Does parvovirus B19 have a role in rheumatoid arthritis?

OBJECTIVES--To determine whether parvovirus B19 (B19) infection is associated with rheumatoid arthritis (RA). METHODS--The polymerase chain reaction was applied to serum, cells isolated from synovial fluid, and synovial fluid. Enzyme immunoassay technique was used to detect antibodies against B19. RESULTS--Of 142 patients with early RA (onset of disease under one year) and 67 control patients, serological evidence of recent parvoviral infection was found in 4/135 and 2/62, respectively. However, no evidence for the presence of parvoviral DNA was observed in 18 synovial fluids, 21 samples of synovial fluid granulocytes or 40 sera, all obtained from 65 patients diagnosed with early RA. CONCLUSION--Although there is published evidence of chronic rheumatoid-like arthropathy following acute parvovirus infection, our findings do not support the involvement of B19 in the aetiopathogenesis of RA.     

Transient rheumatoid factor positivity in acute human parvovirus B19 infection

The relationship between parvovirus B19 infection and classic rheumatoid arthritis remains to be determined. We describe two adult patients with serologically documented acute parvovirus B19 infection who presented with sudden onset of symmetric polyarthritis, skin eruption, and rheumatoid factor positivity. Rheumatoid factor positivity and symptoms resolved within five months. We conclude that a diagnosis of B19 arthropathy should be considered in any patient with recent acute or subacute onset of symmetric polyarthralgia or polyarthritis and rheumatoid factor positivity, which would otherwise suggest a diagnosis of early rheumatoid arthritis.     

Infection and musculoskeletal conditions: Viral causes of arthritis

Several viruses cause postinfectious arthritis. The disease is a typical manifestation of arthritogenic alphaviruses, rubella virus and human parvovirus B19. In addition, arthritis is not uncommon after infection by HIV, cytomegalovirus, hepatitis B virus, hepatitis C virus, or Epstein-Barr virus (EBV). Also prolonged arthritis may result from viral infections, particularly with alphaviruses and human parvovirus B19. Viruses such as EBV and B19 may have significant roles in initiating chronic arthropathies, which in some cases may be indistinguishable from rheumatoid arthritis.     

Viral arthritis.

Identifying viral infections related to rheumatic syndromes and understanding the pathophysiologic mechanisms by which they cause disease are crucial steps to furthering our understanding of the pathogenesis of rheumatic disease. Many common viral infections can induce autoantibody formation. Parvovirus B19 (B19) can cause acute arthritis, and occasionally chronic arthropathy, in infected adults. Persistent B19 infection can be found in synovium of some patients. Antibodies reactive with B19 epitopes can cross react with some autoantigens. Studies of rheumatic syndromes associated with other viral infections, including alphaviruses, rubella, hepatitis C, and retroviruses, suggest differing mechanisms of host interaction with the infectious agents to cause disease.     

Absence of parvovirus b19 infection in chronic fatigue syndrome

Objective. To evaluate the presence of infection with parvovirus B19 in patients with chronic fatigue syndrome (CFS) who also had rheumatologic symptoms and mild hematologic abnormalities. Methods. Seven patients meeting the Centers for Disease Control and Prevention working case definition for CFS who also had mild leukopenia, thrombocytopenia, or anemia were studied. Bone marrow was aspirated from each patient, and examined for morphologic abnormalities, including features seen in marrow infections with parvovirus B19, as well as for parvoviral DNA, using polymerase chain reaction (PCR) amplification. Serum obtained at the time of marrow aspiration was also evaluated for parvoviral DNA, using the PCR method, and was examined for the presence of IgM and IgG antibodies to the virus. Results. No evidence of marrow involvement with parvovirus B19 was found in any patient. One patient had antibody evidence of a transient parvoviral infection, during which time an underlying thrombocytopenia worsened. Conclusion. Despite examining a selected group of patients thought most likely to have parvoviral infection, based on clinical and hematologic measures, no evidence of clinically important parvoviral infection was noted. Thus, it seems unlikely that parvovirus B19 plays a role in CFS, even though it has been associated with fibromyalgia, a clinically similar syndrome.     

