Two Illustrative Patients

Patient One

A twenty-eight-year-old woman who works at a day care center presents to her physician complaining of two weeks of pain in her metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of both hands. No other symptoms are described except for morning stiffness, which lasts forty minutes. On the review of systems, the patient mentions having had a recent cold. Her physical exam reveals mild tenderness over the MCP and PIP joints bilaterally but the joints are not warm or swollen. The rest of the exam was within normal limits. Blood for sedimentation rate, rheumatoid factor, anti-CCP antibodies, hepatitis profile, parvovirus B19 IgM and IgG antibodies, CBC and a basic metabolic profile was ordered, as well as an x-ray of her hands. The patient is started on NSAIDs and returns in two weeks at which time she is asymptomatic. Her blood test results taken when she had symptoms were as follows:

• sedimentation rate: 38 mm/hr
• rheumatoid factor: 40 U/ml
• anti-CCP antibodies: negative
• hepatitis profile: negative
• anti-parvovirus B19 IgM antibody: 106 IU/ml (normal 0-12 IU/ml)
• anti-parvovirus B19 IgG antibody: 46 IU/ml (normal 0-34 IU/ml).

The IgM Western blot revealed two bands consistent with parvovirus antibody. The other blood tests were normal. The hand x-rays do not show any erosions or joint space narrowing. The patient remains asymptomatic on follow up six months and two years later.

Diagnosis: parvovirus arthropathy

Patient Two

A fifty-five-year-old man presents to the office with four weeks of symmetrical joint pain involving his MCP joints, PIP joints and wrists. This is associated with one hour of morning stiffness. X-rays of his hands show mild juxtaarticular osteoporosis but no joint space narrowing or erosions. Since his rheumatoid factor was positive and his anti-nuclear antibody screening test was negative, the patient was started on methotrexate, folic acid and NSAIDs. Six weeks later he presents to the office complaining of swelling in the lower extremities and yellow discoloration of his skin and sclerae. Liver function tests were very abnormal. A hepatitis profile showed a positive HCV antibody test and an elevated HCV viral load. His methotrexate and NSAIDs were discontinued and the patient was referred to a hepatologist for evaluation.

Diagnosis: Hepatitis C arthropathy

Human parvovirus B19 (ParvoB19) and hepatitis C virus (HCV) are common causes of arthropathy in adults. A detailed history and appropriate laboratory tests are necessary tools to diagnose these entities which may be mistaken for rheumatoid arthritis or even systemic lupus erythematosus -- conditions that may require treatment with immunosuppressive drugs.

ParvoB19 Arthritis

Virology and Epidemiology

ParvoB19 belongs to the parvoviridae family and was first described by Cospart in 1975 as a non-enveloped single-stranded DNA virus. The infection is more common in children where it occurs in outbreaks especially at the end of winter and in the spring. Adults become infected with ParvoB19 from contact with infected children. In general, the clinical manifestations associated with ParvoB19 infection are: erythema infectiosum (fifth disease) in children; aplastic anemia, hydrops fetalis in pregnant women; and recurrent hematological manifestations in immunocompromised patients.(1)(2)(3) Among immunocompetent adults, the most common manifestation of ParvoB19 infection is arthropathy, which occurs in about 62% of infected patients.(1)

ParvoB19 is usually transmitted through respiratory droplets. Adults who live with an infected child have a 50% risk of getting infected, while people who interact with infected children for a limited portion of the day, for example, elementary school teachers, pediatric nurses and daycare workers, have a 20-30% risk of infection. Reports of nosocomial ParvoB19 infection have also been described in the literature.(2) The virus targets the blood-group P antigen, which is present on erythrocytes, erythroid precursors, megakaryocytes, as well as endothelial, placental and heart cells. ParvoB19 replicates only in erythroid progenitor cells. The genome of ParvoB19 consists of 5,000 nucleotides that encode two structural proteins, VP1 and VP2, and one nonstructural protein, NS1. VP1 and VP2 are antigenic and stimulate the production of IgM and IgG antibodies. The NS1 protein is transported into the nucleus of infected erythroid cells where it plays a major role in inducing apoptosis.(3)

Clinical Manifestations

The initial phase of parvovirus B19 infection is the same in children and adults. After infection, there is a 6- to 18-day incubation period, after which a viremic phase starts. The patient manifests a viral syndrome that is perceived by most patients as a common cold. About 30% of children then develop a characteristic facial rash called erythema infectiosum, "fifth disease," or "slapped cheeks," while adults develop joint pain. A mild rash may appear in adults but it is uncommon. Once the rash appears, the infected child becomes less contagious.

