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. 2022 Jul 29;7(7):CD011819.
doi: 10.1002/14651858.CD011819.pub2.

Stem cell transplantation for systemic sclerosis

Sebastian Bruera  1 , Harish Sidanmat  2 , Donald A Molony  3 , Maureen D Mayes  4 , Maria E Suarez-Almazor  5 , Kate Krause  6 , Maria Angeles Lopez-Olivo  5
Affiliations

Stem cell transplantation for systemic sclerosis

Sebastian Bruera et al. Cochrane Database Syst Rev. .

Abstract

Background: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by systemic inflammation, fibrosis, vascular injury, reduced quality of life, and limited treatment options. Autologous hematopoietic stem cell transplantation (HSCT) has emerged as a potential intervention for severe SSc refractory to conventional treatment.

Objectives: To assess the benefits and harms of autologous hematopoietic stem cell transplantation for the treatment of systemic sclerosis (specifically, non-selective myeloablative HSCT versus cyclophosphamide; selective myeloablative HSCT versus cyclophosphamide; non-selective non-myeloablative HSCT versus cyclophosphamide).

Search methods: We searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, Embase, and trial registries from database insertion to 4 February 2022.

Selection criteria: We included RCTs that compared HSCT to immunomodulators in the treatment of SSc.

Data collection and analysis: Two review authors independently selected studies for inclusion, extracted study data, and performed risk of bias and GRADE assessments to assess the certainty of evidence using standard Cochrane methods.

Main results: We included three RCTs evaluating: non-myeloablative non-selective HSCT (10 participants), non-myeloablative selective HSCT (79 participants), and myeloablative selective HSCT (36 participants). The comparator in all studies was cyclophosphamide (123 participants). The study examining non-myeloablative non-selective HSCT had a high risk of bias given the differences in baseline characteristics between the two arms. The other studies had a high risk of detection bias for participant-reported outcomes. The studies had follow-up periods of one to 4.5 years. Most participants had severe disease, mean age 40 years, and the duration of disease was less than three years. Efficacy No study demonstrated an overall mortality benefit of HSCT when compared to cyclophosphamide. However, non-myeloablative selective HSCT showed overall survival benefits using Kaplan-Meier curves at 10 years and myeloablative selective HSCT at six years. We graded our certainty of evidence as moderate for non-myeloablative selective HSCT and myeloablative selective HSCT. Certainty of evidence was low for non-myeloablative non-selective HSCT. Event-free survival was improved compared to cyclophosphamide with non-myeloablative selective HSCT at 48 months (hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.16 to 0.74; moderate-certainty evidence). There was no improvement with myeloablative selective HSCT at 54 months (HR 0.54 95% CI 0.23 to 1.27; moderate-certainty evidence). The non-myeloablative non-selective HSCT trial did not report event-free survival. There was improvement in functional ability measured by the Health Assessment Questionnaire Disability Index (HAQ-DI, scale from 0 to 3 with 3 being very severe functional impairment) with non-myeloablative selective HSCT after two years with a mean difference (MD) of -0.39 (95% CI -0.72 to -0.06; absolute treatment benefit (ATB) -13%, 95% CI -24% to -2%; relative percent change (RPC) -27%, 95% CI -50% to -4%; low-certainty evidence). Myeloablative selective HSCT demonstrated a risk ratio (RR) for improvement of 3.4 at 54 months (95% CI 1.5 to 7.6; ATB -37%, 95% CI -18% to -57%; RPC -243%, 95% CI -54% to -662%; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; low-certainty evidence). The non-myeloablative non-selective HSCT trial did not report HAQ-DI results. All transplant modalities showed improvement of modified Rodnan skin score (mRSS) (scale from 0 to 51 with the higher number being more severe skin thickness) favoring HSCT over cyclophosphamide. At two years, non-myeloablative selective HSCT showed an MD in mRSS of -11.1 (95% CI -14.9 to -7.3; ATB -22%, 95% CI -29% to -14%; RPC -43%, 95% CI -58% to -28%; moderate-certainty evidence). At 54 months, myeloablative selective HSCT at showed a greater improvement in skin scores than the cyclophosphamide group (RR 1.51, 95% CI 1.06 to 2.13; ATB -27%, 95% CI -6% to -47%; RPC -51%, 95% CI -6% to -113%; moderate-certainty evidence). The NNTB was 4 (95% CI 3 to 18). At one year, for non-myeloablative non-selective HSCT the MD was -16.00 (95% CI -26.5 to -5.5; ATB -31%, 95% CI -52% to -11%; RPC -84%, 95% CI -139% to -29%; low-certainty evidence). No studies reported data on pulmonary arterial hypertension. Adverse events In the non-myeloablative selective HSCT study, there were 51/79 serious adverse events with HSCT and 30/77 with cyclophosphamide (RR 1.7, 95% CI 1.2 to 2.3), with an absolute risk increase of 26% (95% CI 10% to 41%), and a relative percent increase of 66% (95% CI 20% to 129%). The number needed to treat for an additional harmful outcome was 4 (95% CI 3 to 11) (moderate-certainty evidence). In the myeloablative selective HSCT study, there were similar rates of serious adverse events between groups (25/34 with HSCT and 19/37 with cyclophosphamide; RR 1.43, 95% CI 0.99 to 2.08; moderate-certainty evidence). The non-myeloablative non-selective HSCT trial did not clearly report serious adverse events.

