Continuing Education Activity

Acute-onset polyarticular arthritis is the most common presentation of viral arthritis. The most commonly implicated viruses are parvovirus, the alphaviruses, hepatitis B, hepatitis C, Epstein-Barr virus, and tropical viruses such as the Zika virus and the chikungunya virus. The diagnosis of viral arthritis should be considered in all patients presenting with acute-onset polyarticular symptoms. Although viruses cause only a small proportion of cases of acute arthritis, the differentiation of virally-mediated arthritis from primary rheumatological disease is important as it influences subsequent management. This activity examines when viral arthritis should be considered on differential diagnosis and how to evaluate it properly. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Describe the pathophysiology of viral arthritis.
• Differentiate primary rheumatological disease from virally-mediated arthritis.
• Identify management options for viral arthritis.
• Explain the importance of improving care coordination, emphasizing communication between interprofessional medical teams, to enhance prompt and thorough delivery of care to patients with viral arthritis.

Introduction

Acute-onset polyarticular arthritis is the most common presentation of viral arthritis. The most common viruses causing arthritis and/or arthralgias are parvovirus, the alphaviruses, hepatitis B, hepatitis C, Epstein-Barr virus (EBV), and tropical viruses, such as Zika and chikungunya (CHIKV). The diagnosis can be difficult to confirm but should be considered in all patients presenting with acute-onset polyarticular symptoms. Although viruses cause only a small proportion of all cases of acute arthritis, differentiation of virally mediated arthritis from primary rheumatological disease is important. Low-titer autoantibodies, such as rheumatoid factor and antinuclear antibody, can occur in the context of acute viral arthritis.

Overall, viral arthritis is milder than osteoarthritis or rheumatoid arthritis. Most patients respond to NSAIDs, and antiviral treatment is rarely needed.

Etiology

Many viruses could be responsible for causing viral arthritis, the most common being Parvovirus, alphavirus, rubella, Hepatitis B, C, and flavivirus. Some other viruses can also cause arthritis/arthralgia rarely. These are EBV, HIV, mumps, herpes, and cytomegalovirus (CMV). Recently, there has been an increase in the occurrence of mosquito-borne virus-related arthropathies, such as the ones associated with Zika and CHIKV.  Occasionally, the virus causing arthritis could be related to the patient's comorbidities. For example, EBV causing viral arthritis in patients on immunosuppressive agents.

HIV-induced arthritis is more common than once believed. It may be the first presentation in at least 30% of HIV patients; however, it can occur at any stage of the viral illness. These patients are not at risk for developing septic arthritis, but they may be at risk for pyomyositis. In addition, some patients may develop reactive arthritis and even psoriatic arthritis.

Epidemiology

Viral arthritis is reported worldwide, but the exact incidence and prevalence are unknown. This could be related to the multitude of viruses causing the arthritis syndrome, geographic variability, and, more often than not, the self-limited nature of the illness. Rates of viral arthritis are much higher in adults compared to children. Children tend to be susceptible to parvovirus B19, but they rarely develop arthritis.

Pathophysiology

In the majority of patients with viral arthritis, the mechanisms are poorly understood. Viruses can initiate articular symptoms via different mechanisms. These include the direct invasion of the joint, immune complex formation, and immune modulation causing chronic inflammation. The joint synovium is considered home for many arthritis-causing viruses, which can recruit inflammatory cells to the joints and result in the inflammation cascade continuing. For example, in cases related to the alphaviruses, infected macrophages in the synovium are thought to be responsible for much of the pathology and inflammation through the release of pro-inflammatory cytokines and matrix metalloproteinases.[1] They can further transfer these viruses to the resident cells, such as synovial fibroblasts, which, in turn, continue the inflammation cycle.

History and Physical

The constellation of signs and symptoms related to viral arthritis seems to be related to the specific virus causing the infection. As a rule, patients with viral arthritis present with a self-limited episode of symmetric polyarticular arthritis or arthralgia. Monoarthritis is unusual. The presentation might involve fever, rash, and lymphadenopathy. In rare cases, viral arthritis can mimic the presentation of rheumatic diseases like rheumatoid arthritis, especially because these viral arthritis syndromes could be associated with the presence of autoantibodies, namely rheumatoid factor (RF) and antinuclear antibody (ANA). The titers are usually low and disappear quickly. Some viruses, like Chikungunya, are known to produce recurrent and many times chronic arthritis, but the majority of these infections are self-limiting, lasting less than 6 to 12 weeks.

