Introduction
Systemic sclerosis (SSc) is a complex multisystem autoimmune disease, which affects the skin and internal organs, such as the lung, heart, gastrointestinal tract, musculoskeletal system, and kidneys [
1]. Until today, effective treatment options are very limited. Immunosuppression, especially in early disease (<2 years from first non-Raynaud phenomenon), is recommended using methotrexate or cyclophosphamide [
2]. A randomized controlled trial showed equivalent efficacy of mycophenolate and cyclophosphamide in patients with SSc-associated interstitial lung disease (ILD) [
3]. Nintedanib was effective in reducing the progression of SSc ILD as an antifibrotic treatment [
4]. Very recently, tocilizumab showed some benefit with regard to the lung involvement but not for the skin sclerosis [
5]. Furthermore, an observational study of rituximab showed some benefit for the skin sclerosis but not for the lung function parameters [
6]. Currently, no biologic treatment option has been approved for SSc skin sclerosis.
Risk factors for the progressive disease have been identified during the last years, and male patients with early diffuse cutaneous skin manifestations and anti-topoisomerase I (Scl70) antibodies are at high risk for disease-related mortality [
7,
8].
Autologous hematopoietic stem cell transplantation (HSCT) is a very effective and meanwhile well-established treatment option for SSc patients with a severe course of the disease. Therefore, HSCT was included in the current EULAR management guidelines [
2]. Three randomized controlled trials proved its superiority over standard treatment with cyclophosphamide pulses in severe cases [
9‐
11], and a recent non-interventional trial showed its effectiveness also in a real-life setting [
12]. The aim of the treatment strategy is improvement of long-term survival by eliminating the auto-aggressive immune system using high-dose chemotherapy in combination with lymphoablative antibodies or myeloablative radiation. Major points of criticism are side effects, especially the treatment-related mortality (TRM) between 5 and 10% [
9‐
12]. Therefore, it is very important to discuss and compare the risk for disease-related mortality with TRM. To investigate long-term survival in a subgroup of patients with a high risk for disease-related mortality, we compared data of patients with and without HSCT from the registry of the German Network for Systemic Scleroderma.
Methods
The patient registry of the German Network for Systemic Scleroderma (DNSS) was founded in 2003 and up to now includes more than 5000 patients. The network involves more than 40 clinical centers with different subspecialties including rheumatologists, dermatologists, pulmonologists, and nephrologists. The Ethics Committee of the coordinating center, i.e., the Dept. of Dermatology at the University Hospital Cologne, approved the patient information and consent form of the DNSS registry (approval number 04-037), which was used by all participating centers to receive the approval of their local ethics committees prior to registering patients. To participate in the registry, all patients obtained written informed consent. The 4-page disease- and organ-specific questionnaire collects clinical data to determine the current disease status with information on gender, age, disease onset, and auto-antibodies and therapies longitudinally over time [
13,
14].
Definition of included SSc subsets
Patients met the 2013 American College of Rheumatology (ACR)/European League against Rheumatism collaborative initiative criteria for systemic sclerosis [
15]. The SSc subtype was based on the classification criteria established by LeRoy et al. [
16,
17]. Follow-up visits were performed at least once per year. In the present analysis, we focused on male patients with dc-SSc and positive Scl70 antibodies as a control group.
Assessment of skin sclerosis
The modified Rodnan skin sclerosis (mRSS) score was used to quantify skin sclerosis. Repetitive determination of the mRSS score was preferentially performed by the same trained investigator to minimize variations.
Definition of heart involvement
Heart involvement was defined as the presence of elevated troponin T, pericardial effusion, pathologic changes in cardiac MRI, ventricular extrasystoles > Lown 3, or the presence of endomyocardial fibrosis in a biopsy specimen.
HSCT protocols
Patients received HSCT between 1997 and 2018. Cyclophosphamide 2×2g/m2 was used for mobilization chemotherapy until 2012 and 2×1g/m2 after 2012 with equally sufficient hematopoietic stem cell (HSC) harvest gains. All patients received G-CSF from day +4 until the end of the HSC harvest. Some transplants were manipulated by enhancing HSC using CD34-loaded columns and/or anti-CD3 and anti-CD19 monoclonal antibodies to minimize residual autoreactive T- and B-cells in the transplant. In any case, the goal was to receive 2.5×106 CD34+ HSC per kg body weight at the end of the harvesting procedure. Conditioning chemotherapy was performed by using cyclophosphamide 200 mg/kg, melphalan 140 mg/m2, or a combination of cyclophosphamide 100 mg/kg and thiotepa 10 mg/kg in patients with cardiac involvement. After the hematologic reconstitution, a prophylaxis with cotrimoxazole, nystatin, and aciclovir was continued for 3 to 6 months to prevent pneumocystis, candida, and herpes virus reactivation. We did not recognize any significant differences between patients and outcomes and between the several protocols.
