Department of Paediatric Immunology, University Hospital for Children `Het WKZ', Utrecht, The Netherlands and
1 Department of Paediatrics, British Columbia Children's Hospital, Vancouver, Canada
Correspondence to:
N. M. Wulffraat, Department of Paediatric Immunology, University Hospital for Children, `HET Wilhelmina Kinderziekenhuis', Utrecht, The Netherlands.
Juvenile chronic arthritis (JCA), the most frequent autoimmune disease of childhood, is not a benign disease. Functional disability occurs in 2030% of patients with JCA and 510% develop a serious handicap [1]. Children with a polyarticular and systemic-onset form are especially at risk. To improve the outcome of these patients is a challenge for paediatric rheumatologists.
To improve disease outcome, immunosuppressive drugs like methotrexate [2], cyclosporin [3] and azathioprine [4] have been introduced in the treatment of JCA. Although these drugs have been proven to be effective in a substantial number of the JCA patients, the disease lingers on and results in more or less serious functional handicaps.
Treatment strategies resembling those used as an induction regimen for haematological malignancies are now being introduced. An example is the treatment regimen built up from methothrexate, pulses of methylprednisolone and cyclophosphamide [5]. The toxicity of this treatment regimen is high and effectiveness has not been proven. Case reports of adult patients with autoimmune diseases treated with autologous or allogeneic stem cell transplantation for a secondary haematological malignancy or bone marrow aplasia showed that patients may be cured of their original `autoimmune' disease [6]. This success motivated rheumatologists and haematologists to use autologous stem cell transplantation (ASCT) for the treatment of autoimmune diseases and there is a rapid expanding experience with ASCT [6]. The advantage of ASCT is that the conditioning treatment leads to radical eradication of mature T cells, while the stem cells are rescued by collecting them in advance. Theoretically, another advantage is that naive T cells should be re-educated after ASCT, resulting in peripheral tolerance. In this way, ASCT should not only be regarded as a heavy immunosuppressive (myeloablative) treatment, but should also induce protective `anti-inflammatory' responses. The experience in the first transplanted children with JCA is in line with this `theoretical concept' [7].
Of course, many questions have to be dealt with. Is ASCT the treatment of choice? After ASCT, the immunogenetic genotype does not change. However, the alternative, allogeneic stem cell transplantation, is not acceptable because of the higher mortality risk in a non-lethal disease. What is the best conditioning regimen? A hot topic is the use of total body irradiation (TBI). In experimental animal models, TBI is necessary to sustain remission [8]. On the other hand, TBI is rather toxic with a risk for infertility, growth retardation and cancer [9]. Another issue is the handling of the graft. Should we deplete for T cells and which method do we use for depletion [10]? Last, but not least, is the question whether we should use bone marrow as a source of stem cells or pure blood. The latter method certainly has advantages. Collection is much easier and in general more stem cells can be harvested. However, the patient should be pre-treated with G-CSF, which in theory could worsen the disease and, especially in the systemic-onset form, the risk of inducing macrophage-activating syndrome.
In this issue of Rheumatology, many experts are invited to give their opinion on the above-mentioned questions. Of course, we cannot solve all the answers at this stage, but the experience in experimental models and of the use of bone marrow (stem cell) transplantation in haematological malignancies can direct our way.
In this issue, the first results are presented after ASCT of four children with JCA [7], one child with systemic scleroderma [11] and patients with systemic lupus erythematosus [12]. Although the follow-up period is rather short, the first results are promising. Of course, long-term follow-up is necessary to determine the real place of ASCT in the treatment of these autoimmune diseases.
In May, during the `First workshop on the use of autologous stem cell transplantation in rheumatic diseases of childhood', we reached consensus about inclusion criteria for JCA, the conditioning regimen and graft handling, which is published in this issue [13]. It is important that we restrict ourselves to a very limited number of protocols, so we can really compare and evaluate the results. The articles in this issue are the result of a workshop where many paediatric rheumatologists and haematologists have discussed the major topics of ASCT.
In the near future, consensus has to be reached on other autoimmune diseases of childhood, e.g. scleroderma and systemic lupus erythematosus.
References