Patients

In the Netherlands, we conducted a pilot study in 1997 and 1998, that was reported earlier.¹⁰ Since then 31 patients with a follow-up of 8–60 months (median 33 months) were transplanted in eight different European pediatric centers. A total of 41 cases were identified in the registry of the European Blood and Marrow Transplantation Group (EBMT). Of these, 31 were reported in detail that enabled evaluation of follow-up and these were included in this review.

The inclusion criteria were failure to respond to high-dose MTX i.m. or s.c. (1 mg/kg/week), failure to respond to at least two DMARDs, steroid dependency, unacceptable toxicity to Disease modifying anti-pneumatic drugs (DMARDs') or steroids. Exclusion criteria were cardiorespiratory insufficiency, chronic active infection such as Epstein-Barr Virus (EBV), Cytomegalovirus (CMV) toxoplasmosis, spiking fever despite steroids, end-stage disease or poor compliance. We studied 25 children with systemic JIA (sJIA) and six with polyarticular JIA (polyJIA), all with progressive disease activity for more than 5 years despite the use of NSAIDS, prednisone (both maintenance dose and pulses), cyclophosphamide pulses (750 mg/m²), MTX up to 1 mg/kg/week i.m. or s.c. and CsA (2.5 mg/kg/day). The clinical characteristics in all children were a polyarticular course, the majority with erosions and osteoporosis, stunted growth and in those with systemic onset JIA (sJIA), periods of spiking fever and exanthema. Most of them suffered from steroid-related side effects. The mean time interval between diagnosis and transplant was 6 years (range 13–137 months). The clinical follow-up of these children ranges from 8 to 60 months (median 31 months).

Outcome measures

We used the core set of outcome variables for clinical trials in childhood arthritis.^{11,12,13,14,15} This includes a physician's global assessment of disease activity, the child health assessment questionnaire, (CHAQ) (a parent/patient assessment of overall well-being, the functional ability and disease severity), the number of joints with active arthritis, the number of joints with limited range of motion and the sedimentation route (ESR). Giannini¹¹ proposed a 30% improvement from baseline of three out of six variables, with no more than one of the remaining variables worsening more than 30%. The evolution of the disease was followed at three monthly intervals.

Bone marrow harvest and T-cell depletion

Unprimed bone marrow was harvested in 23 cases and peripheral stem cells in eight after mobilizing with cyclophosphamide (2 g/m²) and granulocyte-colony-stimulating factor (G-CSF). The graft was T-cell depleted with two cycles of purging with CD2 and CD3 antibodies, or using positive stem cell selection using CD34 selection devices. These techniques yielded a final suspension with a CD34 positive stem cell count of at least 0.5 10⁶ cells/kg and 1 to 5 10⁵ CD3 cells/kg.¹⁶

Conditioning for ASCT

The conditioning regimen included 4 days of anti-thymocyte globulin (ATG, Sangstat; 5 mg/kg from day -9 to -6), cyclophosphamide (50 mg/kg/day from day -5 to -2) and low-dose total body irradiation (TBI, 4 G, single fraction) on day -1. A total of 10 children did not receive TBI as a part of their conditioning. On day 0, the frozen stem cell suspension was thawed and infused. Anti-TNF therapy, MTX and CsA were stopped before ASCT, prednisone was tapered after 2 months.

Results

Neutrophil recovery (>0.5 10⁹/l) occurred at day +12 to +30 and the platelet count reached 20 10⁹/l at 16–35 days post ASCT. At 5–9 months after ASCT the numbers of circulating T cells were normal with normal in vitro mitogenic responses at 6–18 months after ASCT. In all, 17 patients showed a drug-free follow-up of 8–60 months with a marked decrease in the scores of the CHAQ, the physician's global assessment and joint swelling (Figures 1 and 2). The measurement of the limitation of motion (EPM-ROM) largely reflects permanent erosive destruction to the joints and, as expected is not subject to change after ASCT. Sedimentation rate (ESR), CRP and hemoglobin returned to near normal values within 6 weeks. In two of these patients the ESR increased again after 3 months, with mild and transient synovitis of the hip and knee, following Variella Zoster Virus reactivation (VZV) and tonsillitis. A relapse was noted in seven children 18 months after ASCT. These relapse have so far been mild, with oligoarthritis and sporadic fever, that could be controlled easily with a 3-month course of low-dose prednisone and NSAID. These patients nevertheless showed a 30% improvement of their disease, using the Giannini criteria for improvement of disease. Four children were resistant to ASCT and showed a persistent recurrence of the disease that was as severe as before.

Figure 1.

The mean parent/patient assessment of overall well-being (CHAQ) before and after ASCT. The CHAQ contains three domains: pain (upper panel), severity (middle panel) and disability (lower panel). The score ranges between 0 and 3. Only patients with a follow-up of at least 12 months are given.

Full figure and legend (30K)

Figure 2.