Evaluation

Clinical Presentation and Pathophysiology Related to Individual Viral Entity

1. Parvovirus B-19: Commonly known for causing "fifth disease" or erythema infectiosum, parvovirus B-19 can also cause arthritis/arthralgia in children and adults. Joint symptoms occur in as many as 60% of infected adults.[2][3] Arthralgias or arthritis may accompany or follow the skin eruption. Rash in adults is less common, though. A typical pattern in adults is RA mimicking, acute onset symmetrical polyarticular arthritis with the proximal interphalangeal with the metacarpophalangeal joints most commonly affected. The diagnosis of acute parvovirus infection is made by finding circulating IgM antibodies to parvovirus. IgG antibody could be evidence of a preexisting infection, but it has been found in a substantial number of healthy adults as well. As mentioned above, parvovirus arthritis could be related to low titers of RFs as well as ANAs. B19-associated arthritis is usually self-limited and generally resolves in a few weeks.
2. Hepatitis Viruses: Hepatitis A sometimes can cause arthralgias but usually no arthritis. Both hepatitis B (HBV) and hepatitis C (HCV) viruses can cause arthritis and arthralgia. Approximately 10% to 25 % of patients with HBV develop symptoms of arthralgia and arthritis. Arthritis in patients with HBV is mediated through the formation and deposition of immune complexes.[4] It can be symmetrical and polyarticular. The symptoms of arthritis usually occur in the prodromal stage of the disease and could be without any other clinical manifestations of hepatitis. The presence of rash and fever may provide clues to the underlying diagnosis.[5] One characteristic feature of HBV-related arthritis is its resolution with the onset of jaundice.[6] Rarely, arthritis can also be seen in HBV-related polyarteritis nodosa. Immune complex formation and deposition are also considered the pathophysiologic mechanism for arthritis in patients with hepatitis C. Arthritis can be seen in at least 2% to 20% of HCV patients.[7] It manifests in two patterns, a  polyarticular, non-erosive, and small joint arthritis resembling RA and an oligoarticular affecting medium and large joints, especially involving ankles, and is associated with mixed cryoglobulinemic vasculitis. In both HBV- and HCV-related arthritis syndromes, RF can be elevated. It is positive in around 25% of cases in HBV and up to 80% in HCV, especially with HCV cryoglobulinemia.
3. HIV: The arthritis syndromes associated with HIV include many entities such as HIV-associated arthritis, reactive arthritis, septic arthritis, psoriatic arthritis, and rarely described painful articular syndrome.[8] The incidence of these arthritis syndromes has significantly declined in the HAART (highly active antiretroviral therapy ) era. Initiation of HAART has been noted to precipitate IRIS (immune reconstitution inflammatory syndrome), which sometimes unmasks the underlying rheumatological disorders.
4. EBV: Arthralgias are the most common joint manifestation of Epstein-Barr viral infection, with the rare case of arthritis causing occasional large joint swelling. The joint signs and symptoms are self-limited, and treatment is symptomatic. A triggering role in the development of chronic inflammatory arthritis in RA has been proposed, but no definite evidence has been found.
5. Alphaviruses: These viruses are mosquito-borne RNA viruses that cause epidemics of febrile arthralgia and polyarthritis. This group includes the Ross River virus, Barmah Forest virus, O'nyong-nyong, Sindbis virus group, Mayaro, and CHIKV.[9][10] These viruses are usually geographically restricted (e.g., Ross River virus in Australia) and cause infections with rather predominant joint symptoms. The most notable is CHIKV which has become very important in recent times with regards to global health and travel. Earlier considered to be a tropical disease, outbreaks of CHIKV disease have occurred in Africa, Asia, Europe, and islands in the Indian and Pacific Oceans and Carribeans.[11] Mosquitoes Aedes aegypti and Aedes albopictus are the vectors of CHIKV. The arthritis of CHIKV is typically symmetrical and most commonly involves the fingers, wrists, knees, and ankles. Raynaud phenomenon has been reported as well in some patients. Chronic symptoms of joint pain and swelling have been reported to be relapsing and remitting in a majority (up to 80%) of patients.[12] The diagnosis of Chikungunya infection should be considered when evaluating patients with recent onset of symmetric polyarthritis and a history of travel to an endemic area. The diagnosis of CHIKV is established by the detection of CHIKV viral RNA via real-time reverse-transcription polymerase chain reaction (RT-PCR) or serology.
6. Flaviviruses: Dengue and Zika virus are prominent members of this group causing febrile illnesses and symptoms of joint pain and swelling. As with the above-mentioned alphaviruses, the geographical distribution of these viruses has significantly expanded in recent times. Aedes aegypti is the principle vector for Dengue.[13] While arthralgia is a common feature of dengue, true arthritis and synovitis are rare in dengue. Zika virus, known for its association with congenital microcephaly and fetal losses among women infected during pregnancy, also manifests with joint symptoms.[14] While arthralgia of the small joints of the hands and feet is common, clinically evident arthritis with Zika virus infections, it should be noted that due to the overlapping geographic distribution and same Aedes mosquitoes vectors, CHIKV, Dengue virus, and Zika virus infections can present with the similar clinical picture and should have RT-PCR done to correctly identify the culprit virus.
7. Other viruses: Mumps, HTLV-1, rubella, and some enteroviruses can also cause arthralgia and arthritis.