Parvovirus B19-related chronic monoarthritis: immunohistochemical detection of virus-positive lymphocytes within the synovial tissue compartment: Two reported cases

Apart from systemic symptoms of viral infection parvovirus B19, the infectious agent in erythema infectiosum, can lead to mainly self-limited acute and chronic arthropathy. Because mild subclinical features of the disease can be easily overlooked, joint affections might appear as isolated symptoms. We here report two cases of chronic monoarthritic symptoms of unknown origin, where immunohistochemical detection of B19-positive lymphocytic cells in the synovial tissue led to the diagnosis of B19 arthropathy. In conclusion, respective virus diagnostics should be considered even in chronic monosymptomatic arthritic lesions. The pathology of B19 arthropathy seems to be due to direct virus infection of cells within the synovia.     

Fifth (human parvovirus) and sixth (herpesvirus 6) diseases

Fifth (erythema infectiosum) and sixth (roseola infantum) diseases are common rash illnesses of childhood that have long been recognized in clinical medicine. The discovery of the viruses that cause these illnesses has revealed relationships with other syndromes. Primary infection with the agent of erythema infectiosum, human parvovirus B19, is associated with transient aplastic crisis in hemolytic anemia, arthropathy in adults, chronic anemia in immunocompromised patients, and nonimmune fetal hydrops in pregnant women. The only documented illness associated with primary infection with human herpesvirus 6 is roseola or exanthema subitum in young children. However, reactivated infections in adults and immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy, and bone marrow suppression leading to transplant failure or graft-versus-host disease. Diagnostic studies for both viruses have been limited, although reliable serologic tests for human parvovirus B19 have recently become available. Diagnosis of human herpesvirus 6 remains problematic, because current tests cannot differentiate primary from reactivated disease. This is more of an issue for the putative relationship of these viruses to more chronic conditions, such as rheumatologic disease for human parvovirus B19 and multiple sclerosis for human herpesvirus 6. The relationship between the viruses and these conditions remains controversial, and better diagnostic tests and further information on viral pathogenesis for both viruses are required in order to make a reliable judgment in this regard.     

Different patterns of disease manifestations of parvovirus B19-associated reactive juvenile arthritis and the induction of antiphospholipid-antibodies

Children with rheumatic oligo- and polyarthritis frequently establish persistent parvovirus B19 infections, which may be associated with the production of antiphospholipid antibodies. Reported in this paper are the data of five girls with polyarticular rheumatic diseases of different types and persistent parvovirus B19 infection associated in four cases with the presence of antibodies against phospholipids. Clinical parameters, virus load, and antiphospholipid-IgG levels were determined during an observation period up to 92 months. In two patients, erythema infectiosum preceded the development of arthritis and B19 viremia persisted. Two other girls showed antibodies against parvoviral structural proteins at time of the manifestation of the rheumatic disease. Subsequent samples also revealed persistent B19 infection. In the fifth patient, parvovirus B19-specific IgG antibodies were detected for the first time after 120 months of progressing disease at an age of 11 1/2 years. Five years later, quantitative polymerase chain reaction (PCR) revealed viral DNA. In a synovial tissue specimen subsequently obtained, parvovirus B19 structural proteins could be detected by immunohistochemistry. Three of five patients recovered completely without severe sequels. One patient is in remission under immunosuppressive therapy. The fifth patient suffers from progressive erosions despite intensive therapeutical efforts. In consequence, parvovirus B 19 should generally be taken into consideration as a trigger of various forms of juvenile arthritis and persistence of infection should be evaluated.     

Infection with parvovirus B19

Human parvovirus B19 is common and widespread. Major manifestations of B19 infection are transient aplastic crisis, erythema infectiosum, hydrops fetalis, acute and chronic rheumatoid-like arthropathy and, in the immunocompromised host, chronic or recurrent bone marrow infection. Less common presentations include skin eruptions, isolated cytopenias, vasculitis, hepatitis, and neuropathies. Increasing awareness of the clinical manifestations of B19 infection makes parvovirus B19 an emerging virus. B19 may persist in healthy or immunocompromised individuals. B19 has been suggested as a candidate agent in rheumatic diseases.     