Number of joints with active arthritis before and after ASCT. The Fuchs Swelling Index (FSI) refers to 18 joints, with a cumulative score of 0–3 for each joint (scores ranging 0–54). Only patients with a follow-up of at least 12 months are given. The children that did not receive TBI as part of their condition (solid triangles) show the same response to treatment.

Full figure and legend (16K)

During the 36 months of follow-up, the first patient showed a catch-up growth of 22 cm (and a corresponding increase in shoe size), in contrast to the minimal gain of only 2 cm in the three preceding years. The second patient also showed a rapid drug-free remission of the disease that persisted at 30 months follow-up. She is on a physical therapy program to improve muscle strength after years of immobilization and prednisone-induced obesity. Since ASCT she has grown 18 cm in 30 months. For each age a mean length and standard deviations have been described. A given length can thus be expressed as a Standard Deviation Score (SDS) of height for age. Prior to the onset of their disease the children in this study had a height between -0.2 and +2 s.d. of the mean height for their age. During the course of their disease these children lost 3–5 SDS. After ASCT, most younger children show a catch-up growth of 1–2 SDS, but the older children in our study, with the longest disease duration did not show catch-up growth.

Infectious complications

All children developed chills, fever and malaise during infusion of ATG. During the aplastic period, blood cultures were positive for S. epidermidis in two children. They responded favorably to i.v. antibiotics. Seven patients developed a limited varicella Zoster virus (VZV) eruption, 3–18 months after ASCT, which was treated by aciclovir. In addition, one case of localized atypical mycobacterial infection and one case of Legionella pneumoniae were seen, that resolved completely. Two patients died of a macrophage activation syndrome (MAS) (also known as infection associated hemophagocytic syndrome, IAHS). The first case was induced by an Epstein–Barr virus (EBV) 4 months after ASCT. At the time of the EBV infection, her JIA was in remission. The other fatal MAS case occurred 18 days post-transplant, while he was still in complete aplasia.¹⁷ The occurrence of MAS in sJIA after ASCT may be caused by the T-cell depletion resulting in inadequate control of macrophage activation. A third case fatality resembling IAHS, or MAS, shortly after auto-SCT was reported in Paris and was caused by a disseminated toxoplasmosis infection.¹⁸

Discussion

In our study, ASCT induced a remission of disease in all children with severe and drug-resistant JIA. Prolonged prednisone-free catch-up growth and general well-being is a major therapeutic gain in such children. Since this approach was introduced only 4 years ago, the current experience includes only case reports of selected patients. At the 28th annual EBMT meeting, early 2002, we summarized the European experience, including a total of 32 cases, performed by nine centers. Overall, in about 50%, complete remission was observed even after prolonged withdrawal of antirheumatic drugs. This was also the case in the 10 children that did not receive low-dose TBI as part of their conditioning. Given the obvious concerns over the use of TBI and since TBI did not induce higher response rates, it will probably be eliminated from future conditioning regimens.

Initially, we did not perform bone marrow harvests or peripheral blood stem cell mobilizations because G-CSF has been associated with reactivation of RA and development of leucocytoclastic vasculitis, but peripheral stem cell mobilization using cyclophosphamide and G-CSF in six patients in other centers was performed without any complication. At present, it is not clear whether T-cell depletion of the marrow is crucial to the process of the transplant, or that an intense but nonmyeloablative regimen without stem cell support would be just as effective.

The observation of MAS after ASCT is a very serious problem and illustrates that this procedure in such children carries a mortality risk between 5 and 12%.¹⁹ The occurrence of MAS in sJIA after ASCT may be caused by a profound T-cell depletion (leaving no regulatory T cells) in the graft which may result in activation of macrophages, leading to hemophagocytosis.²⁰ It is advised that patients with active disease (fever), that cannot be controlled by steroids, are excluded from the study. The immune suppression after ASCT must be tapered more slowly. In case of unexplained fever >39°C for 48 h, MAS must be considered and treatment with methylprednisolone 20 mg/kg/day (in four divided dosages) and cyclosporin 2 mg/kg/day should be started immediately.

This treatment-related mortality illustrates that the selection of patients with this nonlethal disorder must be restricted to those with severe, refractory disease before the stage of severe permanent joint destruction. With the recent availability of soluble TNF receptor (etanercept) and anti-TNF receptor antibodies (infliximab), we added failure to respond to anti-TNF treatment as an additional inclusion criterion for future cases.

In conclusion, ASCT in this severely ill patient group induces a very significant and drug-free remission of the disease in the majority of patients but carries a significant treatment-related mortality which will probably decrease with continued experience.

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Acknowledgements

Patient data were obtained from nine pediatric university centers in Europe. The clinical studies in the Netherlands were supported in part by a grant from the Dutch League against Rheumatism. LW was supported by a grant from SPARKS (Sport Aiding Medical Research for Kids).