings. (See "Hepatitis B virus: Clinical manifestations and natural history" and "Hepatitis B virus: Screening and diagnosis" and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents".)
In individuals with chronic HBV infection, arthritis may persist for longer periods of time and other laboratory and clinical manifestations of immune complex-mediated disease may be present. These include evidence of clinical syndromes such as polyarteritis nodosa [12], glomerulonephritis [13], and essential mixed cryoglobulinemia [14]. Such manifestations have become much less common with the availability of more aggressive and targeted treatment of the infection. Examination of joint fluid may reveal inflammatory changes [8].
Joint symptoms associated with HBV infections are believed to be due to the formation and deposition of immune complexes; cryoprecipitates containing hepatitis B surface antigen (HBsAg) and complement components have been reported in affected patients [10,11]. Affected patients may have an earlier anti-HBsAg response, promoting immune complex formation [10].
HBV infections can be either asymptomatic or symptomatic; asymptomatic infection is more common, especially in young children. Most primary infections in adults are self-limited, with clearance of the virus from the blood and liver and the development of lasting immunity. However, some primary infections in healthy adults, generally less than 5 percent, do not resolve but develop into persistent infections. The clinical manifestations, diagnosis, and management of HBV infection are described in detail separately. (See "Hepatitis B virus: Clinical manifestations and natural history" and "Hepatitis B virus: Screening and diagnosis".)
Hepatitis C virus — Hepatitis C virus (HCV) infection is often associated with extrahepatic symptoms, including arthralgia and myalgia, with arthritis noted in 2 to 20 percent of HCV patients, including patients both with and without mixed cryoglobulinemic vasculitis [15-17]. The arthritis, which is typically nonerosive and nondeforming, has an evanescent rheumatoid-like presentation in two-thirds of reported patients and an oligoarthritis in the rest. These findings have typically been observed in patients with chronic HCV infection, although joint symptoms have also been described in some patients with acute infection, with arthralgia and myalgia reported in a quarter and a third of patients, respectively, among a cohort of 25 patients with acute HCV [18].
HCV infection becomes chronic in the majority of infected patients and is often detected in an asymptomatic individual because of elevated transaminase levels noted on a chemistry panel. The clinical manifestations and diagnosis of acute and chronic HCV infection and the extrahepatic manifestations of HCV are described in detail separately. (See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults" and "Clinical manifestations and natural history of chronic hepatitis C virus infection" and "Screening and diagnosis of chronic hepatitis C virus infection" and "Hepatitis C virus infection in children" and "Extrahepatic manifestations of hepatitis C virus infection".)
A number of patients with HCV infection demonstrate an antibody response to viral products that results in the formation of circulating immune complexes. These immune complexes may then deposit in tissues resulting in a small portion of patients in the mixed cryoglobulinemia syndrome that includes arthritis, glomerulonephritis, and vasculitis [17,19]. The clinical manifestations, diagnosis, and management of the mixed cryoglobulinemia syndrome are discussed in detail separately. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)
PARVOVIRUS — Parvovirus B19, which can cause arthralgias and arthritis that can mimic the joint manifestations of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), is the only known parvovirus that infects humans. It is the cause of fifth disease or erythema infectiosum, a self-limited febrile-rash-producing disease of childhood. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
The arthritis is associated with the outbreaks of the viral illness. Joint symptoms occur in approximately 8 percent of infected children and 60 percent of infected adults. Arthralgias or arthritis may accompany or follow the skin eruption. Arthropathy occurs more commonly in women (59 percent) than in men (30 percent), with many adults having arthritis alone without other preceding or concurrent symptoms [20,21]. A typical pattern in adults is acute-onset symmetrical polyarticular arthritis with the proximal interphalangeal and metacarpophalangeal joints most commonly affected. In children, the arthropathy can be asymmetric and oligoarticular, affecting the knees most often [21]. Arthralgias are more frequent than actual joint swelling, although both may occur. Joint stiffness is common. The joint symptoms may persist for weeks to occasionally months with resolution, but recurrences are reported [21].
B19 infection can also present as a nonspecific febrile illness with a systemic autoimmune rheumatic disease-like syndrome, both in children and adults [22,23]. The syndrome is manifested by rash, arthralgias/arthritis. Laboratory abnormalities can include positive antinuclear antibodies (ANA) and positive rheumatoid factor, which may be present during the acute period in some patients, although their presence is often transient [21]. Other laboratory findings are typically remarkably normal in most patients. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are occasionally elevated, and the peripheral blood leukocyte count remains normal. Although a role for B19 infection in the pathogenesis of SLE has been proposed by some authors, this hypothesis remains unproven [24].
