Rationale for high-dose cyclophosphamide and medium-dose total body irradiation in the conditioning of children with progressive systemic and polyarticular juvenile chronic arthritis before autologous stem cell transplantation.

Abstract

Despite the fact that the aetiology of juvenile chronic arthritis (JCA) is unknown, there is ample indirect evidence of a pivotal role of T cells in the onset and probably also in the maintenance of this autoimmune disease. Notwithstanding adequate firstand second-line anti-rheumatic therapy, systemic-onset JCA and polyarticular JCA will lead to destructive arthritis, growth retardation and severe invalidity in 10–25% of the cases. In order to halt the disease progression in the latter group of JCA patients, a clinical trial was started in F. 1. Autologous T-cell-depleted BMT of JCA patients. order to study the effect of severe immune suppression followed by ‘unbiased’ immune recovery on the course of the disease. Based on animal studies, showing the immunity severely, but is supposed not to be myeloregression of adjuvant-induced arthritis by bone marrow ablative. The short-term effect may be the occurrence transplantation (BMT), both allogeneic and T-cellof viral infections or reactivations, especially with herpes depleted autologous BMT [1, 2], a study protocol for viruses. The possible long-term side-effects may be a autologous stem cell transplantation in children with slightly increased risk for premature cataract formation severe progressive systemic and polyarticular JCA was and some effect on spermatogenesis in boys. Our experidrafted. ence so far with this pre-treatment in eight children, There are two conditions which have to be fulfilled in who received an allogeneic BMT for severe aplastic order for autologous stem cell transplantation to posanaemia, four of whom were prepubertal at BMT and sibly be effective in the treatment of JCA, i.e. first, the reached final height at evaluation [3], is as follows: no conditioning has to wipe out the (dysfunctioning) adverse effect has been observed on physical growth, all immunological memory and, second, the re-infused graft recipients had a normal pubertal development, but haematopoietic stem cell suspension has to be purged the boys had a somewhat decreased testicular volume, of mature ‘memory’ T cells. In order to achieve these indicating germ cell damage. Both the boys and the girls goals, the following procedure has been proposed: a showed normal function of the gonads and thyroid pre-treatment regimen comparable to the one in use for gland by endocrinological testing on follow-up. It is still allogeneic BMT of transfusion-sensitized patients with too early to assess fathering/mothering possibilities in severe aplastic anaemia (frequently also an autoimmune this group of ex-BMT recipients. A slight increase in disease), followed by the re-infusion of a T-cell-depleted secondary malignancies has to be expected, as was also (TCD) autologous BMT, i.e. containing ∏104 T cells/kg seen after immunosuppression or allogeneic BMT for body weight of the recipient (see the scheme in Fig. 1). severe aplastic anaemia [4]. Although the use of radiSuch a conditioning suppresses host memory T-cell ation, mostly limited-field irradiation such as total lymphoid irradiation or thoracoabdominal irradiation, was found in that retrospective study to be a strong risk Accepted 15 March 1999.