Therapeutic management of fibrosis in systemic sclerosis patients – an analysis from the Swiss EUSTAR cohort

OBJECTIVES: Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations

Recommendations regarding its treatment have been published by both the European League Against Rheumatism (EULAR) and the European Scleroderma Trials and Research (EUSTAR) groups in 2009 and were then updated in 2017 [6,7].Furthermore, other national societies, such as the British Society of Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR), have also published recommendations for treating systemic sclerosis [8,9].Despite significant agreement between both guidelines, especially regarding organ manifestations, the BSR guidelines offer more suggestions regarding non-pharmacologic treatment; they also cover topics like calcinosis, musculoskeletal, and cardiac symptoms [8].In addition, consensus guidance for SSc-ILD management has been published by European experts [10].
For systemic sclerosis-related skin fibrosis, the recommendations suggest that methotrexate may be considered for early diffuse systemic sclerosis, given its effect on skin fibrosis [6,8,11].However, the evidence behind these recommendations should be interpreted with some caution.A randomised controlled trial of methotrexate versus a placebo in early diffuse systemic sclerosis showed a trend in favour of methotrexate, but it did not indicate statistical significance [12].Another randomised controlled trial with methotrexate versus a placebo was statistically significant for methotrexate in treating early skin fibrosis, but most patients in the methotrexate group had limited systemic sclerosis with less severe organ involvement; as such, an mRSS reduction could hardly be deemed as clinically relevant [11].Furthermore, both trials had a relatively small sample size.
The EULAR recommends considering cyclophosphamide for treating progressive SSc-ILD, despite the medication's toxicity [6,13,14].However, studies showed that once cyclophosphamide is discontinued, its beneficial effects decline [15].Mycophenolate mofetil demonstrated improvement versus baseline similar to cyclophosphamide in a large randomised controlled trial for the following: Forced Vital Capacity (FVC), the transition dyspnea index (TDI), some but not all quantitative measures of lung fibrosis on high-resolution computed tomography, and the modified Rodnan skin score (mRSS) for skin fibrosis [16][17][18][19].
In the two trials, it was observed that randomised placebocontrolled trials with tocilizumab indicated a trend of improving skin fibrosis and had a strong effect on stabilizing interstitial lung disease [20][21][22].There was also a non-significant, but consistent directionality of efficacy regarding skin and interstitial lung disease in the EUSTAR real-life cohort treated with tocilizumab [23].The RECITAL trial revealed that rituximab was not superior to cyclophosphamide, but it did suggest comparable effects to cyclophosphamide when treating patients diagnosed with connective tissue disease with associated interstitial lung disease, including systemic sclerosis [24,25].Similarly, a recent single country, smaller double blind, placebo-controlled, randomised trial with rituximab showed a significant improvement of skin sclerosis and lung function in systemic sclerosis without major safety concerns [26].
In carefully selected patients with rapidly progressive systemic sclerosis and a risk of organ failure, hematopoietic stem cell transplantation should also be considered [6].Studies showed substantial improvement in skin fibrosis and a general stability of internal organ involvement, which is estimated to extend at least three years and was associated with significantly improved quality of life [7,8,[27][28][29][30].Nevertheless, haematopoietic stem cell transplantation is still associated with high treatment-related mortality of around 10% [29,30].This study's aim was to analyse the therapeutic management of systemic sclerosis patients in the Swiss EUSTAR cohort in light of current recommendations, with a focus on advanced skin fibrosis and systemic sclerosis-related-interstitial lung disease.

Study population and criteria
Systemic sclerosis patients from all six EUSTAR Swiss expert centres (Aarau, Basel, Bern, Geneva, Lausanne, and Zurich) were extracted from the multicentre, prospective EUSTAR database and included in this analysis (exported on 26.07.2019).Characteristics of the Swiss EUSTAR cohort have been reported recently [31].All Swiss centres obtained ethics approval and all patients signed informed consent forms.The Cantonal Ethics Committee Zurich (BASEC Nr.2017-02102) approved the data analysis.
In the present study, only systemic sclerosis patients' visits between 2013 and 2019 were analysed, namely because the extended data on patients' treatments were collected from 2013 onwards in the EUSTAR database.
The European Scleroderma Trials and Research group (EUSTAR)is an international research network, which was launched in 2004, that seeks to raise the awareness, understanding, research, and management of systemic sclerosis throughout Europe and worldwide.The main research tool is a multicentre online registry with prospectively collected data.More than 100 clinical, laboratory, and demographic data are collected annually, with patients having signed informed consent forms first.Over 200 international centres have contributed since 2004.Patients had to fulfil the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline [32].
Furthermore, eligible patients were sub-categorised according to the extent of their skin and interstitial lung disease at baseline.Regarding skin fibrosis, two different patient groups were formed.The first cohort was comprised of all patients with a modified Rodnan skin score (mRSS) >0, identifying those with skin fibrosis in general; the second was comprised of those with more advanced skin fibrosis, indicated by a mRSS of ≥7.This threshold was chosen because it reflects the lowest value classifiable as diffuse cutaneous systemic sclerosis [4,33].
The presence of interstitial lung disease was determined by either chest X-Ray or high-resolution computed tomography, as listed in the EUSTAR database.The expert radiologist from the local centres, following the method described by either Goh et al or by local practice, assessed the extent of interstitial lung disease [34].A patient was presumed to have more advanced interstitial lung disease if, in addition to showing interstitial lung disease on chest X-Ray or high-resolution computed tomography, one of the following criteria applied: interstitial lung disease extent of >20% on high-resolution computed tomography, dyspnea by New York Heart Association (NYHA) stage 3/4, or predicted FVC of <70%.
In addition, haematopoietic stem cell transplantation lung transplantation, oxygen supplementation and proton-pump inhibitor usage were recorded, the latter because gastrooesophageal reflux disease is hypothesised to initiate and progress interstitial lung disease [6,8,36,37].The use frequency of each treatment was compared with the abovementioned sub-groups.