B19 infections can also cause severe catastrophic illness with life-threatening aplastic anemia [25]. Nonarticular manifestations of parvoviral infection are discussed in more detail elsewhere. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
At times, children with the infection may meet criteria for juvenile idiopathic arthritis. A child's anti-B19 antibodies may crossreact with other antigens, leading to autoantibody formation and immune complex deposition [26].
Parvovirus B19 does not appear to be a specific cause of RA. Patients with RA are not more likely to be seropositive for parvovirus than are controls [27,28], and B19 arthropathy does not progress to RA [29]. Parvovirus B19 deoxyribonucleic acid (DNA) may be present in inflamed joints, but is also found in equivalent proportion of control samples of synovial tissue [30].
RUBELLA AND RUBELLA VACCINE VIRUS — Rubella and rubella vaccine virus are associated with a high incidence of associated arthritis; in one report, rates were as high as 30 percent of females and 6 percent of males with rubella infection [31]. The onset of joint symptoms due to rubella virus is typically abrupt, occurring in most patients within a one-week period before and after the characteristic rash [31,32]. Rubella virus infection classically presents with acute maculopapular rash accompanied by significant lymphadenopathy involving the posterior auricular, posterior cervical, and suboccipital lymph nodes [33]. The rash is light pink, beginning as a maculopapular eruption on the face and spreading to involve the trunk, hands, and feet, while sparing the palms and soles. Rubella virus infection and its complications are described in detail separately. (See "Rubella".)
Joint symptoms may develop approximately 7 to 21 days after vaccination with rubella virus vaccine [32,34]. Arthralgia occurs in 25 percent of adults and postpubertal adolescents, and 10 percent develop arthritis, which is typically transient [35]. Among children, joint pain, usually of small peripheral joints, has been reported in 0.5 percent of young children. One study also showed that the risk of arthropathy following rubella vaccination may be higher in women who have very low prevaccine levels of antibody, particularly in assays measuring functional (neutralizing) antibodies [36]. Rubella vaccine virus and an attenuated strain of viral-type rubella virus rarely give rise to rash, fever, or lymphadenopathy. The adverse effects of rubella vaccination are described in detail separately. (See "Measles, mumps, and rubella immunization in adults", section on 'Adverse effects' and "Measles, mumps, and rubella immunization in infants, children, and adolescents", section on 'Adverse effects'.)
The pattern of joint involvement with both viruses is similar to that in rheumatic fever, being symmetric, migratory, and additive, with resolution of most joint symptoms within two weeks [32,37,38]. The small joints of the hands, wrists, and knees are most commonly involved, with the larger joints less often affected. Arthralgias are much more common than true joint swelling; however, there is often considerable pain and swelling in the soft tissues surrounding the joint as well as synovial tendon sheath involvement, occasionally leading to tenosynovitis and carpal tunnel syndrome [32,37,38]. Joint symptoms may on rare occasions persist for long periods of time, as long as a year. However, there is no evidence of chronic joint disease or joint damage [37,38]. Recurrence of joint symptoms, although uncommon, is seen more frequently after rubella vaccine virus inoculation, occurring in approximately 1.3 percent of the patients with joint symptoms [39].
Joint fluid findings are consistent with an inflammatory arthropathy [40,41]. Both rubella and rubella vaccine virus are believed to grow preferentially in synovial tissues, giving rise to symptoms because of direct infection. Both rubella and rubella vaccine virus have been cultured from joint tissues [40,42-44]. Rubella virus has been shown to persist in lymphocytes recovered from people infected years earlier, thereby providing a mechanism for subsequent viral infection of the joint tissues or for production of viral products that could give rise to an immune complex-mediated pathogenesis [42,45,46].