Adults infrequently have another kind of rash limited to the hands and feet called "gloves and socks syndrome." The rash is papular, purpuric, symmetrical, and associated with edema of the hands and feet. These skin lesions can evolve into vesicles and bullae, and lead to skin sloughing. The lesions typically have a sharp demarcation. Other areas that may be involved are cheeks, elbows, knees, inner thighs, glans penis, buttocks and vulva. Usually, the lesions resolve in one to three weeks without scarring.(2)

Compared to the pediatric population, adults are more likely to develop arthropathy, 8% versus 62.5%. Women are more likely to develop joint pain (2:1). In children, the arthropathy is usually symmetrical and most commonly involves the knees (82%) and ankles, usually resolving within a few weeks without causing erosions.

In adults, joint involvement is usually symmetrical and polyarticular. The patients typically have morning stiffness and their symptoms resemble those of rheumatoid arthritis. The joints most commonly involved are the proximal interphalangeal (PIPs) and metacarpophalangeal (MCPs), the knees and the wrists. The ankles are less frequently affected. The arthropathy is usually self-limited and lasts for one to three weeks but in 20% of cases (especially in women) it can persist for months or years.(4) Usually there are no erosions associated with ParvoB19 arthropathy but Lowry et al. described one case in 2005 where a patient developed chronic arthropathy for more than three years with wrist erosions, which necessitated the use of intravenous immunoglobulin (IVIG) infusion.(5)

Diagnosis

Patients with ParvoB19 arthropathy can easily be misdiagnosed as rheumatoid arthritis because the symptoms are similar in the two diseases; some patients with ParvoB19 can have a weakly positive rheumatoid factor. In addition, the history of a viral syndrome preceding the start of joint pain is often missed by the physician or seen as insignificant by the patient. As with all other diseases, it is crucial to get a detailed history, which includes a complete review of systems and social history. Defining the high-risk group is important because adults who live or work with children have a much higher risk for infection than the normal population. Young adults who present with an acute onset of symmetrical polyarthritis with inflammation at the MCPs and PIPs following a viral syndrome should be screened for ParvoB19 arthropathy.

In children, the presence of erythema infectiosum rash is enough to make the diagnosis but in adults serologic tests are necessary. The sedimentation rate and C reactive protein may be elevated secondary to the joint inflammation but normal results do not rule out the disease. Specific antibodies against viral proteins can be detected using an enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA). These antibodies are secreted at different times during the infection and they have different characteristics.

After the incubation period, the viral load reaches its peak at 10¹⁰ to 10¹³ particles per milliliter of blood and persists for about a week. This leads to the production of IgM anti-capsid antibodies directed against the two structural proteins VP1 and VP2. Presence of IgM antibodies, confirmed by Western blotting, in the blood is the best diagnostic test of recent ParvoB19 infection in immunocompetent patients because it has a sensitivity of 89% and a specificity of 99%.

IgM antibodies are first detected in the blood nine to twelve days after infection, peak one to two weeks later and rapidly decline to undetectable levels about six to ten weeks after peaking. These antibodies are associated with a rapid decline in the viral load. When the IgM antibodies start to decline, IgG anti-VP1 and anti-VP2 antibodies start to increase. IgG anti-VP1 remains elevated lifelong and is protective against future ParvoB19 infections. IgG anti-VP2 remain in the blood for a several years, but the level progressively declines to become undetectable.(6)

