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Exacerbation of chronic active Epstein–Barr virus infection in a patient with rheumatoid arthritis receiving humanised anti-interleukin-6 receptor monoclonal antibody
  1. J Ogawa1,
  2. M Harigai2,
  3. T Akashi3,
  4. K Nagasaka4,
  5. F Suzuki5,
  6. S Tominaga6,
  7. N Miyasaka7
  1. 1Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
  2. 2Department of Pharmacovigilance, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
  3. 3Department of Human Pathology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
  4. 4Department of Internal Medicine, Ome Municipal General Hospital, Tokyo, Japan
  5. 5Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
  6. 6Department of Internal Medicine, Yokosuka Kyosai Hospital, Kanagawa, Japan
  7. 7Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
  1. Correspondence to:
    Nobuyuki Miyasaka
    Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; miya.rheu{at}tmd.ac.jp

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We describe deterioration of chronic active Epstein–Barr virus (CAEBV) infection in a patient with rheumatoid arthritis who received a single infusion of humanised anti-IL6 receptor monoclonal antibody (tocilizumab). A 60-year-old woman with rheumatoid arthritis who had been treated with methotrexate developed lymphadenopathy in October 1999, which was ameliorated in 2 months by cessation of methotrexate. Re-institution of methotrexate in September 2000 led to recurrence of lymphadenopathy, which was diagnosed as necrotising lymphadenitis by histological examination, with high titres of anti-Epstein–Barr virus (EBV) antibodies (antiviral capsid antigens IgG 1:1280, anti-early antigens IgG 1:640) and EBV DNA in plasma (3100 copies/ml). The lymphadenopathy gradually disappeared after cessation of methotrexate at the expense of active arthritis. In July 2001, the patient was enroled in a clinical trial for tocilizumab1 and intravenously treated with the trial drug (8 mg/kg). Arthritis dramatically improved, but EBV DNA increased from 520 (3 September 2001) to 2600 copies/106 white cells (12 September) and liver enzymes also increased. The patient became febrile and showed hepatosplenomegaly, pleural effusion and blepharoedema. She was diagnosed as having haemophagocytic syndrome and capillary leak syndrome with exacerbation of CAEBV infection2,3 according to her clinical manifestations and laboratory data including results of bone marrow biopsy. Treatment with high-dose corticosteroid, cyclosporin A and IL-2 activated T cells4 was not effective. Multiple gastric ulcers were identified by gastrointestinal fibrescope. She died of disseminated intravascular coagulation and multiple organ failure (fig 1).

Figure 1

 Clinical course of the patient.

Because of this tragic complication, the amounts of EBV DNA in other patients enroled in the same clinical trial were measured, but this was the only patient who showed EBV DNA of over 2000 copies/106 white cells. Considering the fact that IL-6 regulates growth, differentiation and activation of cytotoxic T lymphocytes,5–8 it is plausible that blockade of IL6–IL6 receptor interaction by tocilizumab would have resulted in the final breakdown of immunosurveillance for EBV. The treatment with tocilizumab might have exacerbated pre-existing Hodgkin’s disease (see below) and worsened the clinical course. The present case strongly indicates that treatment with tocilizumab should be avoided for patients with underlying CAEBV infection. The amount of EBV DNA in white cells should be measured before the institution of tocilizumab when patients show clinical manifestations suggestive of CAEBV infection.

Autopsy showed enlarged para-aortic and mesenteric lymph nodes. Histologically, small islands of lymphocytes were seen in lymph nodes, with scattered large atypical lymphocytes which were positive for CD15 and CD30 but negative for CD3, CD4, CD20, CD56 and CD68. These characteristics are compatible with Hodgkin’s lymphoma cells (Reed–Sternberg cells) and these lymphocytes expressed EB-encoded small RNA-1 (EBER-1) (fig 2A). Infiltrating CD45RO+ T lymphocytes in the liver were also EBER-1+ (fig 2B). The bone marrow was mainly occupied by CD68+ histiocytes with haemophagocytosis (fig 2C, D). The stomach had multiple ulcerations owing to infiltration of both Hodgkin’s lymphoma cells and EBER-1+ lymphocytes. A small number of Hodgkin’s cells were retrospectively identified in the biopsy specimen of the lymph node at the recurrence of lymphadenopathy in March 2001.

Figure 2

 Histopathological features of the lymph node (A), liver (B) and bone marrow (C,D) at autopsy. (A) Small blue–black dots in the nuclei indicate EB-encoded small RNA (EBER)-1 mRNA by in situ hybridisation in Hodgkin’s lymphoma cells (arrows; original magnification ×50). (B) Thin arrows indicate CD45RO+ T cells by immunohistochemistry. Thick arrow indicates both EBER-1-positive (in situ hybridisation) and CD45RO+ T cells (original magnification ×400). (C) Brown staining indicates CD68+ cells (original magnification ×50). (D) Histiocytes with haemophagocytosis were observed (arrows; haematoxylin and eosin staining; original magnification ×200).

REFERENCES

Footnotes

  • Competing interests: None.

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