ALPHAVIRUSES — Among all of the viruses that can cause arthritis, the alphaviruses are unusual because nearly all symptomatic infections in adults result in arthralgia and/or arthritis [47-49]. Other common symptoms of these infections include fever, rash, myalgia, fatigue, and headache. Alphaviruses that cause arthritis/arthralgias are globally distributed mosquito-borne ribonucleic acid (RNA) viruses causing epidemics of polyarthritis/arthralgia, with disease emerging or reemerging and increasingly being reported in travelers [47-49]. They are maintained in nature by continuous cycles of transmission between hematophagous arthropods (usually mosquitoes) and enzootic vertebrate hosts (usually mammals or birds). Bites by infected mosquitoes can result in epizootic infections of humans, with most cases occurring after seasonal rains when mosquito numbers are high [47,48].
Ross River virus disease, causing several thousands of cases annually in Australia and the Pacific islands, and Chikungunya virus disease, referred to as Chikungunya fever and estimated to affect more than 1.3 million patients worldwide since 2013, have received considerable attention. Diseases caused by the African and Asian arthritogenic alphaviruses have not been extensively studied because they largely occur in underdeveloped and resource-limited countries, where they often do not represent a major health priority. (See "Ross River virus infection" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
There are six genera of alphaviruses in the family Togaviridae, representing a group of enveloped, positive-sense single-stranded RNA arboviruses, including:
●Ross River virus and Barmah Forest virus – Ross River virus affects as many as 8000 Australians annually, and the Barmah Forest virus, also found in Australia and Pacific islands, causes approximately 500 to 1500 symptomatic infections per year. These infections are described in more detail separately. (See "Ross River virus infection" and "Potential health hazards in travelers to Australia, New Zealand, and the southwestern Pacific (Oceania)", section on 'Arboviral infections'.)
●Chikungunya virus – Chikungunya was found mainly in South and East Asia, Africa, and the Western Pacific, with recurrent epidemics with as many as 40,000 involved in Thailand in 1962 [47,48,50]. It has subsequently become a much more global disease with increasing world travel and global warming, with increasing arthritic symptoms including large outbreaks in Italy, India, and Indian Ocean islands, as well as reports from islands in the Caribbean since 2013 [51,52]; subsequently, local transmission was confirmed in many countries and territories in the Caribbean region and in North, Central, and South America [51,53-57]. Chikungunya fever and the musculoskeletal manifestations of the infection are described in detail separately, as are approaches to the treatment of affected patients and the prevention of infection. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis" and "Chikungunya fever: Treatment and prevention".)
Since late 2013, chikungunya has become much more prevalent, with more than 1.3 million cases reported worldwide, including almost 2400 cases in United States citizens, almost exclusively travelers, although locally acquired cases have been reported in Florida.
●Sindbis virus and Sindbis-like viruses – Another group is the Sindbis virus group, which is found in Africa, Asia, and Australia, and the Sindbis-like viruses, which occur more frequently in Europe [48,58]. It goes by the different names of Karelian fever in Russia, Ockelbo in Sweden, and Pogosta in Finland.
●Mayaro virus – The Mayaro virus, constituting another group, is found mainly in South America and occurs in small sporadic epidemics [48,59].
●O'nyong'nyong – O'nyong'nyong is found in Central and East Africa with occasionally small epidemics; however, greater than 2 million people were affected in an epidemic from 1959 to 1962 [48,60].
●Igbo-Ora virus – Igbo-Ora, considered as a separate group, is a virus related to O'nyong'nyong and found mainly in Africa, with an outbreak in 1988 [48].
The incubation period for these viruses lasts from several days to three weeks. Infection is typically associated with a triad of fever, arthritis, and rash [47]; however, all aspects of the triad may not be present, making the diagnosis difficult at times. The symptomatic-to-asymptomatic ratio varies from 4:1 to 1:1 between O'nyong'nyong, Mayaro, and Ross River virus.
In children, the disease is often clinically indistinguishable from other febrile illnesses and is usually mild with Ross River virus. The onset in chikungunya and O'nyong'nyong viruses is abrupt with fever and joint symptoms and can be severe in nature [48,61,62]. The other alphaviruses are associated with a more gradual onset of fever and nonspecific constitutional symptoms prior to joint involvement [47].
Most patients have polyarthralgia, usually involving the feet, ankles, knees, lower back, fingers, wrists, elbows, shoulders, and/or neck. Approximately one-third to one-half often experience rash, fever, myalgias, and/or fatigue, with tendinitis and periarticular involvement also being present at times. In most patients, symptoms progressively resolve over an average of a three- to six-month period, although the Ross River virus has appeared to last longer than one year in the occasional patient [63,64] and 12 percent of those with chikungunya had chronic arthralgia lasting more than three years [65]. The rash occurs several days after the onset of joint symptoms and is short-lived, involving the face, trunk, and flexor surface of the extremities. Mild lymphadenopathy may be seen with all of the viral types.
