Reversible Lymphomas Associated with Epstein-Barr Virus Occurring during Methotrexate Therapy for Rheumatoid Arthritis and Dermatomyositis

Kamel, Onsi W.; Rijn, Matthijs van de; Weiss, Lawrence M.; Zoppo, Gregory J. del; Hench, P K; Robbins, Bruce A.; Montgomery, Peter; Warnke, Roger A.; Dorfman, Ronald F.

doi:10.1056/nejm199305063281806

Cited by 401 publications

(198 citation statements)

References 22 publications

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“…In these 2 patients, the lymphomas spontaneously regressed after withdrawal of MTX therapy (1). The spontaneous disappearance of the lymphomatous process in these 2 patients was similar to the regression of lymphoproliferative disorders seen upon withdrawal of cyclosporine therapy in transplantation patients (2).…”

supporting

confidence: 60%

Epstein‐Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis

Rijn

Cleary

Variakojis

et al. 1996

Arthritis & Rheumatism

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Objective. A causative role for Epstein-Barr virus (EBV) in the development of lymphoma in patients with rheumatoid arthritis (RA) has been proposed. We investigated the molecular features of EBV-positive diffuse large cell lymphomas in 2 patients with RA.Methods. Southern blot analysis for immunoglobulin gene rearrangements, terminal repeat analysis for clonality of the EBV genome, and double-labeling of the lymphoma cells by in situ hybridization and immunoperoxidase staining were performed.Results. In both cases, double-labeling studies localized the EBV genome to the malignant B cells. Both neoplasms contained clonal immunoglobulin gene rearrangements and clonal EBV genomes.Conclusion. Our data indicate that EBV infection was an early step in the development of these neoplasms. The findings further extend knowledge on the similarity of this subset of lymphomas to posttransplantation lymphomas and emphasize the role of immunosuppression in their genesis.Previous studies have shown that a subset of lymphomas in patients with rheumatic disease share features with Epstein-Ban-virus (EBVtpositive posttransplant lymphoproliferative disorders (PTLD). Initially, we reported 2 cases of EBV-associated lymphoma in patients who received methotrexate (MTX)

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supporting

confidence: 60%

Epstein‐Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis

Rijn

Cleary

Variakojis

et al. 1996

Arthritis & Rheumatism

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“…Among our patients with NHL, EBV was detected in lymphoma cells in 2 of 3 patients who experienced remission after MTX withdrawal alone, but in only 1 of the 15 others. Hence, like others, [4][5][6][7][8] we suggest an association between the presence of EBV in lymphoma cells and spontaneous regression after withdrawal of the drug. Therefore, among lymphomas occurring in RA patients treated with MTX, there is probably a minor subset that can spontaneously resolve after withdrawal of the drug.…”

Section: Discussionsupporting

confidence: 87%

“…4 These results are particularly interesting, because EBV is frequently found in the synovium of RA patients 28 and these patients could have impaired immunologic control of EBV. 29 As compared to populations with no immunodeficiency, an association with EBV could be slightly more frequent in our patients: EBV was detected in 5 of 7 HD patients, in 2 of 12 with diffuse large B-cell NHL, and in 1 with LGL T-cell NHL.…”

Section: Discussionmentioning

confidence: 96%

“…[1][2][3] Recently, it was shown that RA patients treated with methotrexate (MTX) can develop lymphoproliferative disorders that share characteristics with the lymphomas occurring in immunosuppressed patients; the EpsteinBarr virus (EBV) genome was present in lymphoma cells and spontaneous regression was possible after withdrawal of the drug alone. [4][5][6][7][8] MTX, now the most common disease-modifying antirheumatic drug (DMARD) used in RA, was, however, introduced 20 years ago and no excessive risk of lymphoma has been observed in one retrospective study 9 and in several longitudinal studies of patients receiving MTX, even after long-term follow-up. [10][11][12][13] However, these studies included only several hundred patients, which might not be enough to detect an excessive risk of a rare event, which is the occurrence of lymphoma.…”

Section: Introductionmentioning

confidence: 99%

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Erratum for vol. 99, p. 2310

2002

Blood

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-1.7). The estimated annual incidence rate of HD among men and women was, respectively, 27.8.10 ؊5 (0-70.1) and 2.8.10 ؊5 (0-9.6). The incidence of HD was significantly increased compared with the French incidence, with an SMR adjusted for age and sex of 7.4 (3.0-15.3; P < .001). Thus, this 3-year prospective study indicated that, whereas the risk of NHL was not significantly increased in RA patients treated with MTX, the incidence of HD appeared to be higher in these patients compared to the French population.

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“…As a consequence of the present widespread use of disease-modifying antirheumatic drugs (DMARDs) in RA patients, most data concerning lymphoma features in RA patients are derived from studies and case reports in which patients were treated with different immunosuppressive drugs (12,14,(18)(19)(20)(21)(22)(23)(24)(25)(26). Information about lymphoma characteristics in RA patients not influenced by immunosuppressive drug treatment is limited.…”

mentioning

confidence: 99%

Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma

Baecklund

Sundström

Ekbom

et al. 2003

Arthritis & Rheumatism

153

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Objective. Patients with rheumatoid arthritis (RA) have an increased risk of developing malignant lymphoma. It is not clear whether the increase is confined to certain subtypes of lymphomas. Immunosuppressive therapy and Epstein-Barr virus (EBV) have been linked to the development of these lymphomas. To gain information about the baseline pattern of lymphoma subtypes in RA before the current widespread use of immunosuppressive drugs, we examined the distribution of lymphoma subtypes and the presence of EBV in a cohort of RA patients with a low frequency and duration of treatment with immunosuppressive drugs.Methods. By linking data from the Swedish Hospital Discharge Register and the Swedish Cancer Register, 42 cases of lymphoma were identified among 11,683 patients with RA in the Uppsala Health Care Region between 1964 and 1984. The medical records and paraffin-embedded lymphoma tissues were collected, and the lymphomas were reclassified using the World Health Organization classification. In situ hybridization was used to detect EBV.Results. Tissues from 35 patients were reviewed. Non-Hodgkin's lymphoma (NHL) was found in 33 patients and Hodgkin's lymphoma in 2 patients. There was an increased frequency of diffuse large B cell lymphoma (DLBCL) (22 of 33 NHL patients, 67%) compared with that in the general population (30-40%). EBV was detected in 5 of 30 examined lymphomas from patients (17%). Twenty of the 22 DLBCL patients had RA with medium or high inflammatory activity, and 6 had been treated with a disease-modifying antirheumatic drug for >1 year.Conclusion. The findings of this study suggest an increased incidence of one specific lymphoma subtype,

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Reversible Lymphomas Associated with Epstein-Barr Virus Occurring during Methotrexate Therapy for Rheumatoid Arthritis and Dermatomyositis

Cited by 401 publications

References 22 publications

Epstein‐Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis

Epstein‐Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis

Erratum for vol. 99, p. 2310

Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma

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