Elsevier

The Lancet

Volume 353, Issue 9152, 13 February 1999, Pages 550-553
The Lancet

Early Report
Autologous haemopoietic stem-cell transplantation in four patients with refractory juvenile chronic arthritis

https://doi.org/10.1016/S0140-6736(98)05399-9Get rights and content

Summary

Background

Autologous haemopoietic stem-cell transplantation (AHSCT) had been described as a possible treatment for severe autoimmune disease refractory to conventional treatment. We report the first four children with severe forms of juvenile chronic arthritis (JCA) treated with AHSCT.

Methods

We studied three children with systemic JCA and one child with polyarticular JCA. Unprimed bone marrow was taken 1 month before AHSCT. T-cell depletion of the graft was done with CD2 and CD3 antibodies. We used a preparative regimen of antithymocyte globulin (20 mg/kg), cyclophosphamide (200 mg/kg) and low-dose total body irradiation (4 Gy). Methotrexate and cyclosporin were stopped before AHCST, prednisone was tapered after 2 months.

Findings

Our patients showed a drug-free follow-up of 6–18 months with a marked decrease in joint swelling, pain, and morning stiffness. Erythocyte sedimentation rate, C-reactive protein, and haemoglobin returned to almost normal values within 6 weeks. Despite T-cell depletion there was a rapid immune reconstitution in three out of four children. Two patients developed a limited varicella zoster virus eruption, which was treated by aciclovir.

Interpretation

AHSCT for severe JCA was well tolerated and induced a remission of disease in four children with JCA that was resistant to conventional treatment. Prolonged prednisone-free growth catch-up and general well-being is a major therapeutic gain in such children. The actual follow-up is too short, however, for us to conclude that these children are completely cured of their disease.

Introduction

Autologous haemopoietic stem-cell transplantation (AHSCT) has been described as a possible treatment for patients with severe autoimmune disease such as systemic sclerosis, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus refractory to conventional treatment.1, 2, 3, 4, 5, 6 A consensus report on inclusion criteria, conditioning regimen, and manipulation of the graft for AHSCT in adults was jointly written by the European League Against Rheumatism and the European Group for Blood and Marrow Transplantation (EULAR/EBMT).4, 7 Although the overall prognosis for most children with chronic arthritis is good, in a small proportion of children with systemic or polyarticular juvenile chronic arthritis (JCA), the disease is refractory to combinations of non-steroidal anti-inflammatory drugs (NSAIDs) and immunosuppressive drugs such as methotrexate, cyclosporin, cyclophosphamide, and prednisone. Many of these children have severe joint destruction and adverse effects from long-term treatment with second-line antirheumatic drugs. These children may potentially benefit from therapy that suppresses the autoreactive T-cellular immunity and gives a normal immune competence de novo by the infusion of naïve T-cell precursors. We report 6–18 months' follow-up in the first four children with longstanding and severe JCA treated with AHSCT.

Section snippets

Patients

The first patient, a girl aged 6 years, had had severe systemic JCA since the age of 1 year. She presented with periods of spiking fever, a fine pink rash, hepatosplenomegaly, and a polyarthritis affecting wrists, metacarpophalangeal joints, elbows, knees, and ankles. On presentation, the haemoglobin concentration level was 5·3 mmol/L (8·5 g/dL), the platelet count was 470·109/L, and erythrocyte sedimentation rate (ESR) was persistently high (range 35–100 mm/h). Rheumatoid factor and

Results

NSAIDs were continued, methotrexate and cyclosporin were stopped before AHSCT, and prednisone was tapered and stopped two months after AHSCT. Neurophil recovery (>0·5·109/L) occurred 20–30 days after AHSCT and the platelet count reached 20·109/L after 15–28 (table 1). 2–5 months after AHSCT the numbers of circulating T cells were normal with normal in-vitro mitogenic responses at 3–5 months after AHSCT.

The evolution of the disease was followed by the factors described by Giannini and colleagues,

Discussion

The conditioning was well tolerated in all four patients and there was a substantial resolution of signs and symptoms of active disease after AHSCT. The rapid initial response may have been due to high-dose cyclophosphamide, but the duration of the remission suggests to us that it is a specific effect of the AHSCT. The delayed recovery of blood-cell numbers after HSCT, may be caused by the effect of an intensive pretreatment on a subnormal haematopoiesis, by the manipulation of the graft, or

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