There may be mild leukopenia with a relative lymphocytosis present, and occasional thrombocytopenia has been reported with chikungunya and Mayaro infection.
FLAVIVIRUSES
Dengue virus — The classic findings of dengue virus infection are an acute febrile illness with headaches and marked muscle and joint pain. A term used to describe it is "break-bone fever" [66]. Arthralgias occur in 60 to 80 percent of patients. Leukopenia and thrombocytopenia may be present, and liver enzymes may be elevated [67]. Most cases are mild, but a small percentage of patients have potentially lethal forms called dengue hemorrhagic fever and dengue shock syndrome [68]. (See "Dengue virus infection: Clinical manifestations and diagnosis".)
Zika virus — Clinical manifestations of Zika virus infection include fever, rash, headache, arthralgia, myalgia, and conjunctivitis. Although arthralgia is characteristic, particularly of the small joints of the hands and feet, clinically evident arthritis with a synovial effusion and joint swelling has not been reported [69]. Symptoms of the infection usually resolve within two to seven days, but asymptomatic infection is common. Zika virus infection has also been associated with congenital microcephaly and fetal losses among women infected during pregnancy; further investigation is ongoing. (See "Zika virus infection: An overview".)
MUMPS VIRUS — Mumps virus has an incubation period of two to three weeks, usually followed by a short prodromal phase with nonspecific constitutional symptoms. Arthritis is uncommon, with fewer than 100 cases reported in the literature. Parotid signs and symptoms may follow, with bilateral involvement in 75 percent of symptomatic patients; however, mumps virus infection is subclinical in 20 to 40 percent of cases, and some symptomatic patients do not have parotitis [70,71]. (See "Mumps".)
Joint symptoms typically occur after the onset of parotitis. A migratory polyarthritis involving both large and small joints is the most common presentation, but disease limited to polyarthralgia or a monoarthritis can also occur [70,71]. Low-grade fever typically accompanies the joint symptoms, which generally resolve over a period of weeks. No long-term joint damage has been reported. The mechanism by which mumps virus gives rise to joint symptoms is not known.
Laboratory studies may show a moderate leukocytosis and an elevated erythrocyte sedimentation rate (ESR); patients are usually rheumatoid-factor negative [71].
ADENOVIRUS INFECTION — Adenoviruses comprise a large family of immunotypes because of a wide range of clinical illnesses. Only a small number of cases of adenovirus-associated arthritis have been reported [72]. Affected patients typically present with mild fever, nonspecific constitutional symptoms, arthralgias, arthritis mainly of the knees, and rash. The disease is typically self-limited, but may persist over a year in some cases [72]. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Diagnosis, treatment, and prevention of adenovirus infection".)
HERPESVIRUS INFECTIONS — A number of arthritis syndromes may be associated with the herpesvirus family; Epstein-Barr virus (EBV) is the most common cause of arthralgias and arthritis of this group, but the other members of this family, including varicella-zoster virus, herpes simplex virus, and cytomegalovirus, may infrequently also cause joint symptoms. (See 'Epstein-Barr virus' below and 'Varicella' below and 'Herpes simplex virus' below and 'Cytomegalovirus' below.)
Epstein-Barr virus — EBV, the primary agent of infectious mononucleosis, is a double-stranded DNA virus that establishes persistent mostly asymptomatic infection for life in 90 percent of the human population worldwide [73]; approximately 90 percent of patients newly infected with EBV are asymptomatic, but of the 10 percent with symptoms, the majority will have arthralgias, with frank arthritis less often [74,75]. EBV is transmitted in saliva and establishes replicative infection in oropharyngeal cells and latent infection in B cells and is associated with the development of B-cell lymphomas, T-cell lymphomas, Hodgkin lymphoma, and nasopharyngeal carcinomas in certain patients. The clinical manifestations, diagnosis, and management of EBV infection are described in detail separately. (See "Virology of Epstein-Barr virus" and "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Infectious mononucleosis".)