In immunocompromised and rarely in immunocompetent patients, the infection can become chronic, which causes the viral load to remain detectable in the blood and synovial fluid for months or years after the infection. Besides the usual symptoms, patients with chronic Parvo19 infections may also have chronic hypoplastic anemia, aplastic anemia, thrombocytopenia or pancytopenia. In these patients, the IgM and IgG levels may be undetectable, so the best diagnostic test is polymerase chain reaction (PCR) for viral DNA. The sensitivity and specificity of PCR varies among labs.(2) The presence of IgG antibodies against NS1-proteins has been frequently reported in patients with chronic ParvoB19 infections and declines years later but the significance of the NS1-protein and its corresponding antibody as a marker of continued viral infection have not been clearly established.(7)

ParvoB19 infection can occasionally lead to the production of multiple IgM autoantibodies. The most frequently present antibodies are anti-double-stranded DNA, anti-nuclear (ANA), anti-smooth muscle, anti-SSA/Ro, anti-SSB/La, antibodies to gastric parietal cells, reticulin and mitochondria, as well as low levels of rheumatoid factor. These antibodies are transient and are not associated with chronic symptoms. It is important to be aware of these viral-induced autoantibodies because their presence is often thought to be specific for rheumatoid arthritis and systemic lupus in a patient with inflammatory polyarthritis. There are no reports of positive anti-CCP antibodies in chronic or acute ParvoB19 infections. Anti-phospholipid antibodies, especially β2 glycoprotein-I, IgM or IgG anti-cardiolipin, and anti-phosphatidyl serine can be elevated in ParvoB19 infections but there were no cases described in the literature of anti-phospholipid antibody syndrome associated with the infection.(7)

Treatment

ParvoB19 arthropathy is usually self-limited and the symptoms resolve within a few weeks. In 20% of cases, however, the arthropathy lasts for months (and rarely for years). The treatment goal for acute arthropathy is symptom relief, primarily with nonsteroidal anti-inflammatory drugs (NSAIDs) or other pain killers. None of these medications shortens the duration of the disease. One case report described the successful use of IVIG to relieve the pain caused by chronic ParvoB19 arthropathy resistant to NSAIDs.(5) Usually, IVIG usage is indicated in immunodeficient patients with persistent ParvoB19 infection or with chronic or recurrent bone marrow suppression. A vaccine has been developed, described as safe, and found to result in the production of neutralizing antibodies but is not yet on the market.(8)

HCV Arthropathies

Virology and Epidemiology

HCV belongs to the Flaviviridae family and was first described in 1989 as a single stranded RNA virus.(9) Chronic HCV occurs in 80% of patients after the acute infection, which is often subclinical. Cirrhosis, hepatocellular carcinoma and multiple rheumatologic manifestations can be associated with the chronic infection.

The most common rheumatologic manifestations are arthritis and cryoglobulinemia. Vasculitis, lymphocytic sialadenitis with or without sicca syndrome, fatigue, fibromyalgia and membranoproliferative glomerulonephritis have also been reported in association with chronic HCV infection. We will focus on the HCV-induced arthropathy and cryoglobulinemia which are the most common rheumatologic complications.(10)

HCV is the most common blood-borne infection in the United States. Individuals at risk are patients who received transfusions prior to 1992, intravenous illegal drug users, hemodialysis patients and health care workers. Transmission through sexual intercourse occurs mainly in individuals with high-risk sexual behavior. Vertical transmission occurs in 5-6% of infected mothers. Acute HCV infection leads to the activation of CD4 and CD8 T lymphocytes that can eliminate the virus. However, patients who have a weak T cell response and those who are infected by resistant types of HCV end up with a chronic HCV infection. CD8 cells continue attacking the virus but they also lead to liver injury.(6)

Clinical Manifestations

Extra hepatic manifestations occur in 74% of chronic HCV infections. These are more common in women, in patients with extensive liver fibrosis on biopsy and in older people. Among the most frequent extra hepatic manifestations are two different types of arthritis.

The more common form is a symmetrical non-erosive arthritis that involves the small joints, is usually associated with a positive rheumatoid factor and can result in a mistaken diagnosis of rheumatoid arthritis. While this form of arthritis may fulfill the American College of Rheumatology criteria for early rheumatoid arthritis, it differs from rheumatoid arthritis in that it does not lead to erosions or rheumatoid nodules and the anti-CCP antibody test is uniformly negative.

