Systemic juvenile idiopathic arthritis, Kikuchi's disease and haemophagocytic lymphohistiocytosis—is there a link? Case report and literature review

A. V. Ramanan, R. F. Wynn1, A. Kelsey2 and E. M. Baildam

Departments of Paediatric Rheumatology
1 Paediatric Haematology and
2 Paediatric Histopathology, Royal Manchester Children's Hospital, Charlestown Road, Blackley, UK

SIR, Necrotizing lymphadenitis (Kikuchi's disease) is a benign cervical lymphadenopathy that typically affects young women and usually remits spontaneously with no recurrences [1]. Histology of involved lymph nodes shows a characteristic picture [26]. Systemic juvenile idiopathic arthritis (JIA) accounts for 10–20% of JIA, affecting males and females equally and occurring most frequently under the age of 5 yr. Generalized lymphadenopathy is found in 70–80% of cases [7, 8]. There are very few reports in the literature of systemic JIA being associated with Kikuchi's disease. One report describes three cases of adult-onset Still's disease associated with Kikuchi's disease [9]. There is only one report in children and we believe this is the first report of an association between the two in a Caucasian child.

A 1-yr-old girl presented to her local hospital with a 3-week history of fever and an erythematous rash over her face, forearms and lower limbs characteristic of ‘systemic JIA’ and violaceous eyelids. Koebner phenomenon was also demonstrated. She had marked generalized lymphadenopathy. The rest of her systemic examination was normal. A diagnosis of probable systemic-onset JIA was made. She was commenced on ibuprofen at 40 mg/kg per day initially. A complete work-up, including lymph node, muscle, skin and bone marrow biopsy, was done to exclude malignancy and dermatomyositis. Her laboratory investigations showed a deranged lactate dehydrogenase of 1317U/l (normal <620), a haemoglobin of 8.9g/dl, white cell count of 13.9, platelets of 431x109/l and an erythrocyte sedimentation rate (ESR) of 77mm/h. The bone marrow was normal. Her immunology, which included complement, immunoglobulins and autoantibody profile, was normal. Her blood, stool, urine cultures and viral serology were all negative. An ultrasound scan of the abdomen showed splenomegaly. The skin biopsy showed no inflammatory changes and no evidence of vasculitis, but the lymph node biopsy showed classic features of necrotizing lymphadenitis with a peripheral irregular zone of necrosis containing fragments of nuclear debris. The infiltrate surrounding these areas consisted of histiocytes, lymphocytes and immunoblasts (Fig. 1Go). The muscle biopsy showed some non-specific changes only.



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FIG. 1. Trephine biopsy of bone showing replacement of normal haemopoietic tissue by an infiltrate of macrophages, with abundant cytoplasm. Many of the macrophages demonstrate active haemophagocytosis.

 
After her initial results she was commenced on i.v. immunoglobulin at 2 g/kg over 48 h and 5 weekly doses of methylprednisolone (20 mg/kg). There was an initial response with subsequent relapse. She was therefore commenced on methotrexate, and oral prednisolone at 1 mg/kg per day was continued. She made a gradual recovery, but over the subsequent weeks developed a transient arthropathy with effusions of knees, wrists and proximal interphalangeal joints, which settled. Thirteen months after diagnosis she presented to her local hospital with prolonged seizures. She was intubated and ventilated in the intensive care unit. Her haematology showed a haemoglobin of 11.8 g/dl, white cell count of 45.2x109 with neutrophils of 34.9x109, lymphocytes of 8.4x109 and platelet count of 887. The ESR was 15 and C-reactive protein >180. Her aspartate aminotransferase was 55 (normal 0–45), international normalized ratio (INR) 1.04 and fibrinogen 4.2. An MRI and magnetic resonance angiography scan were normal. Cerebrospinal fluid analysis was also normal. An electroencephalogram performed 8 days post-seizure showed non-specific, high-voltage, slow-wave activity with no epileptiform changes. Over the next few days she deteriorated with swinging fevers, cervical lymphadenopathy, a characteristic rash of systemic JIA and episodes of haematemesis. Her haemoglobin dropped from 11.8 g/dl on admission to 5.8 and she was given a transfusion. The white cell count was 4.1 with a platelet count of 89. Her liver function deteriorated and clotting indices were also deranged. A clinical diagnosis of haemophagocytic lymphohistiocytosis (HLH) was made. Bone marrow aspirate showed haemophagocytosis (Fig. 2Go). Ferritin was 41 500 (normal <200) and the triglycerides were raised at 4.09 (0.4–1.5). Methotrexate was stopped and cyclosporin commenced at 3 mg/kg per day along with low-dose steroids. She made a good recovery on the cyclosporin and is currently in remission with no systemic features or joint problems.