Arthralgias are the most common joint findings, with occasional large-joint swelling, and arthrocentesis may reveal an inflammatory joint fluid [70,74]. The joint complaints usually occur in the first weeks of the infection and can be acute in nature. Overall, the joint signs and symptoms are self-limited [74,76]. Epstein-Barr viral infections have been implicated in complicating treatment of juvenile idiopathic arthritis, especially for patients on biologic response modifiers [75]. Awareness of a past or present EBV infection may help in determining treatment options [75].
EBV has also has been extensively investigated as a possible cause of rheumatoid arthritis (RA) [76], and a role in the pathogenesis of systemic lupus erythematosus (SLE) has also been of interest, but remains unproven [77,78].
Varicella — Arthritis associated with chickenpox (varicella) is a rare but well-described phenomenon that occurs within several days of the onset of the rash [79,80]. Monoarticular knee involvement is most common, with swelling, pain, and limitation of motion. Patients with chickenpox and an acute monoarthritis should undergo joint aspiration to be sure there is no underlying bacterial infection. In patients with arthritis laboratory findings are nondiagnostic with synovial fluid white counts of up to 6000, all mononuclear cells [79,80]. The patients with zoster may have acute and severe joint pain that mimics a septic joint. However, the pain is thought to be due to viral involvement of the nerve root, rather than the joint itself. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)
Herpes simplex virus — Arthritis associated with herpes simplex virus has been reported in a few occasions, all associated with a generalized herpes simplex virus type 1 infection [81,82]. In most cases, the disease is self-limited, resolving in 10 days to three months. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)
Cytomegalovirus — Cytomegalovirus arthritis is rare, but severe cytomegalovirus polyarthritis has been described in several immunocompromised bone marrow transplant recipients [70,81]. These cases were found to have painful, warm, swollen knees, and joint aspiration yielded a noninflammatory synovial fluid; joint symptoms persisted for several months. Cytomegalovirus reactivation may occur in patients on immunosuppressive agents [83]. Acute arthralgias have also been reported in renal transplantation patients with cytomegaloviral infections [70,84,85]. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults" and "Approach to the diagnosis of cytomegalovirus infection" and "Overview of cytomegalovirus infections in children".)
CORONAVIRUS — Coronavirus is not usually associated with rheumatologic symptoms; however, post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been noted in two pediatric cases as a post-reactive arthritis [86]. Both patients responded well to naproxen 250 mg twice a day. Also, arthralgias have been noted in children with multisystem inflammatory syndrome (MIS-C) [87]. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)
HIV INFECTION — Human immunodeficiency virus (HIV) infection has been associated with several rheumatic disease syndromes [88-91]. These include manifestations presumed to be related to HIV infection itself, including a painful articular syndrome, inflammatory arthritis, and arthralgia, which is sometimes associated with diffuse infiltrative lymphocytosis syndrome (DILS); and rheumatic disorders that typically occur independently of HIV infection, but whose expression and course may be affected by the concurrent viral infection, such as reactive arthritis, septic arthritis, and other rheumatic disorders. Rheumatologic manifestations in some patients are evident as a possible consequence of improved survival that has followed the introduction of potent antiretroviral therapy (ART) [88,92]. The clinical manifestations of HIV infection are discussed in detail separately. (See "The natural history and clinical features of HIV infection in adults and adolescents".)
A combination of immunodeficiency, immune hyperactivity, dysregulated production or activity of cytokines, and molecular mimicry may contribute to the rheumatic manifestations of HIV infection [88]. Potent ART changes the course of HIV infection and may ameliorate some manifestations while contributing to the appearance of others. As an example, before the advent of ART, the prevalence of reactive arthritis in HIV-positive patients was reported to be approximately 5 to 10 percent, which was 100 to 200 times higher than in the general population [93]. Similarly, DILS, which was reported before triple-drug therapy, is now exceedingly rare. New syndromes such as the immune reconstitution inflammatory syndrome have emerged. (See "Immune reconstitution inflammatory syndrome".)
HIV-related joint conditions — Several conditions affecting the joints appear to be HIV-specific, including a painful self-limited articular syndrome, a seronegative inflammatory arthritis, and arthralgia associated with DILS:
●Painful articular syndrome – The painful articular syndrome is a self-limited disorder lasting for less than 24 hours in patients with HIV infections [89]. It is reported in up to 10 percent of African HIV-seropositive patients and some other groups, but not in all case series [90]. Bone and joint pain is noted, especially in the lower extremities in an asymmetric pattern, which is out of proportion to clinical findings. The etiology is not known and treatment is symptomatic. Rarely, HIV-associated arthralgia progresses to active joint inflammation [94].
