Sir, We present the case of two patients with DM treated with prolonged double-agent immunosuppressive therapy, who developed fatal Epstein–Barr virus (EBV)-associated lymphoproliferative disease.

Case 1

A 33-year-old woman was hospitalized for persistent fever over the previous week. She had been diagnosed with DM at another hospital in 1999. Muscle biopsy showed characteristic findings, and cancer screening, including a complete physical examination, laboratory tests (haematocrit, serum chemistry panel and tumour markers), thoraco-abdominal CT, gynaecological ultrasound and mammography, was negative. Because of corticosteroid-refractory disease (persistent activity despite a dose of ⩾1 mg/kg/day of prednisone), she had received MTX (10 mg/week) and AZA (2 mg/kg/day; 150 mg/day) with clinical improvement. The patient wished to become pregnant; hence, immunosuppressive therapy was tapered over the following 6 months to 25 mg/day AZA and 2.5 mg/week MTX. DM activity resumed and re-treatment with prednisone (1 mg/kg/day), AZA (100 mg/day), MTX (7.5 mg/day) and intravenous (i.v.) immunoglobulin (0.4 g/kg/day) was necessary. In May 2006, while she was receiving AZA (75 mg/day), MTX (7.5 mg/week) and low-dose corticosteroids (5 mg/day), she developed fever that reached 40°C, without chills. After 1 week of persistent fever, she was hospitalized and immunosuppressive agents were discontinued. Physical examination revealed a woman in good general health without muscle weakness, rash or peripheral lymphadenopathy. Laboratory tests showed slight normochromic normocytic anaemia, elevated liver enzymes, dissociated cholestasis and normal creatine kinase values. Blood and urine cultures for bacteria were negative, as was serology for Q fever, EBV, cytomegalovirus and Leishmania, Brucella and Salmonella species. Chest radiography was normal, and thoraco-abdominal CT scans revealed mild splenomegaly. The patient's clinical status worsened over the next days. Liver biopsy was performed and a large B-cell lymphoma was identified. Although the patient was treated with rituximab 375 mg/m2, high-dose corticosteroids, rasburicase and hydration therapy, she developed multi-organ failure and died. Necropsy studies revealed tumour lysis syndrome, and chromogenic in situ hybridization (CISH) detected extensive EBV-encoded RNA (Fig. 1).

Fig. 1.

Strong positivity for EBV-encoded RNA detected by CISH.

Case 2

A 59-year-old woman was hospitalized in April 2008 for intermittent fever reaching 38°C in the previous month. In 2005, she presented with proximal muscle weakness, ‘mechanic's hands’ and skin rash, with mildly elevated creatine kinase values. Muscle biopsy showed typical findings of DM. Anti-Jo-1 antibodies were positive, and chest CT scans showed extensive ground glass opacities. Cancer screening was negative. The patient was treated initially with prednisone (50 mg/day), monthly i.v. immunoglobulins (0.4 g/kg/day) for 6 months and tacrolimus (2 mg/12 h). While on treatment, disease activity flared and mycophenolate mofetil (1 g/8 h) was added. After 1 year of dual therapy (tacrolimus–mycophenolate mofetil) with good control of disease activity, the patient experienced fever and night sweats for 1 month. She was hospitalized, and immunosuppressive agents were discontinued. Blood and urine cultures for bacteria were negative, as was serology for Q fever, EBV, cytomegalovirus and Leishmania, Brucella and Salmonella species. Physical examination disclosed an enlarged liver and spleen, but no lymphadenopathy. Bone marrow aspirate was normal, and Ziehl–Neelsen stain and culture for Mycobacterium tuberculosis were negative. A full-body CT scan revealed multiple retroperitoneal lymphadenopathies, and enlarged liver and spleen. A retroperitoneal adenopathy specimen was obtained by mini-laparotomy and subjected to pathological examination. The tissue architecture was effaced by varying numbers of multi-nucleated Hodgkin and Reed–Sternberg (HRS) cells, admixed with a rich inflammatory background containing histocytes, eosinophils and plasma cells. On immunohistochemistry, HRS cells were positive for CD30, CD15, PAX5 and EBV LMP1 protein. Detection of EBV-encoded RNA (EBER) by CISH was positive in 15% of the atypical cells. The ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) chemotherapy protocol was established, but the patient developed hepatic failure due to lymphoma infiltration; she died 2 months later of fulminant Staphylococcus sepsis.

The mainstay therapy for DM is immunosuppression [1]. EBV-associated lymphoma, particularly diffused large B-cell lymphoma, has become more common with increasing use of immunosuppressive agents in patients with autoimmune disease [2–4]. EBV-associated lymphoma may gradually resolve after discontinuation of cytotoxic therapy, but occasionally progresses to a life-threatening condition.

The special relationship that exists between DM and cancer [5], in which the presence of DM can be considered as an expression of the immunologic response that constrains cancer development, may explain the more aggressive behaviour in DM than is observed in other autoimmune diseases. We reviewed the records of 124 consecutive patients with idiopathic inflammatory myopathy consulting at our hospital between 1983 and 2008. Patients with paraneoplastic disease or inclusion body myositis were excluded. Only 8 of 102 patients reviewed had received therapy with two immunosuppressive agents for >12 months to control disease activity, and two of them are the patients described herein with EBV-associated lymphoma. None of the other patients presented with EBV-associated disease.

Refractory myositis is a challenge. Aggressive cytotoxic therapy can be life saving, but carries the possibility that life-threatening EBV-associated lymphoma may develop. Physicians should be aware of this potential complication when prolonged double immunosuppression is used in DM patients.

graphic

Acknowledgement

Funding: This study was funded in part by a grant (FIS/2008 PI 08-0450) from Ministerio de Sanidad y Consumo (Spanish Ministry of Health and Consumer Affairs).

Disclosure statement: The authors have declared no conflicts of interest.

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