Diagnosis

There is no single test or clinical presentation which is suggestive of viral arthritis. The diagnosis is mainly clinical, supported by other tests, including inflammatory markers, autoantibodies, and serology. A viral etiology should be suspected in a patient presenting with acute onset of arthralgias or polyarticular symptoms, especially if the duration of symptomatology has been less than six weeks. The presence of extra-articular symptoms, viz rash or lymphadenopathy, should be noted. Testing for antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA) could be helpful if the features of inflammatory arthritis persist. In suspected cases of viral arthritis, the serum should be collected for serology. Serologic testing, however, must be directed against the specific viruses suspected based upon both epidemiologic and clinical data. As a general rule with serology, an IgM antibody response would be indicative of acute infection and would be converted to an IgG isotype after a few weeks. Due to the high rate of infections in the general population, for example, with EBV and hepatitis, positive IgG antibodies, especially if stable in titers, are non-diagnostic. Other laboratory features are related to the specific viral syndromes. For example, the detection of positive HBsAg elevated aminotransferases and IgM anti-HBc antibodies in a patient with recent-onset polyarthritis could provide the clue to the diagnosis of HBV-associated polyarthritis. Isolation of virus from the joint itself or viral cultures is not useful except in rare circumstances.

Treatment / Management

Treatment in viral arthritis is generally symptomatic. NSAIDs and acetaminophen should be used for pain and inflammation. The use of corticosteroids is usually discouraged and not recommended. In some cases, as in arthritis-related to Hepatitis B/C or HIV, anti-viral treatment alone can lead to the resolution of the joint symptoms.

Differential Diagnosis

• Lupus
• Psoriasis
• Lyme
• Gonorrhea
• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis

Prognosis

Viral arthritis is a mild self-limited disorder in most people. There is no specific treatment, and recovery is usually complete in a matter of weeks. Joint dysfunction is acute and has no residual effects.

Enhancing Healthcare Team Outcomes

Because of the difficulty in diagnosis, the disorder is best managed by an interprofessional team. Viral arthritis is uncommon but should be strongly considered in the differential diagnosis of polyarticular joint pain for less than six weeks. 

High-risk groups include travelers from the endemic areas, healthcare workers, and IV drug abusers and should be specially considered. The early diagnosis and management are crucial for arboviruses; for example, Chikungunya from public health and epidemiological perspective.[15] [Level 5] 

The pharmacist, primary care provider, and nurse practitioner are in the ideal position to educate patients. The key is prevention by getting the relevant vaccines before travel, practicing safe sex, drinking clean water, and preventing mosquito bites.  Clinicians also should not assume that all joint pain is viral; sometimes, one has to rule out septic arthritis, Lyme disease, or gonococcal infection.

It should be recognized that many of these viral arthritis syndromes are associated with elevated markers of inflammation, namely rheumatoid factors and antinuclear antibodies. As mentioned, the titers for these markers are usually low and transient. Many of these cases can be managed in a primary care setting; however, if the arthralgia and joint swelling persist or worsen, referral to a rheumatologist would be prudent. [Level 5] With open communication between members of the team, the outcomes of viral arthritis can be significantly improved.