1 Case Presentation
A 45-year-old male patient with good past health was admitted to the medical ward for arthritis in 2008. He had pain and swelling over small hand joints with morning stiffness for 1 month. He also complained of generalized myalgia. On physical examination, there was mild arthritis over small hand joints. Gottron’s papules and mechanic’s hands were noted. There were fine crackles over bilateral lung bases. Blood tests showed elevated serum creatine kinase (CK) up to 5,239 U/ L, although he had no significant weakness. Antinuclear antibody and rheumatoid factor were negative but anti-Jo-1 antibody was positive. Muscle biopsy revealed findings suggestive of inflammatory myopathy. The initial malignancy screening was unremarkable. High-resolution computer tomography (CT) of the chest showed features of interstitial lung disease. No significant ground glass opacity was noted. Transbronchial biopsy yielded organizing pneumonia changes. The diagnosis of dermatomyositis with antisynthetase syndrome was made according to the criteria proposed by Solomon et al .
Oral prednisolone 60 mg daily (body weight of ~70 kg) was started, and the arthritis subsided. Azathioprine was added 1 month later, whereas prednisolone was being tapered. However, the disease control was suboptimal despite 150-mg daily azathioprine with on and off flares with worsening rash and CK elevation. Intermittent courses of intravenous methylprednisolone pulses (100 mg for 3 days) have been given for three times. Cyclosporine A 100 mg twice daily was added since 2011. The disease was relatively quiescent in the following few years despite three episodes of shingles. In May 2015, the patient started to have worsened rash again and weight loss. The immunosuppressive regimen was changed to mycophenolate mofetil up to 1000 mg twice daily. The patient was admitted to the hospital in October 2015 for right upper limb weakness and slurring of speech for 1 week. CT of the brain showed a 3.5-cm space occupying lesion in the deep region of left frontal lobe with lots of perilesional edema, which is shown in Figure 1. Biopsy of the lesion was performed, and the histological features were compatible with diffuse large B-cell lymphoma. The in-situ hybridization (ISH) for the Epstein-Barr encoding region (EBER) was positive in the specimen. Positron emission tomography–CT revealed no lymphomatous lesions outside the brain. Human immunodeficiency virus (HIV) test was negative. He was referred to the oncologists, and the diagnosis of Epstein-Barr virus (EBV)-associated primary central nervous system (CNS) lymphoma, likely secondary to his immunosuppressed state, was made. The immunosuppressants were stopped, and he was put on dexamethasone. Immunochemotherapy was given by the oncologists with rituximab and methotrexate. However, the patient developed non-neutropenic fever and hospital-acquired pneumonia after the second course. His condition deteriorated despite treatment with broad-spectrum antibiotics and antifungal agents, and he finally died on November 2015.
Here we report a male patient who had refractory idiopathic inflammatory myopathy (IIM) presented with antisynthetase syndrome, being treated with potent immunosuppressants for years, developed EBV-associated lymphoma. Despite the stepping down of the immunosuppressives and active lymphoma therapy, the patient died because of infective complications.
EBV is an enveloped herpes virus with a 172-kb double-stranded DNA genome. More than 90% of the adults worldwide are EBV seropositive, primarily after developing the infection during childhood . It is transmitted through saliva and targets oral epithelial cells as well as B-cells in the submucosal lymphoid layer. Its life cycle can be divided into the lytic phase, when it can infect other cells or spread infection, and the latent phase, when it persists lifelong in memory B-cells. EBV infection can be either primary or secondary because of either reactivation of latent EBV or reinfection with a new EBV strain. It is known to be carcinogenic, as it can encode oncoproteins that are able to promote cellular transformation. The typical associated cancers are nasopharyngeal carcinoma and lymphomas. The latter is a well-recognized complication of congenital or acquired systemic immunosuppression. CNS is a frequent site and they are almost always B-cell in origin. The more common causes are iatrogenic immunosuppression following organ transplantation, the posttransplantation lymphoproliferative disorders (PTLD), and HIV infection. Improved detection and management of EBV infection in organ transplant recipients has led to a reduction in PTLD over time . However, there are increasing reported cases of patients on immunosuppressants without organ transplants developing EBV-associated lymphoma, and almost all immunosuppressants have been reported as potent culprits. They are more frequently observed with primary EBV infection. The host’s ability to control EBV is reliant on a functional T-cell repertoire. Patients receiving immunosuppressants especially T-cell-specific agents may not be able to develop an adequate population of EBV-specific cytotoxic CD8+ T lymphocytes (EBV-CTL) to contain the virus; therefore, the oncogenic properties of the virus may become apparent . EBV-associated lymphoproliferative disease affecting the CNS usually presents with constitutional symptoms, headache, or focal neurological complaints. The typical finding is ring-enhancing lesions on CT. Diagnosis is by ISH for EBER, a marker of EBV-infected cells, in the biopsy specimens. The management of EBV-associated lymphoproliferative disorders varies significantly according to the subtype and original disease and from institution to institution. Often it is based on the typical treatment for lymphomas in adult patients. Surgery, radiotherapy, chemotherapy, and rituximab have been used. Reduction of immunosuppressants, allowing recovery of the host’s immune system and development of cytotoxic T-lymphocytes (CTL) against EBV, has been regarded as an essential part of management and was successful as the stand-alone treatment in case reports [5,6]. Antiviral drugs such as acyclovir or ganciclovir neither have activity against latent EBV nor have been effective in treating acute EBV infection. The addition of arginine butyrate, which induces switch from latency to lytic phase in EBV-infected lymphocytes, thereby making infected cells susceptible to the effects of antiviral agents, has been tried with some preliminary results . Other experimental strategies include sirolimus, which is a mammalian target of rapamycin (mTOR) inhibitor and infusion of EBV-specific CTL either from the patient or from healthy donors. EBV quantitative viral load monitoring by polymerase chain reaction (PCR) of the peripheral blood is available and has been advocated for the high-risk groups such as seronegative recipients receiving organs from seropositive donors . A study looked concurrently at measuring EBV loads and EBV CTL activity in pediatric liver transplant recipients and found a 100% positive predictive value for the development of PTLD in recipients who experienced primary EBV infection without developing a significant EBV CTL response . Preemptive treatments, including reduction of immunosuppression, treatment of viral reactivation and rituximab, have been tried in high-risk patients [10, 11, 12].