Another form of arthropathy seen with HCV infection is a mildly inflammatory, pauciarticular, non-erosive large joint arthritis often involving the knees. This is type of arthritis is often accompanied by mixed cryoglobulinemia with its associated manifestations (small vessel vasculitis, peripheral neuropathy, glomerulonephritis, sicca syndrome and B cell lymphoproliferative disorders).(11)

Olivieri et al. described three mechanisms that could explain HCV-induced arthropathy.(12) The first consists of a direct synovial tissue invasion by HCV; the second is an immune response to HCV antigens that crossreact with synovial antigens and the third involves deposition immune complexes consisting of viral antigens, viral antigens and rheumatoid factor in joints as well as blood vessel walls.

In support of the first mechanism are reports that HCV can be detected in the synovial tissue of some patients with HCV arthropathy. There are very limited data regarding the significance and the prevalence of this finding. In support of the second mechanism is the finding that HCV core antigen has sequences that mimic self-antigens. Autoantibodies are present but of unknown significance. With regard to the third mechanism, immune complexes are commonly found in the serum of patients with chronic HCV infection but there are not enough data to support the theory of immune complex deposition causing inflammation of the synovium.(11)

Diagnosis

Since the clinical manifestations of rheumatoid arthritis and HCV arthropathy are very similar, differentiating between the two entities is very challenging. Checking the blood for markers could be helpful. Rheumatoid factor can be positive in 37.5% of HCV arthropathy versus 80%-90% in rheumatoid arthritis. Anti-cyclic citrullinated peptide antibodies (anti-CCP) were found to be positive in 77% of rheumatoid arthritis but are not present in any of the HCV-induced arthropathy patients. Since the prevalence of rheumatoid arthritis in the general population and the hepatitis C population are the same, it remains a challenge to diagnose non-erosive and anti-CCP negative rheumatoid arthritis in patients who have a concomitant chronic HCV infection. New antibodies specific for rheumatoid arthritis in addition to anti-CCP are currently under investigation.

Treatment

The management of the arthropathies associated with HCV infection is very different from the management of rheumatoid arthritis coexisting with HCV infection. For most of the arthritic manifestations of HCV infection, there is no indication to give antiviral therapy. The most commonly used medication is a low dose corticosteroid. Nonsteroidal anti-inflammatory drugs (NSAIDs) may ameliorate symptoms but these agents should be used with caution, especially diclofenac, because they can worsen liver function and are contraindicated in cases of cirrhosis as a result of an increased risk of variceal bleeding. Corticosteroids do not cause liver damage but they can occasionally increase the viral load.

Patients in whom cryoglobulinemic manifestations predominate are candidates for antiviral treatment with pegylated interferon-α and ribavarin. These patients may also respond to a course of rituximab, a monoclonal antibody to circulating B cells.

In patients with definite rheumatoid arthritis and concomitant HCV infection the choice of a disease modifying drug (DMARD) is complicated by the fact that the two most popular DMARDs -- methotrexate and leflunomide -- can cause liver inflammation and are contraindicated. Another DMARD, hydroxychloroquine, should be used with caution because in one study the drug was associated with worsening of liver function in 53% of cases.(11) There are very limited data concerning hydroxychloroquine and viral load.

Only a few reports address the use of anti-TNF agents in HCV-infected patients. Peterson et al. reported 24 patients with HCV infection and arthritis who received etanercept or infliximab for one to 34 months without liver toxicity or increased viral load. Other reports mentioned that the use of etanercept was safe in HCV-infected patients. In a small number of patients given rituximab for HCV mixed cryoglobulinemia, the viral load was unchanged. There are no published reports of the use of abtacept in HCV patients and no randomized controlled studies regarding the safety and efficacy of such medications, so clinicians should be cautious when prescribing them.(13)

Conclusion

Parvovirus and Hepatitis C virus arthropathies are common causes of non-erosive arthritis, arthralgias, characteristic skin rashes and autoantibody production. As a result, these infections are often misdiagnosed as early rheumatoid arthritis or SLE. Screening by history, physical exam and blood tests for antibodies to these viruses in the appropriate group of patients is recommended in order to give the right treatment and avoid serious complications.