Arthritis as an unusual manifestation of Kikuchi-Fujimoto disease

M. Douglas, R. Bradbury2, S. Kannangara3 and D. Mitchell1

Centre for Virus Research, Westmead Millennium Institute and
1 Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead,
2 Department of Infectious Diseases and Microbiology, Concord Repatriation and General Hospital and
3 Concord Repatriation and General Hospital, NSW, Australia

SIR, The cases are described of two young women presenting with arthritis, who were diagnosed with Kikuchi-Fujimoto disease (KFD; also called histiocytic necrotizing lymphadenitis).

Arthritis has been described previously in patients in whom KFD is associated with other autoimmune disease, such as adult Still's disease and systemic lupus erythematosus (SLE). In our patients there was no evidence of coexistent autoimmune disease. To our knowledge, this is the first report of arthritis as a presentation of isolated KFD. We discuss the typical clinical features of KFD, its aetiology, associations and treatment.

Case 1 (NM) was a 36-yr-old woman who recently immigrated to Australia from Sri Lanka. She had undergone microdiscectomy for left sciatic pain in Sri Lanka 6 months previously, and took occasional paracetamol for residual pain. She was otherwise well. NM was seen by her local doctor for worsening back pain. She displayed no neurological signs, and was prescribed bed rest, non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy, with some relief. Three months later, she developed neck pain and was referred to a rheumatologist. There was no associated paraesthesia or weakness, X-rays of the neck were normal, and more physiotherapy was recommended.

A few weeks later, NM presented to a Sydney teaching hospital emergency department complaining of worsening neck pain, sore throat and a fever despite 2 days of oral amoxycillin. She described arthralgias affecting her feet for 2 weeks and her hands for 1 week, but denied headache, cough, dysuria, vomiting, diarrhoea, and dry eyes or mouth.

On examination she looked moderately unwell. Temperature was 38°C, but cardiovascular and respiratory examinations were unremarkable. A moderate symmetrical small joint polyarthritis involved the metacarpophalangeal, metatarsophalangeal and proximal interphalangeal joints of her hands and feet. Tender cervical lymphadenopathy was present, more prominent on the left than the right. There was no rash and no hepatosplenomegaly.

Investigations showed borderline leucopenia (total leucocytes 4.0x106/l, neutrophils 2.3x106/l, lymphocytes 1.1x106/l), erythrocyte sedimentation rate (ESR) 20 mm/h and C-reactive protein (CRP) 6 mg/l. Liver function tests were mildly abnormal (alkaline phosphatase 119 U/l, alanine transaminase 89 U/l, aspartate transaminase 63 U/l, albumin 35 g/l, bilirubin 6 µmol/l). Haemoglobin was 130 g/l and platelets 166x106/l. Chest X-ray was normal.

NM's fevers settled spontaneously over several days, recurring 2 weeks later. Arthritis was no longer present in her feet and had decreased in her hands. Her cervical lymph nodes were still enlarged, although less tender, smaller (1–2 cm) and firmer. Mild tenderness was elicited over the midthoracic spine. ESR was 25 mm/h and leucocytes 3.5x106/l. Chest X-ray, X-ray of the thoracic spine and radiolabelled technetium bone scan of the spine were normal.

No pathogens were isolated from blood or sputum cultures. Tests for rheumatoid factor, antinuclear antibodies (ANA), anti-double-stranded DNA antibody, extractable nuclear antigens and ANCA (anti-neutrophil cytoplasmic antibody) were negative. Serology for the following infectious agents was negative: Epstein–Barr virus (IgM), cytomegalovirus (IgM), toxoplasma, parvovirus B19, rubella (IgM), Ross River virus, hepatitis B surface antigen, hepatitis C, HIV-1 and -2, Brucella, Orientia tsutsugamushi (scrub typhus), Rickettsia australis (Queensland tick typhus), Coxiella burnetii (Q-fever), Bartonella henselae (cat-scratch disease), Yersinia and human T-cell leukaemia virus 1.

Cervical lymph node biopsy was performed, and the histology was diagnostic for KFD. There was patchy replacement of normal lymph node architecture by irregular pale cellular areas, with prominent individual cell necrosis and foci of more confluent necrosis. Residual areas of lymph node tissue showed some reactive change. In the abnormal areas the predominant cells were large, very atypical lymphoid cells, immunoblasts and histiocytes. No granulomas or giant cells were seen. Immunoperoxidase staining demonstrated T-cell markers (UCHL-1 and CD3) and histiocyte markers (CD68). Staining for KI-1 (CD30) was negative.

NM was treated with NSAIDs, with resolution of symptoms and lymphadenopathy over several months.