Systemic manifestations of Parvovirus B19 infections

PURPOSE: Parvovirus B19 (B19) causes many clinical disorders, of which the most common are erythema infectiosum, aplastic crisis complicating chronic hemolytic anemia, and hydrops fetalis. In young adults, the skin eruption caused by B19 is accompanied by polyarthritis and polyarthralgia in 60% of the cases. Rheumatoid factors and other antibodies including antinuclear antibodies, anti-ADN, and antiphospholipids can be produced in the wake of B19 infection. CURRENT KNOWLEDGE AND KEY POINTS: These features may simulate systemic diseases as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) (lupus-like eruption over the cheeks, cytopenia, etc.) or vasculitis (purpura, renal involvement). In addition, there have been a few reports of SLE, vasculitis and other connective tissue diseases developing shortly after a B19 infection associated with virus clearance suggesting that B19 can act as a trigger of systemic disease. However, studies in large series indicate that in fact B19 is probably an extremely rare cause of RA, SLE or vasculitis. FUTURE PROSPECTS AND PROJECTS: In fundamental studies B19 interacts with inflammatory cells by regulation of cytokines. More recently, two studies suggest that viral infection due to B19 may affect the course of SLE, leading to specific biological subsets. These preliminary findings require confirmation to elucidate the significance of the presence of B19 in systemic disease.     

Viral arthritis

The role of viruses in the development of acute and chronic arthritis is complex, because viruses are ubiquitous, and all human beings are occasionally afflicted by viral infections. In general, most viral infections are acute and self-limiting and survive by infecting one susceptible host, then moving on to another. Some viruses establish prolonged latency in the host after acute infection, whereas other agents produce chronic infections following the primary stage. The mechanisms whereby these infections produce arthritis are diverse and still poorly understood, but are clearly influenced by both host and viral factors. This review addresses these and other common forms of viral arthritis, such as that caused by parvovirus B19.     

Persistence of B19 parvovirus in synovial membranes of patients with rheumatoid arthritis

Summary Recent clinical observations support the hypothesis that persistent parvovirus B19 is a triggering factor of rheumatoid arthritis (RA) in certain genetically predisposed individuals. If this hypothesis is correct, a number of RA patients may exhibit parvovirus B19 DNA in their synovial membranes. We tested the synovial tissue and peripheral blood leukocytes of 20 patients with RA, 24 patients with other arthritides or osteoarthritis (non-RA), and 34 healthy blood donors for the presence of parvovirus B19 DNA using specific DNA amplification by polymerase chain reaction (PCR). Using this technique, parvovirus B19 DNA was demonstrated in the synovial biopsies of 75% of patients with RA but in those of only 16.7% of patients with non-RA. In autologous peripheral blood mononuclear cells the percentage of PCR-positive patients was about 15% in both RA and non-RA groups and did not differ from that in healthy controls. When the PCR data were correlated with the presence of anti-parvovirus B19 IgG antibodies in serum and synovia all patients with parvovirus B19 DNA in peripheral blood alone or in both peripheral blood and synovial membrane were seropositive. In contrast, about 40% of patients with parvovirus B19 DNA restricted to the synovial membrane were seronegative. These data indicate a highly disease-related persistence of parvovirus B19 in the rheumatoid synovium.     

Unusual localisation of chronic arthropathy in lumbar facet joints after parvovirus B19 infection

Human parvovirus B19 infection may be responsible for acute and chronic arthropathy. We present the case of a woman, who developed a severe chronic parvovirus B19 infection with persistence of DNA parvovirus B19, which was detected in the serum by polymerase chain reaction (PCR). After intravenous immunoglobulin administration she noted a disappearance of the general symptoms and the virus became indetectable by PCR in the serum. However, 1 month later back pain appeared. Magnetic resonance imaging showed bilateral effusions of the apophyseal joints of the lumbar spine (L4–L5). Spine involvement is rarely described during acute or chronic parvovirus B19 infection. In this case it was not possible to determine whether the facet joint arthropathy was reactive or due to persistent articular infection, or induced by immunoglobulin therapy. Received: 4 April 2001 / Accepted: 5 February 2002     

Esophageal manometric findings in autoimmune rheumatic diseases: is scleroderma esophagus a specific entity?