Statistic analyses
The DNSS data registry was analyzed for patients who were treated with HSCT. Two control groups of patients with dc-SSc were used as references. Control group A comprised patients with dc-SSc and moderate risk for mortality. Control group B comprised male patients with dc-SSc who were positive for anti-Scl70 and had a high risk for mortality. To compare demographic and serological parameters, we used data of the initial visit. To compare organ manifestations and HSCT treatment, we used follow-up data of all visits.
The overall survival was assessed using Kaplan-Meier analyses and compared between the HSCT group and control groups using log-rank tests. Results are presented as Kaplan-Meier curves and the corresponding 95% confidence intervals were compared 5, 10, and 15 years after SSc onset which is the time of the first non-Raynaud manifestation.
To compare the disease progression within the HSCT and control cohorts, the mRSS, diffusion capacity of the lungs (DLCO-SB), and the body mass index (BMI) were analyzed after 1, 3, and 5 years and tested for statistical significance using separate dependent t-tests.
To investigate mortality risk factors for HSCT-treated patients, we compared patients younger than age 50 years with older patients and SSc disease duration of less than 3 years between the first non-Raynaud symptom and longer SSc disease duration.
For group comparisons, we used Pearson’s chi-square test (qualitative data) and the Kruskal-Wallis test (quantitative data). All reported p values are 2-sided and p values of < 0.05 were considered statistically significant. As the analyses were regarded as explorative, we did not adjust for multiple testing. Calculations and figures were carried out using SPSS (23.0.0.3 64-Bit, IBM Corp., Armonk, NY, USA) and Excel (Microsoft Corp., Redmond, WA, USA), as well as R (version 3.4.0, R Foundation for Statistical Computing, Vienna, Austria).
Discussion
In this retrospective registry analysis of more than 5000 patients with SSc, we demonstrated the efficacy of HSCT with regard to long-term overall survival in patients with severe SSc. The standard comparator group A was defined as all patients with dc-SSc. However, there were still significant differences in the distribution of risk factors for progressive SSc between the HSCT and group A. Male gender with diffuse cutaneous skin involvement and positivity for Scl70-antibodies are known to have a high risk of disease-related mortality [
7]. Therefore, we defined an alternative comparator group B by adjusting for these risk factors. Despite our attempt to create appropriate control groups with a comparable distribution of risk factors, there were still significant differences between both control groups and the HSCT group, which is a limitation of this study. Analyses of matched pair controls are planned in the future in order to further homogenize the distribution of risk factors within the HSCT and control cohort. In this study, both control groups comprised a significant proportion of patients with lung and heart involvement, but DLCO was significantly better in group A with all dc-SSc patients but not in the Scl70+ male control group B, indicating that the Scl70+ male control group was a more appropriate comparator for the HSCT group. When we compared the HSCT group with the male Scl70+ group, the HSCT patients showed significantly better survival over time. This is in line with the results from three randomized controlled trials, which all showed a significant better overall and event-free survival in HSCT-treated patients when compared to a cyclophosphamide pulse therapy [
9‐
11].
The benefit of this observational registry is its real-life character without the restrictions of inclusion or exclusion criteria. The long-term follow-up of our study and the large number of control patients are the major advantages of a longitudinal registry like DNSS compared to interventional trials.
The decline of patient numbers after 5, 10, and 15 years of follow-up is a limitation of this study. We cannot exclude the possibility that patients with a poor performance status were more likely to be lost to follow-up and the organ function of the remaining cohort seems to improve. However, this scenario seems to be unlikely because our results are consistent with the results from previously reported RCTs [
9,
10]. As absolute patient numbers become very low over time, we focused on the 5-year follow-up and here we were able to observe a decline of survival within the first 5 years associated with rapidly progressive disease but not with HSCT or other treatment. Thus, HSCT was not a risk factor for early mortality but reduced the risk for mortality over the first 5 years. In addition, mRSS, as a marker for the skin involvement, significantly declined after HSCT. Another limitation of this study is the low number of documented fVC during the follow-up visits. However, the DLCO-SB suggests a stabilization of the lung function up to 5 years after HSCT.