●HIV-associated arthritis – HIV-associated arthritis was first reported in 1988 and tends to be seen more often in the sub-Saharan African region [95]. It may develop in some patients, in whom it manifests as a self-limited nondestructive arthritis, usually lasting less than six weeks, a duration similar to that observed with other viral arthritides [95,96]. The prevalence ranges from 0.4 to 13.8 percent [97]. The majority of cases have been reported in males. Joints of the lower extremity are usually involved in an oligoarticular pattern. A more prolonged course with joint destruction has been noted in some patients [89]. Should the synovial fluid be aspirated, it is usually found to be sterile. Plain radiographs of the affected joints are normal, without evidence of joint destruction.
●Diffuse infiltrative lymphocytosis syndrome – Arthralgias, but typically not arthritis, can be seen in patients with DILS, a condition causing salivary (especially parotid) and lacrimal exocrine gland enlargement and sicca symptoms that resembles Sjögren's syndrome [98]. DILS was seen in at least 3 to 4 percent of HIV-infected patients but reported more frequently earlier in the epidemic, and the incidence of DILS has diminished since the introduction of potent ART [99]. In one study, published in 1998, a decrease in the prevalence of DILS in the Houston, Texas area was described following the introduction of ART (from 4 to 0.8 percent) [100]. Changes in prevalence and geographic disparities may be related to treatment differences [101]. A 2003 report from Cameroon described a greater prevalence of DILS among Africans who had not received ART compared with patients from the United States, a majority of whom had received treatment (48 versus 6 percent) [102]. DILS has been seen in all stages of HIV disease irrespective of CD4 counts [88,89,103].
Patients with DILS can develop massive parotid enlargement secondary to predominantly CD8+ T-lymphocytic infiltration [103]. In addition to the parotid gland swelling, patients often complain of dry mouth, dry eyes, and arthralgia. There may be extraglandular CD8+ T-lymphocytic infiltration in the liver, lungs, gastrointestinal tract, kidneys, thymus, and nervous system, leading to hepatitis, renal tubular acidosis, lymphoma, polymyositis, interstitial pneumonitis, and peripheral neuropathy [88,89,103]. On liver biopsy, extensive CD8+ T-lymphocytic infiltration is seen. Polyclonal hypergammaglobulinemia may be present and an association with human leukocyte antigen (HLA)-DR5 has been suggested [103].
HIV patients with DILS differ from patients with idiopathic Sjögren's syndrome in that more males than females have been reported with DILS and they tend to be less than 40 years of age. African-American patients are more affected. These patients have generalized lymphadenopathy with massive parotid swelling, and there is more extraglandular involvement than in idiopathic Sjögren's syndrome. Patients with DILS tend to lack rheumatoid factor and anti-SSA/Ro and anti-SSB/La autoantibodies, and though they may have arthralgias, they usually do not have arthritis [98]. These patients tend to have a slower progression to acquired immunodeficiency syndrome (AIDS), possibly due to suppressed HIV viral replication by the CD8+ lymphocytes [104].
●Arthralgia/arthritis associated with acute infection – Patients newly infected with HIV may experience an infectious mononucleosis-like syndrome that includes arthralgias and myalgias, among the other findings [90,105]. A symmetric "viral polyarthritis" has also been reported [90]. These symptoms are self-limited.
HIV impact on non-HIV rheumatic disorders — The presence of HIV infection may affect other disorders, including rheumatic diseases.
●Reactive arthritis – Reactive arthritis (the primary form of spondyloarthritis seen in HIV patients) was first described in 14 patients with AIDS and arthritis [93]. The prevalence in HIV-infected persons ranges from 1.7 to 11.2 percent [106]. Reactive arthritis, in the context of HIV infection, is likely due to a response to other sexually transmitted or enteric infections, rather than a "reaction" to HIV per se. Two population-based studies did not suggest a significant increase in the incidence or prevalence of reactive arthritis after adjusting for the risk conferred by sexual activity [107]. HLA-B27 antigen is positive in roughly 70 percent of White patients with HIV-associated reactive arthritis [108]. A similar association is not seen in Black Africans.
