Oropharyngeal Epstein-Barr virus excretion in rheumatoid arthritis

We hypothesized that the defective cellular regulation of Epstein-Barr virus (EBV) in rheumatoid arthritis (RA) might be reflected in an increased rate of oropharyngeal virus excretion, but we found that the prevalence of excretion in 45 RA patients (22%) did not differ from 45 age- and sex-matched non-RA patients (24%) who were taking similar medications. Increased excretion rates correlated with corticosteroid therapy and male sex, but not with age or serum levels of EBV antibodies.     

Lytic Epstein-Barr virus infection in the synovial tissue of patients with rheumatoid arthritis

OBJECTIVE: To evaluate the existence of Epstein-Barr virus (EBV) infection in the synovial tissue of patients with rheumatoid arthritis (RA). METHODS: Synovial tissues were obtained at synovectomy or arthroplasty from 32 patients with RA and 30 control patients with osteoarthritis (OA). EBV DNA was detected by Southern blot hybridization and/or polymerase chain reaction (PCR) amplification. To localize the EBV-infected cells, tissue sections were studied by RNA in situ hybridization (ISH) for the EBV-encoded small RNA 1 (EBER-1), by DNA ISH for the Bam HI W region of EBV DNA, and by immunohistochemistry for EBV lytic proteins BZLF1 and gp350/220. RESULTS: EBV DNA was detected by PCR in 15 of the 32 samples from RA patients (47%), but in none of those from the 30 OA patients (P < 0.01). Of the 15 PCR-positive samples, 9 contained >1 EBV copy/1,000 cells (referred to as EBV 2+), and 6 contained 1 copy/1,000-5,000 cells (EBV 1+). Among the 9 EBV 2+ samples, 3 were also positive for EBV DNA by Southern blot hybridization, 5 were positive for EBER-1 by RNA ISH, and 3 were positive for EBV DNA by DNA ISH. Immunohistochemical analysis showed positive signals in all samples for BZLF1 and in 7 samples for gp350/ 220. In each examination, the positive signals were detected not only in lymphocytes, but also in synovial lining cells. CONCLUSION: EBV was frequently detected in the synovial tissue of RA patients. The infected cells were both lymphocytes and synovial cells, and expressed EBV proteins associated with virus replication. These findings suggest that EBV may play a role in the pathogenesis of RA.     

Reversible infliximab-related lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis

Abstract

A 63-year-old woman with active rheumatoid arthritis (RA) had been treated with methotrexate and prednisolone. She developed cervical lymph node swelling 30 months after the initiation of infliximab therapy. A computed tomography revealed cervical and mediastinal lymph node swelling and multiple nodules (up to 13 mm in diameter) in the lungs. A lymph node biopsy showed infiltration of numerous Hodgkin-like and Reed-Sternberg-like cells. Immunohistological studies showed that these cells were positive for CD15, CD30, and Epstein-Barr virus (EBV) latent membrane protein. In site hybridization revealed the presence of EBV RNA in the nuclei of these cells. EBV DNA was detected in the biopsy specimen by southern blot analysis. She was diagnosed as having EBV-associated lymphoproliferative disorder (LPD). Immunodeficiency-associated LPD related with infliximab therapy was considered. Cessation of infliximab therapy only led to dramatic regression of LPD. This case illustrates that EBV-associated LPDs can occur as part of infliximab adverse effects in patients with RA.     

Reversible infliximab-related lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis

A 63-year-old woman with active rheumatoid arthritis (RA) had been treated with methotrexate and prednisolone. She developed cervical lymph node swelling 30 months after the initiation of infliximab therapy. A computed tomography revealed cervical and mediastinal lymph node swelling and multiple nodules (up to 13 mm in diameter) in the lungs. A lymph node biopsy showed infiltration of numerous Hodgkin-like and Reed-Sternberg-like cells. Immunohistological studies showed that these cells were positive for CD15, CD30, and Epstein-Barr virus (EBV) latent membrane protein. In site hybridization revealed the presence of EBV RNA in the nuclei of these cells. EBV DNA was detected in the biopsy specimen by southern blot analysis. She was diagnosed as having EBV-associated lymphoproliferative disorder (LPD). Immunodeficiency-associated LPD related with infliximab therapy was considered. Cessation of infliximab therapy only led to dramatic regression of LPD. This case illustrates that EBV-associated LPDs can occur as part of infliximab adverse effects in patients with RA.     