With this knowledge and considering the rapid progress in the development of new therapies in SSc, every SSc patient should be referred to an experienced SSc center offering the opportunity to discuss all new therapeutic strategies including clinical trials and HSCT at an early stage of disease. There are several novel treatment options including antifibrotic and specific anti-inflammatory agents in development. However, up to now, these treatments cannot replace classic immunosuppressive therapy and HSCT in patients with rapidly progressive disease [
9‐
11].
HSCT protocols have made progress over the years that reduced the risk of TRM and increased the acceptance of this treatment option. Still HSCT should only be performed at an experienced center. Although our patients have been transplanted between 1999 and 2021, we were unable to identify a difference between TRM in the early years compared with transplants in the recent years due to the small numbers of TRM.
Our observational study includes 80 transplanted patients. Therefore, it is one of the largest studies following HSCT treatment in patients with SSc [
12]. We observed a very low HSCT-associated transplant-related mortality (TRM) of only 1.3% when compared with previous HSCT trials [
9‐
11,
19,
20]. Nine patients received HSCT between 1997 and 2003, which was before the DNSS registry was initiated. Patients who received HSCT in the same period and died before 2003 would not be included in the DNSS registry, which could add as recruitment bias. Although we tried to select controls with a similar distribution of risk factor, we cannot exclude a potential selection bias in an open registry. Furthermore, some patients were lost to follow-up at some time. The lost to follow-up rate was indicated to be 3.0–3.7% after 5, 10, and 15 years. We cannot clearly differentiate between delayed follow-up reports and real lost to follow-up patients. Thus, we probably underestimate the real lost to follow-up rate to some extent. The delay of reporting deaths could have added to the low TRM in our cohort. Therefore, an HSCT TRM of 1.3% in our cohort was probably underreported. We can only speculate that the real HSCT TRM is likely rather between 1.3 and 5% when selected patients were treated in specialized HSCT centers.
Recently, Spierings et al. examined the correlation between HSCT RCT inclusion and exclusion parameters with survival as an outcome in an observational SSc cohort not treated by HSCT, but standard immunosuppression [
21]. They showed that patients who meet the RCT inclusion criteria had a particularly poor outcome. Those patients who also meet HSCT exclusion criteria like age, pulmonary hypertension, poor kidney function, or DLCO <40% had an even worse survival [
21]. This defines a group of patients with poor prognosis who might have benefitted from HSCT treatment, but also a group with even worse prognosis in which treatment options are very limited and for which there is a high unmet need. Further studies of therapeutic options for these high-risk patients are warranted.
Another issue is the definition of early progressive SSc, which should be considered for HSCT. Between the late 1990 years and 2012, TRM rates between 10 and 17% were reported [
10,
19]. After 2012 and probably due to standardized selection of SSc patients, the TRM rates were around 7% [
10,
19]. Selection to early SSc means an SSc duration of less than 2 years and clinically progressive skin sclerosis and lung fibrosis before HSCT. Patients with longer SSc duration were considered to accumulate advanced lung fibrosis, heart involvement, and pulmonary arterial hypertension that would contribute significantly to a higher TRM after 4 years of SSc duration. Our data show that HSCT is feasible up to 7 years after the onset of SSc and TRM is not increased in these patients. Our data also show that selection of SSc patients in HSCT referral centers reduced toxicities of mobilization and conditioning regimens and advances in the supportive care probably contribute to lower TRM rates below 7%.
In summary, our results on long-term survival after HSCT from our large DNSS SSc registry demonstrate a benefit of HSCT in a selected patient cohort with a high risk for rapidly progressive disease. Here, Scl70 positivity, dc-SSc, and male gender were the evaluated risk factors but there are even more risk factors that we know from other studies [
7,
20,
22,
23]. Further analyses of risk factors in early SSc disease should define those patients who probably benefit the most from an early intensive intervention like HSCT. Further analyses should also compare the risk of HSCT TRM with the risk of patients with early progressive SSc who meet exclusion criteria for HSCT treatment.
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