The classic triad of arthritis, urethritis, and conjunctivitis is not commonly observed; rather, an incomplete form of reactive arthritis usually occurs [109]. Axial involvement and uveitis are uncommon in HIV-associated spondyloarthritis [89]. Mucocutaneous disease, including keratoderma blennorrhagicum and circinate balanitis, is often present, especially in HIV patients with a positive HLA-B27 antigen, who tend to have worse disease outcome [110]. In sub-Saharan Africa where HIV is highly prevalent, HLA-B27-associated spondyloarthritis is rare. Other genetic factors such as HLA-B*5703 have been noted in HIV-positive patients with spondyloarthritis in Zambia [111]. Both HLA-B27 and -B57 are associated with better control of the HIV infection, delaying the development of AIDS in these patients. Otherwise, clinical manifestations of reactive arthritis in HIV-infected patients are similar to those in other populations. (See "Reactive arthritis".)
Reactive arthritis in HIV is clinically distinguished from HIV-associated arthritis in its chronicity and relapsing nature, by the presence of enthesopathy and mucocutaneous manifestations, and by the HLA-B27 positivity [94].
●Septic arthritis – Nongonococcal bacterial (septic) arthritis in HIV is infrequent, with an incidence of less than one percent, and there is elevated risk associated with substance abuse [112]. As in non-HIV patients with septic arthritis, the most common organism involved is Staphylococcus aureus, although Streptococcus and Salmonella species, atypical mycobacteria, as well as opportunistic infections, may occur, particularly when the CD4 count is less than 200 cells/microL [113]. The usual presentation is monoarticular, though multiple joint involvement has been reported in cases of septic arthritis caused by Salmonella species. (See "Septic arthritis in adults".)
●Psoriatic arthritis – The prevalence of psoriatic arthritis (PsA) in HIV-infected patients is 1 to 2 percent, similar to that in non-HIV-infected patients; the severity is often worse in HIV patients, especially those not being treated with ART [114]. The most commonly and most severely affected joints are generally those of the feet and ankles. As with reactive arthritis, frank synovitis is unusual and enthesitis may be a disabling clinical feature. Axial involvement may occur and be associated with radiographic changes of sacroiliitis [88]. Peripheral joint radiographs may reveal "pencil in cup" deformities and osteolysis similar to those seen with classic PsA, and these may be present in the absence of frank psoriatic skin involvement (ie, PsA sine psoriasis).
Two forms of PsA have been reported in patients with HIV. The first is a sustained and aggressive type of arthritis leading to joint erosion, and the second is a more mild and intermittent pattern of joint involvement. There is a strong association of HLA-B27 with pustular psoriasis and PsA in HIV patients [114].
●Systemic lupus erythematosus, rheumatoid arthritis, and autoantibodies – New-onset systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are rare in untreated HIV-infected patients, and if present in patients with HIV infection, these diseases remit with low CD4 counts until ART is introduced and T-cell function improves [115,116]. HIV patients may have low titer autoantibodies that are rarely of clinical significance; these include rheumatoid factor and anticitrullinated peptide antibodies [117,118], antinuclear antibodies (ANA) [119], cryoglobulins, anticardiolipin antibodies and lupus anticoagulant [119,120], and antineutrophil cytoplasmic antibodies. Typically, once patients are started on ART, these low titer antibodies tend to resolve [88,121-123].
Children with HIV infection with concomitant SLE usually develop manifestations of renal disease including glomerulosclerosis, mesangial hyperplasia, and lupus nephritis [124]. Studies have suggested that increased autoantibody production in SLE patients with HIV may be the protective factor from developing AIDS. Interleukin (IL)-16 may be responsible for this protective effect as levels seem to be elevated in SLE patients and in vitro studies have revealed inhibition of HIV infection in the presence of IL-16. Broadly neutralizing HIV-1 antibodies (bNAbs) have been seen in patients with autoimmune disease and tend to bind HIV and neutralize its activity [125].
●Immune reconstitution inflammatory syndromes – New autoimmune or inflammatory disease or flares of preexisting disease, such as sarcoidosis or RA-like illnesses, have been reported in association with reconstitution of T-cell-mediated immunity [126]. Adult-onset Still's disease has also been reported, as have a number of autoimmune but non-rheumatologic disorders. The pathogenesis and features of the "immune reconstitution inflammatory syndromes" (IRIS) seen in some patients with restitution of immune function are described in detail separately. (See "Immune reconstitution inflammatory syndrome".)
