Department of Paediatric Immunology, University Hospital for Children, `Het Wilhelmina Kinderziekenhuis', PO Box 85090, 3508 AB Utrecht, The Netherlands
Correspondence to:
N. Wulffraat.
Abstract
Objective. In adults, autologous stem cell transplantation (ASCT) has been described recently as a possible treatment for severe autoimmune disease refractory to conventional treatment. We report here the four first children with severe forms of juvenile chronic arthritis (JCA) treated with ASCT.
Methods. We studied three children with systemic JCA and one child with polyarticular JCA. Unprimed bone marrow was harvested 1 month prior to ASCT. T-cell depletion of the graft was performed with CD2 and CD3 antibodies. We used a preparative regimen of antithymocyte globulin (ATG; 20 mg/kg), cyclophosphamide (Cy; 200 mg/kg) and low-dose total body irradiation (TBI; 4 Gy). Methotrexate (MTX) and cyclosporin A (CsA) were stopped before ASCT; prednisone was tapered after 2 months.
Results. After ASCT, our patients showed an anti-inflammatory-drug-free follow-up of 618 months with a marked decrease in joint swelling, pain and morning stiffness. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and haemoglobin (Hb) returned to near-normal values within 6 weeks. Despite T-cell depletion, there was a very rapid immune reconstitution. Two patients developed a limited varicella zoster virus (VZV) eruption which was treated by acyclovir.
KEY WORDS: Juvenile chronic arthritis, Refractory, Treatment, Autologous stem cell transplantation
Juvenile chronic arthritis (JCA) is the most common autoimmune disease of childhood. Although the overall prognosis for most children with chronic arthritis is good, 510% of children with the systemic and polyarticular onset form are refractory to conventional therapy, consisting of combinations of non-steroidal anti-inflammatory drugs (NSAIDs) and immunosuppressive drugs such as methotrexate (MTX) and corticosteroids [1, 2]. These patients ultimately develop severe joint damage and loss of joint function, while the chronic use of immunosuppressive drugs leads to adverse drug effects. To prevent severe joint damage and loss of joint function, new treatment strategies have been developed [3]. Recently, we started a programme for the treatment of refractory JCA with autologous haemopoietic stem cell transplantation (ASCT). We report here the 618 months follow-up in the first four children with long-standing, severe JCA and polyarticular JCA treated with ASCT.
Methods
Patients: inclusion criteria
Children with systemic chronic arthritis and polyarticular chronic arthritis refractory to combinations of NSAIDs and immunosuppressive drugs such as MTX (high dose i.m.), cyclosporin (CsA) and corticosteroids, and with a disease course longer than 1 yr, were included in this study.
Bone marrow harvesting and T-cell depletion
Haemopoietic stem cells were obtained by conventional bone marrow aspiration under general anaesthesia without priming. The graft was purged by two cycles of T-cell depletion with CD2 and CD3 antibodies [4]. Finally, a suspension of 0.56.5x106 CD34-positive cells/kg and <0.5x105 CD3 cells/kg was stored in liquid nitrogen.
Conditioning
The conditioning regimen prior to ASCT included 4 days of antithymocyte globulin (ATG; IMTIX, Pasteur Mérieux, France) in a dosage of 5 mg/kg daily from day -9 to -6, cyclophosphamide (Cy) in a dose of 50 mg/kg daily from day -5 to -2, and low-dose (4 Gy) single-fraction total body irradiation (TBI) on day -1.
Results
The clinical characteristics of the four patients are depicted in Table 1. They were characterized by a refractory chronic arthritis with the occurrence of erosions and growth disturbances of the joints. The duration of disease was >5 yr in all. Laboratory investigations showed increased erythrocyte sedimentation rate (ESR) and a moderate to severe anaemia in all patients.
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The recovery of the bone marrow took 2030 days for neutrophils (>0.5x109 /l) and 1635 days for the platelets (>20x109 /l). The number of T cells and in vitro mitogen responses normalized within 36 months.
Within 2 weeks of ASCT, all patients showed a marked improvement, as measured by a decrease in joint swelling, pain and morning stiffness. ESR, C-reactive protein (CRP) and haemoglobin (Hb) normalized within 8 weeks. As measured by child health assessment questionnaires (CHAQ), EPM-ROM and juvenile arthritis functional scores (JAFAS), there is a marked improvement in the functional activities of all children (Table 2). Because of the longer follow-up in the first two patients, a favourable effect of ASCT on growth could already be seen in patients 1 and 2 (Fig. 1
). In general, the ASCT was well tolerated and there were few complications (Table 3
).
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Discussion
The effect of ASCT on signs and symptoms of chronic joint inflammation in four severely affected patients was very favourable. The initial improvement could be explained by the immune suppression of the conditioning regimen, but the duration of the remission, even after recovery of the T cells and T-cell function, is indicative of an immune modulatory effect of ASCT. However, the follow-up period is too short for definite conclusions. An interesting phenomenon is the occurrence of a benign, oligoarticular synovitis in two of the four patients. This occurred simultaneous with T-cell recovery. The self-limiting character of the synovitis favours the concept of a beneficial immunomodulatory effect post-ASCT. Note that patients 1 and 2 are in complete remission for >12 months in the presence of a fully reconstituted immune system. Whether T-cell depletion of the graft is necessary to sustain remission is not known. Early recurrences of systemic lupus erythematosus by using unmanipulated grafts suggest that T-cell depletion may be essential [5]. The use of TBI in our conditioning regimen is questionable. TBI is very effective in an animal model of arthritis [6, 7], so we included a low-dose TBI in our protocol. By using a low dose, we avoid the negative effects of TBI on growth and maturation [8, 9], although it is not known whether low-dose TBI increases the risk for secondary malignancies [10]. Careful evaluation of these patients is necessary to balance the risk of ASCT against conventional therapy with regard to outcome measurements and toxic side-effects of treatment. In this respect, ASCT still has to be regarded as an experimental therapy for children with severe refractory JCA and other autoimmune diseases. Recent experience in Europe indicates that ASCT for severe autoimmune disease carries a mortality risk of 10%. Therefore, we need consensus on inclusion criteria, conditioning regimen and graft handling. However, the short-term results of ASCT in our four patients are very promising and although the follow-up period is too short, the first impression is that ASCT could be an important weapon in the battle against refractory JCA.
References