It is known that patients with rheumatic diseases, especially Sjogren’s syndrome, rheumatoid arthritis, and systemic lupus erythematous, have a higher risk for developing lymphoma . This is attributed either to the chronic inflammation or to the immunosuppressants given. While most immunosuppressants can cause defective immunosurveillance to EBV leading to lymphomagenesis, some of them are believed to be directly mutagenic. There are reported cases of patients with autoimmune diseases treated with azathioprine or cyclophosphamide complicated by EBV-negative lymphoproliferative diseases . They typically responded poorly to immunosuppressant withdrawal and chemotherapy, in contrary to EBV-related lymphoma.
As far as we know, there are only a handful of reported cases of IIM complicated by EBV-associated lymphoproliferative diseases in the literature and they are summarized in Table 1 [15, 16, 17, 18, 19]. Malignancy has long been associated with IIM, which can be considered as an expression of the immunologic response that constrains tumor development. In contrast, lymphoproliferative diseases associated with immunosuppressive therapy can occur similar to those observed in other immunosuppressed states because of the unchecked proliferation of EBV-transformed B lymphocytes. While myositis disease can be difficult to control and potentially life threatening, requiring sometimes multiple immunosuppressants, these regimens are not without risks. Besides the obvious opportunistic infection risk, EBV-related tumors can also be a complication and lead to fatal outcomes. As the nonspecific constitutional symptoms of EBV-associated lymphoma may mimic active myositis, it is difficult to ascertain if the complaints of our patient were in fact tumor or disease related. Although a causal relationship could not be established, the heavy immunosuppressants used might inadvertently facilitate the growth of the EBV-associated lymphoma. In retrospect, the recurrent episodes of shingles might have hinted that the patient was in a state of overt immunosuppression.
EBV associated lymphoproliferative diseases in idiopathic inflammatory myopathy patients: clinical
|Patient 1||Patient 2||Patient 3||Patient 4||Patient 5||Patient 6||Our patient|
|Disease duration (years)||1||6||6||7||3||3||7|
|Immuno-suppressants used||MTX||MTX, MMF||MMF||AZA, MTX||MMF, TAC||MTX, thalidomide||AZA, CYC A, MMF|
|Site||LN, liver, lung||CNS||CNS||Liver||LN, liver, spleen||Scalp||CNS|
|Symptoms||Fever, lymphadenopathy||Bilateral weakness, seventh nerve palsy||Encephalopathy||Fever||Fever||Scalp mass||Unilateral weakness, slurringof speech|
|Pathology||Hodgkin's lymphoma||DLBL||PLPD||DLBL||Hodgkin's lymphoma||Hodgkin's lymphoma||DLBL|
|Treatment||Discontinuation of immuno- suppressant||Dexamethasone, discontinuation of immuno-suppressants||Dexamethasone, RTX||RTX||ABVD||ABVD, RT||Dexamethasone, RTX, MTX|
On top of the classical association of IIM and malignancy, rare EBV-associated tumors related to EBV infection secondary to the use of potent immunosuppressive therapies could occur. Vigilance should be maintained. Further investigations are advisable if there are new symptoms and signs or in refractory cases. The case also serves as a diagnostic alert that the causation by EBV infection in unusual tumors found in patients with IIM should be considered, as both the treatment and prognosis may differ. Last but not least, it is always the paramount goal for rheumatologists to strike a balance between the risks and benefits of immunosuppressive therapies.
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Smets F, Latinne D, Bazin H, et al. Ratio between Epstein–Barr viral load and anti-Epstein–Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation 2002;73:1603–1610.)| false 10.1097/00007890-200205270-00014 12042647
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Ganschow R, Schulz T, Meyer T, Broering DC, Burdelski M. Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in pediatric liver graft recipients. J Pediatr Gastroenterol Nutr 2004;38:198–203.)| false 14734884 10.1097/00005176-200402000-00018
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Humar A, Hebert D, Davies HD, Humar A, et al. A randomized trial of ganciclovir versus ganciclovir plus immune globulin for prophylaxis against Epstein–Barr virus related posttransplant lymphoproliferative disorder. Transplantation 2006;81:856–861.)| false 16570008 10.1097/01.tp.0000202724.07714.a2
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