Epstein-Barr virus and rheumatoid arthritis: cellular and molecular aspects

Summary Several lines of research have indicated a possible association of the Epstein-Barr virus and rheumatoid arthritis (RA). The earliest evidence suggested that RA patients develop a stronger humoral immune response to EBV nuclear antigens (EBNA) which may in part account for the increased titers of antibody to the RA nuclear antigen (RANA). It was then pointed out that mononuclear cells from RA patients may be impaired in their capacity to control EBV infection. This may be related to a decrease in the production of IFN and a consequence of monocyte-derived inhibitory activities. These cellular defects, however, are not specific for RA and may rather be the result of chronic inflammatory responses. These findings and the lack of increased virus presence in RA tissues did not provide a strong basis for a possible association of EBV and RA. A new concept for this association is now being tested on the basis of the sequence homology between the genetic RA susceptibility determinant HLA DR4 and the EBV glycoprotein 110.     

Antibodies to Epstein-Barr virus associated antigens in Pima Indians with and without rheumatoid arthritis

We investigated anti-rheumatoid arthritis-associated nuclear antigens (RANA) and other anti-Epstein-Barr virus (EBV) antibodies in a uniquely controlled study in female Pima Indians of Arizona, an RA prone population. Four groups of age and sex-matched individuals were formulated: (1) individuals positive for rheumatoid factor (RF) who had clinical evidence of rheumatoid arthritis (RA); (2) individuals seropositive for RF, but without arthritis; (3) individuals seronegative for RF, but with various kinds of arthritis; (4) those seronegative without arthritis. The mean anti-RANA in the seropositive RA group was significantly above those of the other groups but the anti-VCA and anti-EBNA titers did not differ. The anti-RANA was shown to be independent of RF. Comparing the Pima Indians to Caucasians in La Jolla, we found the mean anti-RANA titers of the Pimas to be significantly higher than those of the Caucasians. This study thus establishes clearly that elevated anti-RANA titers are characteristics of this American Indian group, just as they are of Caucasian groups. The elevated anti-RANA titers in RA patients may represent a unique hyperresponsiveness to this antigen, since there is no consistency in the reported levels of antibodies to other EBV-related antigens.     

Absence of Epstein-Barr virus carrying cells in synovial membranes and subcutaneous nodules of patients with rheumatoid arthritis.

OBJECTIVES--To determine whether the Epstein-Barr virus is present in synovial membranes and subcutaneous nodules of patients with rheumatoid arthritis. METHODS--A sensitive in situ hybridisation technique was applied to tissue sections of 11 synovial membranes and five rheumatoid nodules. RESULTS--Cells carrying the Epstein-Barr virus were not detected using EBER and BHLF1 oligonucleotides in the tissue samples investigated here. CONCLUSIONS--Although it has been suggested that the Epstein-Barr virus could play a part in the aetiology of rheumatoid arthritis, it was not detected in synovial membranes and subcutaneous lesions in this study.     

Epstein-Barr virus-specific cytotoxic T cell responses in rheumatoid arthritis patients

Summary The level of Epstein-Barr (EB) virus-specific cytotoxic T cell responsiveness was measured in 21 patients with active, progressive rheumatoid arthritis (RA). A significant number (8 out of 20) of EB virus sero-positive patients showed a markedly impaired responsiveness when compared with a control group of healthy individuals. Serological responses of the RA patients to EB virus antigens were not significantly different from the control group. The defect in EB virus-specific cellular immunity shown by these results is of interest in the light of previous evidence of an alteration in the virus-host balance in RA patients.     