Authors' conclusions: Non-myeloablative selective and myeloablative selective HSCT had moderate-certainty evidence for improvement in event-free survival, and skin thicknesscompared to cyclophosphamide. There is also low-certainty evidence that these modalities of HSCT improve physical function. However, non-myeloablative selective HSCT and myeloablative selective HSCT resulted in more serious adverse events than cyclophosphamide; highlighting the need for careful risk-benefit considerations for people considering these HSCTs. Evidence for the efficacy and adverse effects of non-myeloablative non-selective HSCT is limited at this time. Due to evidence provided from one study with high risk of bias, we have low-certainty evidence that non-myeloablative non-selective HSCT improves outcomes in skin scores, forced vital capacity, and safety. Two modalities of HSCT appeared to be a promising treatment option for SSc though there is a high risk of early treatment-related mortality and other adverse events. Additional research is needed to determine the effectiveness and adverse effects of non-myeloablative non-selective HSCT in the treatment of SSc. Also, more studies will be needed to determine how HSCT compares to other treatment options such as mycophenolate mofetil, as cyclophosphamide is no longer the first-line treatment for SSc. Finally, there is a need for a greater understanding of the role of HSCT for people with SSc with significant comorbidities or complications from SSc that were excluded from the trial criteria.

Trial registration: ClinicalTrials.gov NCT00278525 NCT00114530.

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Conflict of interest statement

SB: none.

HS: none.

DAM: none.

MDM declares the following: Galapagos NV (Independent Contractor ‐ Consultant), Actelion Pharmaceuticals US, Inc. (Independent Contractor ‐ Consultant), Eicos Sciences (Independent Contractor ‐ Consultant), Boehringer Ingelheim (Independent Contractor ‐ Consultant)

KK: none.

MAL: none.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Efficacy – survival, Outcome 1: Overall mortality
1.2
1.2. Analysis
Comparison 1: Efficacy – survival, Outcome 2: Event‐free survival
2.1
2.1. Analysis
Comparison 2: Participant‐reported outcomes – HAQ‐DI, Outcome 1: HAQ‐DI
2.2
2.2. Analysis
Comparison 2: Participant‐reported outcomes – HAQ‐DI, Outcome 2: Improvement in HAQ‐DI (≥ 0.4 change)
3.1
3.1. Analysis
Comparison 3: Efficacy – skin thickness, Outcome 1: Modified Rodnan skin scores
3.2
3.2. Analysis
Comparison 3: Efficacy – skin thickness, Outcome 2: Modified Rodnan skin score improvement ( ≥ 25% change in mRSS OR ± ≥ 5 if baseline mRSS ≤ 20)
4.1
4.1. Analysis
Comparison 4: Efficacy – interstitial lung disease, Outcome 1: Predicted forced vital capacity (% predicted)
4.2
4.2. Analysis
Comparison 4: Efficacy – interstitial lung disease, Outcome 2: Predicted forced vital capacity improvement ( 10% change in FVC % predicted)
4.3
4.3. Analysis
Comparison 4: Efficacy – interstitial lung disease, Outcome 3: DLCO (% predicted)
4.4
4.4. Analysis
Comparison 4: Efficacy – interstitial lung disease, Outcome 4: DLCO improvement ( ≥ 15% change in DLCO % predicted)
4.5
4.5. Analysis
Comparison 4: Efficacy – interstitial lung disease, Outcome 5: Predicted total lung capacity
5.1
5.1. Analysis
Comparison 5: Safety, Outcome 1: Serious adverse events
5.2
5.2. Analysis
Comparison 5: Safety, Outcome 2: Treatment‐related mortality
5.3
5.3. Analysis
Comparison 5: Safety, Outcome 3: Serious non‐lethal infections
5.4
5.4. Analysis
Comparison 5: Safety, Outcome 4: Study withdrawals (including non‐adherence, non‐lethal adverse events, organ failure, dropout)
5.5
5.5. Analysis
Comparison 5: Safety, Outcome 5: Renal failure
6.1
6.1. Analysis
Comparison 6: Efficacy – renal function (creatinine clearance), Outcome 1: Autologous non‐myeloablative selective HSCT
7.1
7.1. Analysis
Comparison 7: Efficacy – cardiac function, Outcome 1: Autologous non‐myeloablative selective HSCT
8.1
8.1. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 1: Physical Function
8.2
8.2. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 2: Physical Role Limitation
8.3
8.3. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 3: Body Pain
8.4
8.4. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 4: General Health Perception
8.5
8.5. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 5: Vital Energy Fatigue
8.6
8.6. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 6: Social Function
8.7
8.7. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 7: Emotional Role Limitation
8.8
8.8. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 8: Mental Health
8.9
8.9. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 9: Physical Component Summary
8.10
8.10. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 10: Mental Component Summary
8.11
8.11. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 11: PCS SF‐36 improvement ( ≥ 10‐point change)
8.12
8.12. Analysis
Comparison 8: Participant‐reported outcomes – SF‐36, Outcome 12: MCS SF‐36 improvement (≥ 10‐point change)
9.1
9.1. Analysis
Comparison 9: Participant‐reported outcomes – EQ‐5D VAS score, Outcome 1: Autologous non‐myeloablative selective HSCT
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