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High dose cyclophosphamide followed by autologous stem cell transplantation for the treatment of intractable rheumatoid arthritis (RA): a 2-year clinical and immunological follow-up
Arthritis Research & Therapy volume 4, Article number: 103 (2002)
To investigate the effects of high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) both clinically and on the synovial infiltrate for selected patients with severe, refractory RA.
12 patients with rheumatoid arthritis, were treated. Mobilization of autologous blood stem cells was accomplished with cyclophosphamide (4 g/m2) and G-CSF. The conditioning regimen consisted of intravenous administration of high dose cyclophosphamide (totalling 200 mg/kg), with subsequent reinfusion of the positively selected graft. Biopsies of synovial tissue from a knee were obtained before and three months after HDC and ASCT. Immunological monitoring and immunohistochemistry on the synovial infiltrate was performed.
The procedure appeared feasible in all patients. The aplastic period lasted less than 4 weeks in all patients. Efficacy data, with follow-up ranging from 6–24 months showed that the mean disease activity score (DAS) decreased from 5.4 (n = 12) to 3.2 at 6 months (n = 12, P = 0.003), 3.1 at 12 months (n = 11, P = 0.005) and 2.9 at 24 months (n = 5, P = 0.043). Mean DMARD-free period was 12.9 months (95% CI: 7.23–18.48). Patients could be classified in clinical responders (Good response (Eular); ACR >50%, n = 6) and non-responders (Moderate or no response; ACR ≤20%, n = 6) at three months post-transplantation. Immunophenotyping of PBMCs showed prolonged (>24 months) depletion of CD45RA+ T cells after transplantation, whereas levels of CD8+, CD3-CD16CD56+ and CD19+ cells quickly recovered. CD4+CD45RO+ cells were not complety depleted after transplantation. High IgG1 in peripheral blood (responders: 9.69 g/l; non-responders 6.24 g/l P = 0.046) and high baseline synovial CD27 (mean infitration score; 3 vs. 0.33; P = 0.036) and CD45RO (mean infiltration score; 3.4 vs. 0.67; P = 0.036) predicted clinical response. Furthermore there were trends towards a decrease in T-cell markers in the synovium before and after transplantation were compared (CD3-CD4-CD25-CD45RA-RO and CD27), but no statistical significant differences were found. IL-1 showed significant higher scores in non-responders than responders after transplantation: 3.5 vs. 0.6 (P = 0.024).
The results of the present interim-analysis underscore the feasibility and potential efficacy of HDC followed by ASCT for the treatment of intractable RA. Clinical effect of HDC and ASCT correlated with T-cell debulking in synovial tissue.
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Verburg, R., Sont, J., Kruize, A. et al. High dose cyclophosphamide followed by autologous stem cell transplantation for the treatment of intractable rheumatoid arthritis (RA): a 2-year clinical and immunological follow-up. Arthritis Res Ther 4, 103 (2002) doi:10.1186/ar438
- Rheumatoid Arthritis
- Synovial Tissue
- Autologous Stem Cell Transplantation
- High Dose Chemotherapy
- Conditioning Regimen