Summary In order to assess whether distal esophageal hypomotility in scleroderma is unique to this disease or not, we studied 25 normal volunteers and 109 patients with autoimmune rheumatic diseases (27 with primary Sjögren's syndrome, 25 with idiopathic Raynaud's phenomenon, 25 with rheumatoid arthritis, 19 with scleroderma, 5 with undifferentiated connective tissue disease, 3 with systemic lupus erythematosus, 2 with mixed connective tissue disease, 2 with sclerodermatomyositis, and one with morphea). Esophageal dysfunction typical of scleroderma was present in 17 patients (15.6%), of whom 13 had scleroderma (68%) and one each primary Sjögren's syndrome, rheumatoid arthritis, undifferentiated connective tissue disease, and mixed connective tissue disease. Twenty-two percent of all patients had nonspecific esophageal motility changes, clustered among primary Sjögren's syndrome, idiopathic Raynaud's phenomenon, and rheumatoid arthritis. We conclude that lower esophageal hypomotility, although most frequent in scleroderma, is not unique to this disease and can be encountered in several other autoimmune rheumatic diseases.     

Human parvovirus B19: historical and clinical review

Human parvovirus B19 has been associated with disease only for the past few years. First isolated from sera obtained for studies on hepatitis B in 1975, it was not until 1981 that infection with this small, single-stranded DNA virus was related to aplastic crisis associated with hemolytic anemia. A nonspecific viral prodrome, the occurrence in family members, and epidemics of aplastic crisis suggested the infectious etiology. Human parvovirus infection has since been associated with arthritis, erythema infectiosum (fifth disease), fetal death, and hydrops fetalis. Through the use of recently developed serologic tests, epidemics of erythema infectiosum and parvoviral infection have been related not only to aplastic crisis but also to intrauterine infection and hydrops; DNA hybridization studies have allowed the detection of viral DNA in serum and tissue extracts. Studies have been hampered by the lack of an ability to culture the virus, but this is now possible utilizing bone marrow culture and erythropoietin. This article is a historical and clinical review of human parvovirus infection and disease and considers potential questions regarding their consequences.     

Prevalence of antibodies to human parvovirus B19 nonstructural protein in persons with various clinical outcomes following B19 infection.

Persistent infections with human parvovirus B19 (B19) associated with debilitating chronic disease have been described, although evidence linking B19 to these more unusual clinical outcomes has been inconclusive. Recent reports have suggested that the development of antibodies to the B19 nonstructural protein (NS1) following B19 infection might be linked to development of severe arthropathy and chronic infection. To confirm these findings, the C-terminal region of the NS1 protein was expressed for use in Western blot assays for detection of anti-NS1 IgG antibodies in human serum. Among 91 persons tested, 0 of 20 not previously infected with B19, 9(36%) of 25 with past B19 infection, and 5 (12.5%) of 40 with recent B19 infection, had detectable anti-NS1 antibodies. Of 6 persons with chronic B19 infection, 2 had detectable antibodies to NS1. The presence of anti-NS1 antibodies did not appear to correlate with unusual clinical outcomes or chronic B19 infection.     

Association between human parvovirus B19 infection and arthritis.

OBJECTIVE--To gain information concerning the association between parvovirus B19 infection and arthritis. METHODS--Blood or synovial fluid, or both, from a total of 77 adult patients with various arthropathies (rheumatoid arthritis 13; mechanical arthropathies 11; crystal induced arthritis 13; idiopathic mono/oligoarthritis 25; suspicion of viral arthritis 15) were tested for the presence of the viral genome and anti-B19 antibodies. B19 DNA in blood and synovial fluid was investigated by nested polymerase chain reaction, and anti-B19 IgM and IgG antibodies were detected in blood by enzyme immunoassay. RESULTS--A recent parvovirus infection was documented by the presence of anti-B19 IgM antibodies in the blood of 13 patients. B19 DNA, together with anti-B19 IgM and IgG antibodies, were detected in the blood of seven patients who had an acute transient arthritis, putatively of viral origin. Viral DNA was detected in a synovial fluid sample and in the blood of one patient with monoarthritis who had an anti-B19 IgG response only. CONCLUSIONS--The prevalence of anti-B19 IgG antibody in these patients with various forms of arthritis (63%) was within the same range as that in the general population (blood donors). However, for the patients with clinical suspicion of viral arthritis, the increased seroprevalence of anti-B19 IgM and the presence of the B19 genome point to an association between human parvovirus infections and acute forms of arthritis.     

