Viral Arthritis

Viruses can cause infection or act as cofactors in the development of rheumatic diseases. Viral infection depends on both host and viral factors. Key host factors include age, sex, genetic background, infection history, and immune response. Key viral factors include mode of host entry, tissue tropism, replication, effects of cytokines, ability to establish persistent or latent viral infections, and alterations of host antigens. Infected cells can undergo apoptosis (programmed cell death).

The immune complexes from an antibody response can be deposited at sites of viral infection or in the synovium. Virus-induced autoimmunity, polyclonal B-cell activation, and immunodeficiency may result in opportunistic infection, largely because of an inability of the immune system to eliminate the virus (eg, HIV, human T-lymphotropic virus [HTLV]-1, or hepatitis C virus [HCV]). Molecular mimicry may cause abnormal self-reactivity by altering immune tolerance. ^[2]

Viruses that can give rise to viral arthritis include the following ^[3] :

• Parvovirus B19
• Hepatitis viruses ( hepatitis A virus [HAV], hepatitis B virus [HBV], and HCV)
• Rubella virus
• Alphaviruses and flaviviruses
• Retroviruses
• SARS-CoV-2 (COVID-19) ^{[4, 5, 6]}

Parvovirus B19

Parvovirus B19 is a small, single-stranded DNA virus that replicates in dividing cells and thus has a remarkable tropism for human erythroid progenitor cells. It may be responsible for about 12% of cases of sudden-onset polyarticular arthritis, especially in adults frequently exposed to children (eg, schoolteachers and pediatric nurses, who have a 50% risk of infection). Outbreaks of erythema infectiosum commonly occur in late winter and spring, but the condition can be observed during summer and fall, with sporadic cases occurring throughout the year.

Respiratory secretions are a vector for transmission. The use of blood products, especially clotting factor concentrates, is another mode of transmission. ^[7] Vertical transmission may occur from mother to fetus. The highest morbidity to the fetus is during the first or second trimester.

Hepatitis viruses

HAV infection accounts for 10-14% of cases of viral arthritis. Arthralgia and skin rash occur during the acute phase. Transmission is via the fecal-oral route.

HBV is an enveloped, double-stranded DNA virus. HBV infection causes 20-25% of cases of viral arthritis. Transmission can be parenteral or sexual.

HCV is an enveloped, single-stranded RNA virus. HCV infection occurs worldwide. Transmission can be parenteral or, uncommonly, sexual.

Rubella virus

Rubella virus is the sole member of the Rubivirus genus (Togaviridae family) and is a single-stranded RNA virus. Rubella virus naturally infects humans, primarily women, and is transmitted via nasopharyngeal secretions, with a peak incidence in late winter and spring. Approximately 50-75% of rubella virus infections are symptomatic; the rest are subclinical.

Alphaviruses

Alphaviruses constitute a genus of the Togaviridae family. Approximately five to six types of alphavirus infection cause rheumatic symptoms and fever as major features; all are mosquito-borne. Geographic distributions are as follows:

• Chikungunya virus – Historically,, East Africa, India, Southeast Asia, and Philippines ^[8] ; however, in 2013 the virus spread to the Caribbean and in 2014 it reached the United States ^[9]  
• O’nyong-nyong virus – East Africa
• Ross River virus – Australia, New Zealand, and South Pacific islands
• Mayaro virus – South America
• Sindbis virus – Europe, Asia, Africa, Australia, and Philippines
• Barmah Forest virus – Australia

Chen and colleagues found that alphavirus infection results in bone loss in a mouse model of Ross River virus, and that bone loss was prevented by inhibition of interleukin-6 (IL-6). Alphaviruses may disrupt bone homeostasis, and osteoblasts may contribute to alphavirus-induced arthritis by regulating IL-6 and contribute to bone loss by disrupting the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin balance. ^[10]

Retroviruses

HIV infection is associated with several rheumatic manifestations, of which arthralgia is the most common (25-40% of cases). ^[11] Other manifestations include the following:

• Psoriatic arthritis
• Rheumatoid arthritis
• Painful articular syndrome (10%)
• Undifferentiated spondyloarthropathy
• Inflammatory myopathy
• Systemic vasculitis
• Diffuse infiltrative lymphocytosis syndrome (5%)
• Fibromyalgia (30%)
• Avascular necrosis
• Gout

Arthritis (ie, arthralgia and arthritic syndromes) in association with HIV infection has been reported in the United States, Europe, and Africa. It can occur at any stage of HIV infection. The pattern of HIV-associated arthritis is similar to that of arthritis associated with other viral disorders: acute onset, short duration, recurrences, and no erosive changes. Patients infected with HIV are not at increased risk for the development of septic arthritis but they do have an increased frequency of pyomyositis.