Statistical analysis
For this observational descriptive study, sample size calculation was not performed.All available data from Swiss EUSTAR centres were used for this analysis.All statistical analyses were performed using SPSS statistics version 25 software (IBM).Data were expressed as frequencies and percentages for categorical variables, or as a median and interquartile range (IQR) for continuous variables according to their distribution.Continuous variables were compared with the Mann-Whitney U test or t-test, and categorical variables with Chi-square test or Fisher's exact test, as applicable.

Study population
Patient selection is summarised in figure 1.
Among 812 Swiss patients in the EUSTAR database, 590 were eligible and their demographic and clinical characteristics are listed in table 1.The population was predominantly female (79.8%) with a median age of 68.0 (57-77) years.The median disease duration was 6.0 (2-13) years, and most patients had been diagnosed with limited cutaneous systemic sclerosis (74%).
Table 2 presents the subclassification into more advanced skin fibrosis and interstitial lung disease.Of the 590 patients, 421 (71.4%) had an mRSS >0, of whom 195 (33.1%) had an mRSS ≥7.Regarding interstitial lung disease, the database included 198 (43.4%) patients with interstitial lung disease on either chest X-Ray or high-resolution computed tomography, of whom 106 (18%) had more advanced interstitial lung disease.
Individual treatments differ based on the extent of skin and interstitial lung disease, in comparison to the entire cohort, are illustrated in figure 3. Cyclophosphamide was used more frequently among patients with more advanced skin fibrosis and patients with interstitial lung disease, including those with more advanced interstitial lung disease.

Original article
Swiss Med Wkly.2024;154:3630 There was a higher prescription rate of methotrexate for patients with more advanced skin fibrosis.Mycophenolate mofetil's prescription rate was higher among patients with interstitial lung disease and even greater for those with more advanced interstitial lung disease.The data also indicate a higher prescription rate for patients with more advanced skin fibrosis [38].Rituximab was more a widely used among patients with more advanced skin fibrosis or interstitial lung disease.Furthermore, tocilizumab was used more frequently among patients with more extended skin fibrosis and with advanced interstitial lung disease.
Of 421 patients with skin fibrosis (mRSS >0), 49 either had taken no medication at all or had only proton-pump inhibitors, while 148/372 (39.8%) received treatment withmethotrexate, mycophenolate mofetil, or rituximab.For the 198 patients with interstitial lung disease, as determined by X-ray or high-resolution computed tomography, 21 were without treatment or had only proton-pump in- Baseline demographic and clinical characteristics of the study cohort (n = 590).Definitions of items and organ manifestation align with EUSTAR [7].Data of listed variables are presented as number (n)/total cases with available data (N) (%).Disease duration was calculated as the difference between the dates of the baseline visit and the first non-Raynaud's symptom of the disease, as reported by the patient.Pulmonary hypertension was judged on right heart catheterisation (RHC).Active disease was defined as a score >3, determined by calculating European Scleroderma Study Group disease activity indices for systemic sclerosis, as proposed by Valentini [56].4).

Demographics
Low-dose prednisone (≤10 mg/d) was used and often and, even more frequently so, among patients with any type of interstitial lung disease.This was particularly the case for patients with advanced interstitial lung disease patients.
Finally, the prescription rates for both proton-pump inhibitors and oxygen supplementation were higher in the   group of patients with advanced interstitial lung disease compared to the other cohorts.
Only seven systemic sclerosis patients were eligible for haematopoietic stem cell transplantation.They were younger than the average population, with a median age of 57.0 (50.5-62.5),yet the median disease duration had already been 5.0 (3-10) years.Most patients (66.7%) were diagnosed with diffuse systemic sclerosis, had reported more vascular and cardiopulmonary problems, and had worse lung function parameters; 40% had an active disease score (VAI >3).More detailed information is listed in table S2 in the appendix.
A total of 315 patients had recorded gastrooesophageal reflux disease and 251 (79.7 %) were treated with protonpump inhibitors (figure 4).

