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Epstein-Barr virus-associated Hodgkin's lymphoma in a rheumatoid arthritis patient treated with methotrexate and cyclosporin A.

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Number 6, June 1995, pp 867-868
0 1995, American College of Rheumatology
Epstein-Barr virus-associated Hodgkin’s lymphoma in
a rheumatoid arthritis patient treated with
methotrexate and cyclosporin A
Methotrexate (MTX) and cyclosporin A (CSA) are
increasingly employed to treat progressive rheumatoid arthritis (RA), even in combination (1). We describe here the
development of an Epstein-Barr virus (EBVtassociated
Hodgkin’s disease after a period of combined therapy in a
patient with RA that was refractory to MTX alone.
The patient, a 61-year-old man, developed symmetric RA in November 1990. At another institution, he was
given sulfasalazine (SSZ) up to 2 gmlday. Because of lack of
efficacy after 6 months, the SSZ was stopped and azathioprine (AZA), 100 mg/day, was started, along with 5 mg/day
of prednisone. The arthritis went into partial remission until
April 1993, when a sudden relapse occurred.
The patient was seen at our institution, and his
treatment was stopped. At that time, he was found to have
small, mobile, nontender lymph nodes in both axillae. His
medical records showed no mention of extraarticular features. He was given MTX (10 mg/week) and leukovorin (7.5
mg, 24 hours later) plus prednisone (5 mg each morning).
In September 1993, because of chronic active disease, CSA 3.5 mg/kg/day was added to the regimen. By
November, the RA was in full clinical remission (no pain, no
rigor, no stiffness), and the prednisone was stopped. However, a firm mass of lymph nodes was present in the right
axilla. During the followup at our institution, there had been
no changes in the lymphocyte count or in the CD4 and CD8
T cell subsets (Table 1). His HLA type was A3,26;B35,38;
Cw4,X;DR3,1 I ;Dw52;DQ2,3.
A biopsy of the right axillary lymph nodes was
performed in December 1993. The clinicopathologic exami-
nation showed a stage IA Hodgkin’s lymphoma, mixed
cellularity subtype (Figure 114). The Reed-Sternberg cells
harbored an EBV genome (tylpe A by the polymerase chain
reaction) and were latent membrane protein 1 (LMP-I)
positive (Figure lB), Epstein-Barr nuclear antigen-2 negative (the antigenic characteristics of EBV-associated
Hodgkin’s lymphoma). The MTX and CSA regimen was
stopped; no prednisone was given.
Unlike the cases reported by Kame1 et a1 (2) and
Shiroky et a1 (3), only a partial spontaneous regression was
observed in this patient after 2 months. This clinical behavior is unusual for Hodgkin’s lymphoma. The persistence of
Hodgkin’s lymphoma was confirmed by a second lymph
node biopsy, which revealed focal involvement, and surgical
and echographic assessments showed only 50% regression.
The patient had refused laparotomy, and bipedal lymphography was unsuccessful. Because the patient had some
negative prognostic factors (i.e., male sex, age >60 years,
histotype, and mass size >2.5 cm) and because of the
likelihood that the Hodgkin’s lymphoma had developed (and
had persisted) during immunosuppression (poor prognosis
for lymphomas during immunosuppression after transplantation [4]), he was treated with MOPP (mechlorethamine,
vincristine, procarbazine, prednisone) and local radiotherapy.
B cell lymphomas, but few Hodgkin’s lymphomas,
are increasingly recognized during long-term treatment of
RA with immunosuppressantis. However, Hodgkin’s lymphoma is not a neoplasm associated with immunosuppression. During long-term treatment with immunosuppressants
and with CSA (5,6), EBV-,associated, LMP-I-positive,
EBNA-Zpositive B cell lymplhomas are increasingly recognized, yet few Hodgkin’s lymphomas have been described
in this setting. However, we know that EBV-associated
Hodgkin’s lymphoma arises only in moderately immunosuppressed, human immunodeficiency virus-infected intravenous drug abusers (7).
Table 1. WBC, lymphocyte, and differential lymphocyte counts before and during treatment*
(April 1993)
WBCs, /mm3
Lymphocytes, /mm3
CD4+ cells, % (/mm3)
CD8+ cells, % (/mm3)
CD4:CD8 ratio
Lymph nodes
After 6 mos. of
(September 1993)
50 (615)
29 (356)
44 (572)
45 (585)
Small, mobile
nodes bilaterally
Small, mobile
nodes bilaterally
After 2 mos. of
(November 1993)
47 (625)
42 (558)
Packed, firm mass
right axilla; small,
mobile nodes left axilla
* A lymph node mass was identified in November 1993, and a biopsy and histologic asse:ssment were
made in December 1993. Hodgkin’s lymphoma was diagnosed at that time. Methotrexate (MTX) and
cyclosporin A (CSA) treatment were discontinued, and 2 months later, a second biopsy was
performed. Surgical and echographic assessment at that time showed a 50% reduction in the lymph
node volume. WBC = white blood cell.
Figure 1. Sections of the patient's lymph nodes obtained at biopsy, demonstrating Hodgkin's disease, mixed cellularity subtype.
A, Reed-Sternberg cells ape present in a mixed background of lymphocytes, eosinophils, and plasma cells (hematoxylin and eosin
stained; original magnificadion X 250). B, Bouin-fixed, paraffin-embedded section, showing Reed-Sternberg cells, with strong
staining for latent rnembrime protein 1 (alkaline phosphatase-anti-alkaline phosphatase stained, hematoxylin counterstained;
original magnification x 5:20).
Since it is well recognized that CSA abrogates EBVspecific T cell control (8,9), we believe that the combination
of CSA and MTX might have played a role in allowing the
lymphoma to develop in this already-overtreated patient.
G . F. Ferraccioli, MD
L. Casatta, MD
E. Bartoli, MD
Universita Degli Studi di Udine
Lrdine, Italy
S. De Vita, MD
R . Dolcetti, MD
M. Boiocchi, PhD
A.. Carbone, MD
C'entro Riferimento Oncologico
Aviano-Pordenone, Italy
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barry, epstein, associates, patients, arthritis, virus, methotrexate, hodgkin, cyclosporin, treated, rheumatoid, lymphoma
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