Antibodies to parvovirus B19 non-structural protein are associated with chronic but not acute arthritis following B19 infection

OBJECTIVE: To determine the incidence and significance of antibodies to the parvovirus B19 non-structural (NS1) protein in B19-infected persons during acute infection and convalescence. METHODS: The B19 NS1 protein was expressed in SF9 cells using the baculovirus expression system and was used to prepare immunofluorescence slides. These were used in a fluorescent antibody test to determine anti-B19 NS1 IgG in a well-characterized cohort of 53 persons at the time of acute B19 infection and again after a follow-up period of 26-85 months. Results were examined for statistical significance by the use of Fisher's exact test. RESULTS: NS1 antibodies were detected in five of 32 persons with acute B19 infection (four with arthritis) and 10 of 53 persons with past B19 infection (six with chronic arthritis and two with chronic arthritis and chronic fatigue syndrome). Regarding the correlation of NS1 antibodies and arthritis, at the time of acute infection four of 24 persons with arthritis had NS1 antibodies detected compared with one of eight persons with any other symptoms (P: = 1). During convalescence, eight of 20 persons with chronic arthritis had NS1 antibodies compared with two of 33 with symptoms of any other category (all except one were asymptomatic) (P: = 0.007). All 10 patients with NS1 antibodies during convalescence had arthritis during acute infection, which persisted in eight persons until the time of follow-up. CONCLUSION: Antibodies to parvovirus B19 NS1 protein are associated with chronic but not with acute arthritis after B19 infection.     

A syndrome of seronegative enthesopathy and arthropathy in children

Thirty-nine children with a syndrome of seronegative enthesopathy and arthropathy were evaluated. The group included 25 patients with no apparent underlying primary disease and 13 with either ankylosing spondylitis, inflammatory bowel disease, reactive arthritis, or Reiter's syndrome. Significant distinguishing characteristics of the group included male predominance, late age at onset, positive family histories of arthritis, oligoarthropathy, axial skeleton involvement, and the presence of the B27 histocompatibility antigen. This syndrome is distinguishable from other childhood rheumatic disorders, including juvenile rheumatoid arthritis. Its recognition may reliably identify children with the prodromal manifestations of seronegative spondylarthropathies.     

Juvenile-onset chronic arthritis: Clinical and roentgenographic features of a unique HLA-B27 subset

Previous studies of HLA-B27 in children with juvenile-onset chronic arthritis have shown an association in boys with pauciarticular disease which may progress to ankylosing spondylitis. The spectrum of B27-associated disease, however, especially as it relates to arthritis persisting into adulthood, has not been fully clarified. Thus, clinical, roentgenographic, serologic and immunogenetic studies were performed in 54 patients (39 adults and 15 children) with persistent juvenile-onset chronic arthritis. All had had the onset of disease in peripheral or axial joints, and patients with typical febrile Still's disease were excluded.Thirty-five patients (65 percent) were seronegative for both rheumatoid factor and antinuclear antibodies. HLA-B27 (B27) was present in 20 of these 35 seronegative patients (54 percent) (p < 0.005). Four of the 20 (20 percent) had an axial onset and typical ankylosing spondylitis. Peripheral arthritis, however, dominated the course of the remaining 16 patients who had the B27 antigen. Polyarticular disease (nine patients) with “rheumatoid-like” hand deformities (eight patients) occurred primarily in female patients. In addition, sacroiliitis or spondylitis occurred in 14 and acute iritis in five. Cervical apophyseal joint fusion, especially at the level of the C2-C3, a lesion previously ascribed to juvenile rheumatoid disease, was common in seronegative patients and correlated with the presence of B27 (p < 0.01) and sacroiliitis (p < 0.0005).These data suggest that the presence of B27 may mark a group of young women with a dominant peripheral and cervical spondylitic syndrome, often beginning in childhood, which mimics rheumatoid arthritis. Determining the absence or presence of the B27 antigen may be a useful test in the proper diagnosis and classification of such patients.