Intense Immunosuppression and Stem-Cell Transplantation for Patients With Severe Rheumatic Autoimmune Disease: A Review

Jacob M. van Laar, MD, Alan Tyndall, MD


Cancer Control. 2003;10(1) 

In This Article

Rheumatoid Arthritis

The most common systemic autoimmune disease is RA, affecting 1% of the population. A minority of patients have severe disease and fail to be controlled by conventional treatments. In the short term, uncontrolled RA results in pain and stiffness, but long-term consequences are irreversible joint destruction, disability, reduced quality of life, and a shortened life expectancy. Following early case reports on patients with refractory RA who were successfully treated with cyclophosphamide 200 mg/kg and an unmanipulated stem-cell graft or with busulfan/cyclophosphamide and a T-cell-depleted autologous graft, several pilot studies were initiated to assess feasibility, toxicity, and efficacy in small groups of patients.[30,31,32,33,34,35] In a multicenter study in the Netherlands on 14 patients, significant improvement in disease activity was recorded at more than half of the visits within the first year of follow-up in 8 of 12 patients who completed all treatment steps.[36] The 4 nonresponders did not differ from responders with respect to disease or patient-related variables such as age, disease activity and duration, previous therapy, presence of rheumatoid factor, and HLA haplotype, although the numbers of patients may have been too low to detect such predictive factors. With longer follow-up, all patients relapsed, requiring reinstitution of disease-modifying anti-rheumatic drugs within 24 months after transplant.[37] Interestingly, serial immunohistochemical studies on synovial tissue biopsies in these patients demonstrated that the clinical effect of SCT correlates with T-cell debulking in synovial tissue. Relapses of disease activity in this and another study were preceded by the re-emergence of T cells in the synovium.[38,39]

These results corroborate experimental animal studies showing the importance of in vivo T-cell depletion. They also may explain in part why a recently completed randomized trial of 31 patients comparing T-cell depleted vs unmanipulated SCT after high-dose chemotherapy (cyclophosphamide 200 mg/kg) without additional in vivo T-cell depleting agents (eg, antithymocyte globulin [ATG]) failed to demonstrate major differences with respect to number and duration remissions between the two groups.[40] One case report of a patient with refractory, active RA treated with cyclophosphamide (200 mg/kg), ATG (90 mg/kg), and CD34+ enriched SCT from his unaffected identical twin brother deserves mentioning: 4 years following transplantation, the patient remains free of disease symptoms without anti-rheumatic medication[41] (Ian Wicks, MD, personal communication, 2001).

A recent retrospective analysis of registry data included 76 patients (including the aforementioned cohorts) from 15 centers and several single and multi-center transplant protocols.[42] The eligibility criteria and treatment schedules varied among individual protocols. Of the 76 patients, 73 had received autologous HSCT and 3 were mobilized but had not undergone transplantation (1 due to good response, 1 due to coincident pulmonary embolism, and 1 due to transplant refusal). The median age of the transplanted patients was 42 years, 74% were women, and 86% were rheumatoid factor positive. They had been previously treated with an average of 5 (range 2-9) disease-modifying anti-rheumatic drugs. Anti-TNF blocking agents, which are now considered the most effective anti-rheumatic therapy, failed in 4 patients. Significant functional impairment was present at baseline, with a median Health Assessment Questionnaire (HAQ) score of 1.4 (range 1.1-2.0; normal range 0-3). Sixty-seven out of 68 patients were reported as having destructive arthritis. The conditioning regimen was cyclophosphamide alone in the majority of patients, mostly 200 mg/kg (n = 62). Seven patients additionally received ATG, 2 received busulfan, and 1 underwent total body irradiation and ATG. One patient received fludarabine with ATG. Following treatment, 1 patient received bone marrow, but the rest received chemotherapy and/or granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral-blood stem cells. The graft was unmanipulated in 28 patients, and the remaining received some form of lymphocyte depletion, mostly through CD34 selection. Median follow-up was 16 months (range 3-55). Forty-nine patients (67%) fulfilled the American College of Rheumatology criteria for 50% improvement at some point following transplant. The level of disability, as measured by the HAQ, was significantly reduced (P ≥.005). In most patients, disease-modifying anti-rheumatic drugs were reinstituted within 6 months for persistent or recurrent disease activity, resulting in improved disease control in half of the patients. The only factor that was significantly related to response was the presence of rheumatoid factor with significantly better responses in seronegative RA patients (P=.02). Disease duration, previous therapies, HLA-haplotype, or T-cell depletion of the graft did not correlate with response to treatment. Five months after transplant, 1 patient who had been treated with myeloablative conditioning (busulfan and cyclophosphamide) and a highly purified autograft died of infection and an incidental non-small lung cancer, corresponding to a treatment-related mortality of 1.4%.

Of note, most of the patients were treated before the introduction of TNF blocking treatments in rheumatologic practice, with only 4 of the 73 patients having received anti-TNF agents before treatment. These drugs have shown major therapeutic benefits in refractory RA with relatively low toxicity. The success of this therapy has led to the development of other so-called biological agents targeted at cytokines and cytokine-receptors (eg, interleukin-1 receptor antagonists). The effectiveness of these therapies reduces the number of patients with severe, resistant disease in whom immunoablation and autologous SCT could be considered.


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