Case 2 (FK) was a 45-yr-old woman who had immigrated to Australia from Pakistan 7 yr previously. She had no significant medical history. She presented to another Sydney teaching hospital emergency department with an 8-week history of fever to 38.5°C without sweats or rigors, malaise and arthralgias. She described a transient fine erythematous rash over her trunk and limbs during the first 3 days of the illness. Swelling and pain of her right elbow, wrists and metacarpophalangeal, left ankle and metatarsophalangeal joints had been a feature of her illness during the first few weeks. At that time she had been reviewed by a renal physician and a rheumatologist, and diagnosed with probable viral arthritis. A differential diagnosis of connective tissue disease had been considered. ESR was 54 mm/h and CRP 7 mg/l; connective tissue and vasculitic screens were negative. Serology for arboviruses, rubella, parvovirus, Epstein–Barr virus, cytomegalovirus and HIV-1 and -2 was negative. Gallium scan was normal.

At the time of admission FK was still febrile. There was no rash, no definite synovitis and no hepatosplenomegaly. Prominent cervical, pre-auricular and axillary lymphadenopathy was noted.

Cervical lymph node biopsy was consistent with KFD, and the patient was discharged with simple analgesics. Fever, lymphadenopathy and rheumatological symptoms resolved over 2 months without specific therapy.

KFD was first described in Japan in 1972 in two separate papers [1, 2]. It is a self-limiting illness, typically affecting young women aged between 20 and 30 yr. Initial symptoms may suggest a viral upper respiratory tract infection, but lymphadenopathy, particularly cervical, is present in most cases [3]. Fever and elevated ESR are common. Diagnosis is based on lymph node histology, with localized proliferation of histiocytes and immunoblasts, associated with abundant nuclear debris and tissue necrosis.

The cause of KFD is unknown, but various infectious aetiologies have been suggested. Initially toxoplasma and Yersinia enterocolitica were suspected, but no supporting evidence was found. One study of Epstein–Barr virus and human herpesvirus 6 failed to detect viral DNA in tissue specimens using the polymerase chain reaction and in situ hybridization [4]. One case was reported in a patient infected with human T-cell leukaemia lymphoma virus (HTLV-1) [5].

KFD in some patients has been associated with autoimmune disease. In patients with SLE it may precede, coincide with or follow typical clinical features, so repeat ANA testing is recommended in anyone with KFD [6]. There is a report of KFD in a patient with a ruptured silicone breast implant [7], and one case associated with adult Still's disease [8].

Treatment for KFD is usually non-specific, with paracetamol and NSAIDs used for symptom control. In patients with concurrent SLE, the addition of corticosteroids may be useful [6]. Since most cases of KFD resolve spontaneously [9], it is important to differentiate from conditions requiring specific, toxic therapy. Lymphoma and SLE can have similar clinical features and lymph node histology to KFD, while tuberculosis can be clinically indistinguishable.

Both patients in our series had clinical arthritis at the time of presentation. To our knowledge, this is the first time that this clinical pattern has been reported in the absence of another diagnosis. One report of a 36-yr-old Saudi man described polyarthralgia and a rash [10], but there was no definite joint swelling as in our patients. Although an association with Still's disease is recognized [8], neither of our patients would fit diagnostic criteria for adult Still's disease [11]: neither had significant leucocytosis, typical rash, splenomegaly, or liver dysfunction. Arthritis has been reported in patients with concurrent KFD and SLE [6], but ANA was not detected in either of our patients. One group [12] has suggested a common pathogenesis for Still's disease, KFD and possibly SLE, reflecting host immune response to certain infectious agents, such as lymphocytotrophic viruses.

Although KFD was described in Japan initially, it has now been reported in many countries around the world. One Australian case of recurrent disease has been reported in a woman from Saudi Arabia who had four episodes [13]. One published case series from Sri Lanka describes 10 patients who were initially misdiagnosed with tuberculosis [14]. Although our cases presented and were diagnosed in Australia, they were both born on the Indian subcontinent.

In summary, KFD is a benign, self-limiting condition causing fever and lymphadenopathy, mostly in young women. Its presentation may suggest lymphoma or tuberculosis, especially in patients from an area where the disease is endemic. It has been associated with SLE and adult Still's disease, both of which should be excluded. The prominent arthritis in our two cases has not been described previously in the absence of other autoimmune disease. These cases reinforce the importance of obtaining a histological diagnosis rather than commencing empirical, potentially toxic therapy.

Notes

Correspondence to: M. Douglas, Centre for Virus Research, Westmead Millennium Institute, PO Box 412, Westmead, NSW 2145, Australia. E-mail: mark_monique{at}student.usyd.edu.au Back

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Accepted 11 November 2002