Diffuse infiltrative lymphocytosis syndrome (DILS) resembles Sjögren syndrome, with sicca symptoms, salivary gland enlargement, and lymphocytic infiltration involving the lungs, gastrointestinal (GI) tract, and kidneys. To make the diagnosis, there needs to be histological confirmation of salivary or lacrimal lymphocytic infiltration, with granulomatous or neoplastic etiologies excluded. In contrast to Sjögren syndrome, the lymphocytes infiltrating these sites in diffuse infiltrative lymphocytosis syndrome are predominantly CD8⁺ (rather than CD4⁺) T cells and the presence of elevated titers of circulating and infiltrating CD8+ lymphocytes is a key feature of the pathophysiology. ^[12]

Reactive arthritis in association with HIV infection occurs in 0.5-3% of cases. Oligoarthritis of the lower extremities and urethritis is common, but conjunctivitis is rare. Severe erosive arthritis is possible and can be very debilitating.  Human leukocyte antigen (HLA)–B27 is found in 80–90 % of Caucasians with HIV-associated reactive arthritis, while studies of Africans with HIV-associated reactive arthritis have found nearly all to be HLA-B27-negative. As in HIV-uninfected patients, antecedent history of genitourinary and gastrointestinal infection is common. This point could hold the key to explaining the geographical differences observed in the prevalence of reactive arthritis – countries with higher rates of HIV contracted through intravenous drug use for example, rather than sexual contact, have observed lower rates of reactive arthritis. ^[13]

Psoriasis and psoriatic arthritis tend to occur late in the course of HIV infection. They are often severe.

Human T-cell lymphotropic virus – 1 (HTLV-1) is a type C retrovirus (an RNA virus in the Oncovirinae subfamily) that infects millions of people worldwide, particularly in the Caribbean, southern Japan, South Africa, and South America. It is transmitted through ingestion of breast milk, sexual intercourse, and use of blood products. HTLV-1 infection is associated with Sjögren syndrome, as well as with the following diseases:

• Adult T-cell leukemia/non-Hodgkin lymphoma (lifetime risk, 5%) – These are commonly associated with hypercalcemia and skin involvement

• Chronic inflammatory syndromes (lifetime risk, 2%) These include a seronegative oligoarthritis or polyarthritis with tenosynovitis and nodules with fibrinoid necrosis; other syndromes include polymyositislike disease, dermatitis, uveitis, and transverse myelitis (known as tropical spastic paraparesis)

SARS-CoV-2 (COVID-19)

Acute arthralgia and arthritis has been reported as a late complication of COVID-19 caused by the SARS-CoV-2 virus. ^{[4, 6]} A retrospective observational study of 44 patients with reactive arthritis following COVID-19 infection reported the following findings ^[5] :

• More common in females than males
• The most prominent  sites were the knees and ankles; small joints in the hands were less commonly involved.
• The mean number of involved joints was 3
• Axial symptoms and enthesitis were often present
• Most cases resolved with administration of NSAIDs and intra-articular steroids 

Other viruses

A number of other viruses have also been found to be capable of causing arthritis, including the following:

• Epstein-Barr virus – This infection is usually associated with polyarthralgia, but monoarthritis of the knee and ruptured Baker cysts may occur

• Varicella-zoster virus (VZV) – This infection in children rarely develops into pauciarticular arthritis ^[14]

• Mumps virus – In infected adults, this infection is associated with small or large joint synovitis that lasts for several weeks; arthritis may precede or follow parotitis by up to 4 weeks

• Adenovirus or coxsackieviruses A9, B2, B3, B4, and B6 – These infections have been associated with recurrent episodes of polyarthritis, pleuritis, myalgia, rash, pharyngitis, myocarditis, and leukocytosis

• Echovirus - This infection can be associated with polyarthritis, fever, and myalgias

• Herpes simplex virus (HSV) or cytomegalovirus (CMV) – Arthritis with these infections is rare; CMV arthritis has been reported in patients after bone marrow transplantation; vaccinia virus has been associated with postvaccination knee arthritis in only 2 reported cases

• Monkey pox (Mpox) – arthritis with osteomyelitis have been reported in patients infected with monkey pox. ^{[15, 16]}

United States and international statistics

Although viral arthritis clearly is not uncommon in the United States, its exact incidence and prevalence are unknown and vary with the type of virus and the age range of specific population groups. It is estimated that approximately 2.7 million people are infected with HCV in the United States, and perhaps 0.01% of the population is infected with HBV.

Viral arthritis is known to occur worldwide, though its exact international incidence and prevalence are unknown,. The rate of HBV infection is higher in Asia (especially China [10% of the population]), the Mideast, and sub-Saharan Africa. HCV infection rates are higher in Africa and Asia.

Age-, sex-, and race-related demographics

Viral infection rates may be higher in adults than in children or the reverse, depending on the virus under consideration. HBV infection rates in childhood may be as high as 5% annually in some parts of the world. In adulthood, HBV is transmitted through sexual activity or needle exposures. Children are more susceptible to infection with parvovirus B19 than adults are, although they rarely experience arthritis. As many as 60% of adults have serologic evidence of past parvovirus B19 infection.

Parvovirus B19 infection is more common in women than in men. Whether HAV or HCV has a predilection for either sex is unknown. Viral arthritis has no recognized racial or ethnic predilection.

Viral arthritis is generally mild and self-limited, typically lasting no longer than a few weeks. There is no specific treatment for the arthritis; simple symptomatic measures (eg, analgesics, nonsteroidal anti-inflammatory drugs [NSAIDs], or, occasionally, low-dose prednisone) are sufficient. ^[17]

The major morbidity of viral arthritis is joint dysfunction. Mortality depends on the type of virus causing the arthritis and on the duration of infection.