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FIG. 2. Lymph node biopsy, stained with haematoxylin and eosin, showing areas of necrosis with nuclear debris (x20).

 
Systemic-onset JIA is a heterogeneous entity with diverse clinical patterns, but characterized by spiking fevers, rash and arthritis. Frequently hepatosplenomegaly, lymphadenopathy and serositis are present. Generalized lymphadenopathy is found in 70–80% of cases [7, 8]. On account of the non-specific nature of the symptoms and lack of specific laboratory tests, diagnosis is usually made on clinical criteria. However, exclusion of malignancies of the lymphoreticular system is very important in establishing the diagnosis.

Although lymph node biopsy is performed whenever the presentation is atypical in these patients to exclude malignancy, there is very little in the literature about the histological appearances in systemic-onset JIA. In a few reports it is described as non-specific, usually with reactive hyperplasia, polymorphous cellular infiltration and no features of necrosis [7]. Lymph node histology in adult-onset Still's disease has been described in a few reports [10, 11]. A distinctive paracortical pattern of reactive lymph node hyperplasia was described in seven out of eight patients in one study in adult-onset Still's disease [10].

Kikuchi's disease or necrotizing lymphadenitis is considered to be a cause of benign lymph node enlargement. Clinically patients have fever, raised ESR, leucocytopenia and hepatomegaly, while some patients are asymptomatic [26]. Occasionally treatment with steroids is needed if lymphadenopathy is found to be persisting.

Review of the literature shows that only six patients (including ours) have been described so far with an association between Still's disease and Kikuchi's disease (see Table 1Go). An underlying diagnosis of systemic-onset JIA/adult-onset Still's disease was made in all cases on clinical criteria. Haemophagocytic syndrome has been recognized with Kikuchi's disease [12]. Reports have shown that defects in apoptotic cell death play a role in the pathogenesis of Kikuchi's disease [13]. Perforin and Fas pathways of cytotoxic T cells in both CD4 and CD8 cells have been implicated in the excess of apoptosis seen in Kikuchi's disease [14]. Recently, the familial form of HLH has been shown to be the result of mutations in the perforin gene leading to decreased expression of this protein [15, 16]. We believe that histological appearances suggestive of Kikuchi's disease when seen in children with a clinical diagnosis of ‘systemic JIA’ should then lead to these children being monitored closely as they are at a much higher risk of HLH. The pathological mechanisms underlying this are still unclear, but the primary event is likely to be a defect in the apoptotic mechanisms. A complete work-up is indicated in children with atypical features of systemic JIA, which must include lymph node biopsy. Further work needs to be done on a larger cohort of patients to determine the biopsy appearances in systemic JIA and the association between Kikuchi's disease and systemic-onset JIA.


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TABLE 1. Demographic details of patients with systemic-onset JIA/adult-onset Still's disease and Kikuchi's disease

 

Notes

Correspondence to: A. V. Ramanan, Flat 508, 77 Elm Street, Toronto, Ontario, M5G 1H4, Canada. E-mail: avramanan{at}hotmail.com Back

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Accepted 9 October 2002