Rheumatology Advance Access originally published online on February 26, 2008
Rheumatology 2008 47(4):553-554; doi:10.1093/rheumatology/ken008
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Association of Kikuchi–Fujimoto's disease with SLE
1Centre for Rheumatology, Department of Medicine, University College London Hospital and 2Arthritis Centre, Northwick Park Hospital, Imperial College London, UK.
Correspondence to: F. Goldblatt, Centre for Rheumatology, Department of Medicine, University College London Hospital, 3rd Floor Central, 250 Euston Road, London NW1 2PQ, UK. E-mail: fgoldblatt{at}ntlworld.com
SIR, Kikuchi–Fujimoto's disease (KFD) is a rare benign form of necrotizing histiocytic lymphadenitis, typically affecting young women of Asian background. Clinical features include lymphadenopathy, predominantly involving cervical lymph nodes, fever, malaise, anorexia, myalgias and arthralgias [1]. Diagnosis is dependent upon presence of appropriate immunohistology of the lymph node, which typically shows abundant CD68+ plasmacytoid monocytes in the node paracortex, eosinophilic fibrinoid material and apoptotic debris [2]. KFD has been reported in association with a number of autoimmune and infectious diseases [3, 4], including infrequent co-existence with SLE [5]. Differentiation between KFD and SLE is imperative because of significant differences in treatment and prognosis. We report the cases of four patients initially presenting with a diagnosis of KFD who subsequently developed SLE.
A 22-yr-old Asian woman was diagnosed with KFD after she presented with fever, malaise and enlarged non-tender cervical lymphadenopathy that on cytopathological analysis demonstrated features characteristic of Kikuchi's lymphadenitis. Sequential samples for ANA (Hep1000) and anti-double stranded deoxyribonucleic acid antibodies (anti-dsDNA) (Crithidia assay) were negative. Treatment with a reducing dose of corticosteroids controlled her constitutional symptoms. Three months later she developed a malar rash, cutaneous vasculitic lesions, strongly positive ANA>1:1280 and antibodies to Sm and Ro antigens, followed by features consistent with lupus cerebritis. Complete recovery was achieved with pulsed i.v. methylprednisolone and cyclophosphamide. She remains in disease remission.
A 39-yr-old Asian woman presented with an acute febrile illness associated with bilateral cervical lymphadenopathy, marked acute-phase responses and negative infectious and immunological serology. Lymph node histological analysis was compatible with a diagnosis of Kikuchi's lymphadenitis and features of SLE lymphadenitis were absent. Fourteen months later, she developed wide-spread arthralgia, fatigue and subacute cutaneous lupus erythematosus, ANA (1:640) (Hep1000) and antibodies to dsDNA (Crithidia assay), Sm, Ro and cardiolipin. Repeated samples demonstrated hypocomplementaemia (C3 0.49 g/l, C4 < 0.05 g/l) and lymphopenia (0.7 x 109cells/l). She was commenced on immunosuppression and low-dose aspirin. She remains in clinical remission.
A 31-yr-old Asian woman presented with a 3-week history of fever associated with bilateral cervical and axillary lymphadenopathy and elevated inflammatory markers. KFD was diagnosed on the basis of negative infectious and autoimmune serology and characteristic lymph node biopsy, without features of lupus lymphadenitis. Six months later, she developed a small joint inflammatory polyarthritis, malar rash, mouth ulcers and an immunological profile consistent with SLE [ANA positive 1:1280 (Hep2), anti-dsDNA antibody positive (Crithidia assay), anti-Ro-positive antibody and hypocomplementaemia (C3 0.45 g/l, C4 0.17 g/l)]. The patient received prednisolone, azathioprine and hydroxychloroquine. Two years later she developed an infectious meningo-encephalitis, and tragically serious cerebral complications have resulted in the development of a persistent neuro-vegetative state.
A 14-yr-old Asian female presented with fever, cough, weight loss and left-sided supraclavicular lymphadenopathy. Infection was excluded and the autoimmune profile was non-diagnostic [ANA 1:1280 (Hep2)]. Lymph node biopsy was typical of KFD. Shortly after the biopsy she developed a widespread inflammatory polyarthritis, malar rash and headaches. Simultaneously, immunological features of SLE were detectable with positive anti-dsDNA antibodies and hypocomplementaemia and she was commenced on appropriate therapy. Her progress has been complicated by episodes of arthritis, pancytopenia secondary to active SLE, fevers and migraines requiring pulses of i.v. methylprednisolone. She developed diffuse proliferative glomerulonephritis [World Health Organisation (WHO) Class IV], which following intolerable side-effects with mycophenolate and later cyclophosphamide, was successfully treated with B-cell depletion therapy.
Since 1991, 32 reports of KFD associated with SLE have been published [5, 6]. On review, many describe the association of KFD diagnosed concomitantly with or following the diagnosis of SLE [4, 7], which in all probability represent lupus lymphadenitis. We expand the literature with the report of four cases in which KFD predated a clinical and immunological diagnosis of SLE by between 3 and 14 months. Unfortunately, however, there are currently no predictive markers to identify as to which of the patients with KFD will develop SLE [6–8].
Clinically, KFD is typically characterized by lymphadenopathy (predominantly cervical), acute fevers and other systemic features. Extra-nodal involvement is less common, although reported [9]. ANA is usually negative and whilst the natural history can occasionally be unpredictable in relation to severity and complications, most cases are self-limiting, improving within 6 months [5, 10]. The clinical and immunological features required for diagnosis of SLE are well documented and specific. Lupus lymphadenitis has been reported in between 12% and 59% of patients with SLE, but in contrast to KFD, is rarely the presenting feature [10]. Careful examination of lymph node histopathology in correlation with clinical features is the most reliable way to differentiate the two entities. KFD is typified by cortical and paracortical necrotizing nodules, apoptotic debris, proliferation of histiocytes and immunoblasts, abundant CD8+ T cells, and an absence/paucity of neutrophils [2, 6]. In contrast, lupus lymphadenitis is diagnosed in patients who meet the validated revised ACR criteria for SLE together with typical biopsy findings of necrotic and thrombosed blood vessels, presence of a necrotizing neutrophilic infiltrate and the pathognomonic feature, haematoxylin bodies [2].
Whilst it is important that the characteristic self-limiting form of necrotizing lymphadenitis and systemic illness of KFD be recognized, the possibility of other diseases including SLE should always be considered. Importantly, however, as in our four patients, SLE is known to develop in a small number following a previous diagnosis of KFD. The present lack of predictive markers for which patients with KFD will progress to SLE, means that all patients diagnosed with KFD should receive periodical clinical and serological follow-up for several years to detect possible evolution of SLE.
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Funding: F.G. is supported by a Neil Hamilton Fairley Post-Doctoral National Health and Medical Research Council Scholarship (Australia).
Disclosure statement: The authors have declared no conflicts of interest.
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