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

Systemic Sclerosis

This rare heterogeneous condition is characterized by abnormal collagen deposition in skin and internal organs and by vasculopathy. Two main clinical subsets of SSc -- limited cutaneous and diffuse cutaneous forms -- are distinguishable by the extent of skin involvement, the autoantibody profile, the pattern of organ involvement, and the specific cutaneous manifestations of limited disease.[45] Both subsets are associated with vascular abnormalities clinically manifest as Raynaud's phenomenon. Many aspects of the complex interactions among autoimmune responses, vasculopathy, and fibrosis remain unresolved. The perceived failure of immunosuppressive treatments in the reversal of established fibrosis suggests that once initiated, the fibrotic process becomes independent of the immune drive and may continue autonomously.

Progressive diffuse SSc is associated with significant morbidity due to skin thickening and excess mortality (estimated to be 40% to 50% in 5 years) due to pulmonary, cardiac, and renal involvement.[6] In clinical trials performed to date, no therapy has been proven effective to prevent disease progression or reverse fibrosis. This can partly be attributed to (1) the heterogeneity of patients included, (2) the low incidence and prevalence of SSc, and (3) the lack of well-defined and validated criteria for disease activity, response, and remission. Skin thickening has been proposed as a surrogate measure of disease severity and has prognostic value, particularly in patients with diffuse cutaneous SSc.[46]

In view of the poor prognosis of SSc, the presumed autoimmune origin, and the lack of effective therapies, this disease was considered suitable for initial investigation of the tolerability and efficacy of autologous SCT.[47] Also, more so than with other autoimmune diseases, it was possible in SSc to identify poor-prognosis patients with much shortened expected survival based on established prognostic criteria. Most groups followed a core protocol based on conditioning with high-dose cyclophosphamide as cyclophosphamide-based therapies have been shown to improve skin thickening, stabilize pulmonary function, and increase survival in nonrandomized studies.[48] The results of treatment in the first 41 patients from the EMBT/EULAR registry, with a median follow-up of 12 months (range 3-55), showed a significant positive impact on skin score and a trend towards stabilization of lung function.[49] Although assessments were not standardized, an improvement of 25% or more in skin score was documented in 69% of the patients. In this cohort, cumulative 1-year survival was 73%, with 17% of mortality attributed to transplant-related causes and 10% to progressive disease.

In the largest single protocol study conducted in a number of US institutions, 19 patients were treated with total body irradiation (8 Gy in 4 fractions), cyclophosphamide (60 mg/kg x 2), and equine ATG (15 mg/kg x 6).[50] Peripheral-blood stem cells were collected with GCSF mobilization and were CD34 selected. Some minor disease reactivations were noted in 4 patients during the mobilizations. In the early phase of the trial, 2 died of pulmonary failure due to presumed regimen-induced pulmonary damage. With 11 subsequent patients, lung shielding was used to reduce the lung dosage to approximately 2 Gy, and no further severe pulmonary toxicity was seen. One patient died of Epstein-Barr virus-related lymphoma after receiving high doses of rabbit ATG (6 x 2.5 mg) as a substitute for horse ATG. One other patient died of disease progression.

Among the other patients, significant beneficial responses (P<.05) were observed as assessed by skin scores and HAQ scores. Among 12 patients with follow-up of more than 1 year, the median change in skin score was -13 (range -8 to -13; normal range 0-51). The HAQ score changed by a median of -1.675 (range 0 to -2.26). Pulmonary, renal, and cardiac functions were overall stable, although several patients had evidence of disease reactivation after treatment. These results suggest that intensive immunosuppression may reverse skin thickening, improve physical functions of debilitated patients, and arrest deterioration of organ functions.

The relatively high overall risks of these procedures have been partly attributed to patient selection and partly to compromised vital organ function in these patients. Risk factors for toxicity have not been fully determined due to the low numbers of patients treated and the confounding variables associated with treatment on many different protocols. High-dose cyto-toxic therapy may be poorly tolerated by some patients, including those with pulmonary hypertension, advanced pulmonary interstitial lung disease, and active cardiac disease.

It is anticipated that the risks of the intervention will diminish with judicious patient selection, current protocol modifications, and intensive monitoring during treatment. Since the analysis of the first cohort, the number of transplants reported to the European and American registries has increased to 72 patients at the time of this writing, and the transplant-related mortality has dropped to 12.3% at 1 year, or 7.7% with exclusion of patients who did not meet the consensus guidelines on patient selection. In the US collaborative group study, with accrual increased to 26 patients, the early treatment-related mortality has fallen from 25% in the initial cohort of 8 patients to 5.5% in the 18 subsequent patients who received total body irradiation with lung shielding. These recent data suggest that disease-specific problems using high-dose therapy have been identified and are now more effectively addressed. Furthermore, the beneficial effects on skin thickening and functional abilities suggest that this treatment will prove valuable if the treatment risks can be reduced to acceptable levels.


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