Original Title: Autolog hematopoietisk stamcelletransplantasjon (AHSCT) ved diffus systemisk sklerose

Authors' objectives: To perform a systematic review of efficacy and safety, an economic evaluation and ethical evaluation related to AHSCT for systemic sclerosis.

Authors' results and conclusions: We included a total of five studies, three randomized controlled studies; the ASTIS- (n = 156), SCOT- (n = 75) and ASSIST-studies (n = 19), one small non-randomized controlled study (n = 16), and one large European multicenter registry study, EBMT (n = 175). Based on the results from the ASTIS and the registry study, we estimated transplant-related mortality to be between 7 and 10%. In the ASTIS study, with a median follow-up of 5.8 years, mortality was highest during the first three to six months in the AHSCT group, for then to gradually level off. From two years of follow-up and beyond, mortality (hazard ratio = 0.29 [0.13 to 0.65]) and the sum of mortality and organ failure (hazard ratio = 0.35 [0.13 to 0.74]), was lower in the AHSCT group than in the control group. A meta-analysis of total mortality in the ASTIS- and SCOT studies gave a risk ratio of 0.61 (0.40 to 0.93) in favor of the AHSCT group after approximately five years. The three randomized controlled studies reported that side effects and adverse events, as well as viral infections, occurred more frequently in the AHSCT group than in the control group, RR = 1.4 [1.04 to 1.87] and RR = 11.74 (3.76 to 36.70), respectively, measured after two and six years. We have low confidence in the results of transplant-related mortality, and moderate confidence for total mortality and organ failure, adverse events and virus infections. Skin involvement measured by the modified Rodnan skin score (mRSS) and forced vital capacity (FVC) improved after AHSCT, estimated as a large (SMD = -0.99, [-1, 33 to -0.66]) and a medium effect (SMD = 0.51 [0.19 to 0.83]) by standardized mean difference (SMD). Total lung capacity (TLC) (SMD = 0.40 [0.09 to 0.72]) and physical health-related quality of life (SF-36: SMD = 0.44 [0.12 to 0.76]) was also significantly better. No differences were found between the AHSCT and the control group in left ventricular echocardiography (MD = -0.30 [-4.77 to 4.17]) and in the lung function measurement diffusion capacity for carbon monoxide, DLCO, (SMD = -0, 04 [-0.35 to 0.28]). We have moderate confidence in the quality of evidence for skin involvement (mRSS), DLCO, and physical health (SF-36) and low confidence in the quality of evidence for the other outcomes (FVC, TLC and mental health SF-36). The total cost of treatment with AHSCT in a one year perspective is approximately 600,000 kroner per patient. Conclusion: Our conclusion is that transplant-related mortality after AHSCT is high, but risk of organ failure and death, for whatever reason, is nevertheless lower after two years follow-up and beyond compared to standard treatment. AHSCT provides a significant improvement of skin involvement and lung function measured by forced vital capacity compared to standard treatment with cyclophosphamide injections two to five years after initiation of treatment, but side effects and adverse events occur more frequently than in standard treatment. Our confidence in the quality of the evidence is low and moderate, mainly due to the limited number of patients in the studies, and that blinding is not possible in this type of study.

Authors' methods: We conducted a systematic search for randomized and non-randomized controlled studies as well as registry studies on 18.02.2016. In addition, we regularly checked PubMed for publications on an expected randomized controlled study. The last search was performed on 06.10.2017. The inclusion criteria were: patients above 18 years with systemic sclerosis. Intervention: autologous AHSCT. Comparison: standard pharmacological treatment. Outcomes: mortality and organ failure, adverse events, disease progression measured by skin, lung, heart and kidney involvement, and health-related quality of life. Risk of bias and methodological quality were assessed with Cochrane's Risk of Bias form and checklist. Effect estimates were calculated as risk ratio for dichotomous outcomes and mean difference or standardized mean difference (SMD) for continuous outcomes. Hazard ratios were used in survival analysis. The quality of the evidence was assessed using the GRADE tool for each outcome. The quality of the evidence, i.e., whether we have confidence in that an effect estimate is close to a theoretically true underlying effect, can be considered as high, moderate, low or very low. Based on the low number of patients potentially eligible for AHSCT according to the suggested criteria in Norway, and lack of a complete cost estimate for standard treatment, we chose to perform a cost analysis from a healthcare perspective. In the description of costs related to AHSCT treatment, we included pre-treatment evaluation of the patient, costs of the procedure itself, and costs of follow-up and infection prophylaxis up to one year after AHSCT. We also searched for literature to discuss selected questions from the "Checklists for ethical evaluations". The issues were discussed from different perspectives: that of the patient, the health care provider and -system, and that of the society.

Project Status: Completed

Year Published: 2018

URL for published report: https://www.fhi.no/en/publ/2018/Autologous-hematopoietic-stem-cell-transplantation-for-Diffuse-Systemic-Sclerosis/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Norway

Organisation Name: Norwegian Institute of Public Health

Contact Address: P.O. Box 222 Skoyen, N-0123, Oslo