Increased expression of Epstein-Barr virus receptor on lymphoblastoid cell lines from subsets of patients with rheumatoid arthritis

We studied the expression of Epstein-Barr virus receptor (EBVR/CR2) on lymphoblastoid cell (LCL) lines established from 23 patients with rheumatoid arthritis and the T cell suppression of IgM secretion by EBV activated B cells. Ten patients had normal T cell suppression of IgM secretion, whereas 13 patients had defective suppressor T cell function. EBVR expression on LCL was assessed using a rabbit anti-gp 140 IgG; Raji cells, used as reference cell line expressed 50,000 EBVR, a 140 k glycoprotein (gp 140). Patients with defective T cell suppression of IgM secretion by EBV activated B cells had a significantly higher EBVR expression on LCL than patients with normal T cell suppression (mean +/- SD; 50.8 +/- 23.8 vs 29.5 +/- 13.2, respectively; p less than 0.05). These data suggest a relationship between the T cell suppression defect and an increased EBVR expression on LCL from patients with RA.     

Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk for malignant lymphomas. Both conditions display a familial aggregation, and there are reports of RA and malignant lymphomas occurring in the same families. This study was undertaken to determine the risk of malignant lymphomas in first-degree relatives of RA patients, in order to investigate whether the increased risk of malignant lymphomas in RA could be due to genetic or environmental risk factors common to both conditions, rather than being a consequence of the rheumatic disease. METHODS: Using Swedish nationwide and population-based registers, we identified 76,527 patients hospitalized with RA in 1964-1999 and 70,290 first-degree relatives of a subset of these patients. These subjects were followed up for more than 3 decades, and information on cancer occurrence was recorded. RESULTS: Patients with RA had a significantly increased risk of malignant lymphomas (535 cases; standardized incidence ratio [SIR] 2.00, 95% confidence interval [95% CI] 1.83-2.17), which was apparent for up to 2 decades of followup. Among the first-degree relatives without RA, no increased risk of malignant lymphomas was found overall, although modest and nonsignificantly elevated risk estimates were observed in subgroups. With respect to childhood cancer (0-14 years of age), we observed an increased risk of Hodgkin's lymphoma (5 cases; SIR 3.18, 95% CI 1.03-7.42). CONCLUSION: Patients with RA are at a markedly, but possibly time-limited, increased risk for malignant lymphomas. There is little to suggest a prominent role for coinherited or common environmental risk factors in malignant lymphomas arising in the context of RA. Instead, lymphomas complicating RA appear to be a direct consequence of the inflammation or its treatment.     

Correlation between the presence of antibodies to the Epstein-Barr virus nuclear antigen type 2 and antibodies to the rheumatoid arthritis nuclear antigen in patients with rheumatoid arthritis

The incidence of antibodies to Epstein-Barr nuclear antigen type 2 (EBNA-2) was determined in sera from rheumatoid arthritis (RA) patients and control subjects, by protein immunoblotting. Sixty-eight percent of the RA patients and 48% of the controls possessed anti-EBNA-2 antibodies. The titer of anti-rheumatoid arthritis nuclear antigen (RANA) in RA patient sera showed a stronger correlation with serum reactions to EBNA-2 than with reactions to EBNA-1. Our results indicate that the presence of EBNA-2 may make a major contribution to the RANA reaction.     

A search for rheumatoid arthritis-associated nuclear antigen and Epstein-Barr virus specific antigens or genomes in tissues and cells from patients with rheumatoid arthritis

Pannus extracts and/or cells and tissues from rheumatoid arthritis (RA) patients and controls were tested for the presence of RA-associated nuclear antigen (RANA), anti-RANA, Epstein-Barr virus (EBV)-specific antigens, and EBV genomes. Using our present rather insensitive methods, RANA was rarely detected in RA pannus extracts or tissues, whereas anti-RANA was commonly found. EBV-specific antigens or genomes could not be detected in a limited number of tissues tested using our present methods. The data suggest that EBV may not be the primary event causing RA through direct infection and transformation of synovial tissues.