SUMMARY
●Arthritis is an uncommon manifestation of enterovirus infections, such as coxsackie virus and echovirus, being seen in less than 1 percent of affected patients; however, with a large number of patients with these illnesses, it can represent a substantial number and proportion of the patients with nonspecific self-limited arthritis. Joint symptoms commonly accompany some episodes of illnesses associated with fever, myalgias, evanescent rash, and constitutional symptoms, which are presumed due to enterovirus infection. (See 'Enterovirus infections: Coxsackie virus and echovirus' above.)
●Arthralgias and arthritis are common in patients with viral hepatitis:
•In hepatitis A virus (HAV) infections, arthralgias and rash occur in 10 to 14 percent of patients, but arthritis is extremely rare. (See 'Hepatitis A virus' above.)
•Ten to 25 percent of patients with hepatitis B virus (HBV) develop joint symptoms, often with a rash, and a symmetrical, migratory, or additive arthritis, usually during the prodromal stage of the disease. Joint symptoms tend to persist for days to weeks and resolve with the onset of jaundice. Chronic HBV infection may be associated with more persistent arthritis and other immune complex disorders, such as polyarteritis nodosa, glomerulonephritis, and essential mixed cryoglobulinemia. (See 'Hepatitis B virus' above.)
•Arthritis is noted in 2 to 20 percent of patients with hepatitis C virus (HCV). The arthritis is an evanescent, rheumatoid-like picture in two-thirds of the cases and an oligoarthritis in the rest. Some patients with chronic HCV infection may develop mixed cryoglobulinemic vasculitis with associated arthritis. (See 'Hepatitis C virus' above.)
●Human parvovirus B19, the cause of fifth disease or erythema infectiosum, can also cause arthralgias or arthritis. Joint symptoms occur in approximately 8 percent of infected children and 60 percent of infected adults. Arthralgias or arthritis may accompany or follow the skin eruption. A typical pattern in adults is acute-onset symmetrical polyarticular arthritis with the proximal interphalangeal and metacarpophalangeal joints most commonly affected. In children, the arthropathy can be asymmetric and oligoarticular, affecting the knees most often; arthralgias are more frequent than actual joint swelling. The joint symptoms may persist for weeks to occasionally months with resolution, but recurrences are reported. (See 'Parvovirus' above.)
●Rubella and rubella vaccine virus are associated with arthritis. The incidence of arthritis with rubella infection is up to 30 percent of females and 6 percent of males. The onset of joint symptoms due to rubella virus is typically abrupt, occurring in most patients within a one-week period before and after the rash. Joint symptoms usually develop approximately two weeks after vaccination with rubella virus vaccine. Joint involvement is similar to that in rheumatic fever, being symmetrical, migratory, and additive, with resolution of most joint symptoms within two weeks. (See 'Rubella and rubella vaccine virus' above.)
●Alphaviruses that cause arthritis/arthralgias are globally distributed mosquito-borne RNA viruses causing epidemics of polyarthritis/arthralgia, with disease emerging or reemerging and increasingly being reported in travelers. A number of agents have been implicated, including Ross River virus, chikungunya virus, and others. (See 'Alphaviruses' above.)
●The classic findings of dengue virus infection are an acute febrile illness with headaches and marked muscle and joint pain, sometimes described as "break-bone fever." Arthralgias occur in 60 to 80 percent of patients. (See "Dengue virus infection: Clinical manifestations and diagnosis".)
●Arthralgias are the most common joint manifestation of Epstein-Barr viral infection, with occasional large-joint swelling, and arthrocentesis may reveal an inflammatory joint fluid; the joint signs and symptoms are self-limited. Other members of the herpesvirus family with which arthritis has been associated include varicella-zoster virus, herpes simplex virus, and cytomegalovirus. (See 'Epstein-Barr virus' above and 'Varicella' above and 'Herpes simplex virus' above and 'Cytomegalovirus' above.)
●Disorders with musculoskeletal manifestations that occur in HIV-infected patients include a painful articular syndrome, arthralgia, a seronegative oligo- or polyarthritis, and the diffuse infiltrative lymphocytosis syndrome (DILS). HIV may also affect the frequency and expression of common rheumatic diseases, including reactive arthritis, septic arthritis, psoriatic and rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). (See 'HIV infection' above and 'HIV-related joint conditions' above and 'HIV impact on non-HIV rheumatic disorders' above.)