Discussion
Overall, a wide range of medications is prescribed for systemic sclerosis patients in Switzerland, nevertheless with consistent adherence to guidelines.Overall, 81 patients (13.7 %) did not receive any medication and 39 (6.6 %) had only proton-pump.It must be account for that treatment decisions are derived by means of a complex process, with many influencing factors (e.g., contraindications, patient preferences, financial considerations, etc.), which cannot be analysed from registry data.
In detail, cyclophosphamide was used more frequently among patients with advanced interstitial lung disease or with interstitial lung disease in general than among the average patient population; this aligns with EULAR recommendations and other guidelines [6,8].In addition, 27.2% of this group fulfils the criteria for advanced interstitial lung disease.Furthermore, skin fibrosis is associated with an increased risk of internal organ manifestations [16].
We also ascertained that methotrexate was used more commonly among patients with advanced skin fibrosis [6,8].
While not yet recommended by EUSTAR, newer studies and BSR and BHPR guidelines recommend mycophenloate mofetil to be used frequently among those in our study cohort for interstitial lung disease, as well as for advanced skin fibrosis among Swiss systemic sclerosis patients [8,16,17,39].
In Switzerland, there is a tendency to use rituximab for treating systemic sclerosis patients with more advanced skin and lung fibrosis.Although it remains a subject of current research, observational studies and smaller randomised controlled clinical trials indicate that anti-CD20 mediated B cell depletion positively effects both skin and lung involvement [35,[40][41][42][43][44][45].Recent data from the RECITAL trial showed similar effects of rituximab compared to cyclophosphamide on FVC in patients with connective-tissue disease associated interstitial lung disease, including systemic sclerosis [46].This explains the wide use of rituximab despite it not yet being recommended by EUSTAR and being only vaguely mentioned in BSR and BHPR guidelines [6,8] Tocilizumab use among patients with interstitial lung diseace can be generally explained by the findings of the faSScinate trial; the outcomes indicated a beneficial effect on stabilizing lung function regarding FVC [20,47].This is consistent with the more recent randomised placebocontrolled phase III focuSSced trial of tocilizumab in systemic sclerosis, which led to the Federal Drug Administration (FDA) of the United States approving tocilizumab for treating SSc-ILD [48].These studies also showed a nu-

Original article
Swiss Med Wkly.2024;154:3630 meric, but not statistically significant, reduction in mRSS changes at week 24.In the phase III trial, in which systemic sclerosis patients received subcutaneous tocilizumab for 48 weeks, there was again a numeric, but not significant, difference between tocilizumab and a placebo in the primary endpoint mRSS at week 48 [21,47,48].
Glucocorticoids, such as prednisone, are frequently used for treating systemic sclerosis despite their efficacy being supported by limited evidence [49,50].Often, there is no correlation between the prescription pattern and the clinical signs of inflammation [50].In Switzerland, this pattern is also reflected by prescriptions given to systemic sclerosis patients.As seen in figure 2, especially daily, low-prednisone doses (≤10 mg/d) are frequently prescribed for patients with systemic sclerosis-related interstitial lung disease and advanced skin fibrosis.is also a tendency to prescribe doses higher than 10 mg per day among the advanced interstitial lung disease cohort.Higher prednisone doses are usually avoided due to a risk of scleroderma renal crisis.
Regarding haematopoietic stem cell transplantation, there was a slight tendency to offer this treatment for patients with more advanced interstitial lung disease.Among the entire Swiss patient population, there were only seven who underwent haematopoietic stem cell transplantation at the baseline visit, or short afterwards.EUSTAR recommends haematopoietic stem cell transplantation only in carefully selected patients with rapidly progressive systemic sclerosis; this accounts for the high risk of treatment-related morbidity and mortality [6].Following EUSTAR recommendations, in Switzerland, systemic sclerosis patients were younger, the majority of whom had diffuse systemic sclerosis with worse lung parameters; 40% had active disease.
Finally, proton-pump inhibitors were prescribed most commonly of the analysed medications among our study population.Accordingly, both EUSTAR and BSR/BHPR guidelines recommend using proton-pump inhibitors in cases of systemic sclerosis-related gastro-oesophageal reflux disease (GERD), despite there being a dearth of specific randomised controlled trials [6,8].Most of our study population (66.4%) had recorded oesophageal symptoms.Another reason, especially for the additional use of protonpump inhibitors among patients with advanced interstitial lung disease, why proton-pump inhibitors are frequently used among patients with interstitial lung disease could be because of a suspected causal correlation between interstitial lung disease and GERD [36,37,51].
Regarding the limitations of our study, these are inevitable due to missing values based on the observational, multicentre nature of the registry.This study captured neither non-pharmacologic treatments, nor alternative medicines.
At the time of exporting data from the EUSTAR database, nintedanib (a drug more recently approved for SSc-ILD treatment, both in Switzerland and worldwide) was not recorded in the EUSTAR database [52].Thus, such treatments could not be analysed using the current dataset.Data were drawn in 2019, and the treatment landscape may have changed since then.Notably, we have no indications that general adherence to guidelines and recommendations has changed since then; as such, we have strong reason to believe that this study's general conclusions remain valid.Fi-nally, we did not have longitudinal data available to assess treatment duration.
In conclusion, in Switzerland, systemic sclerosis patients are being prescribed a wide range of medications.This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.Future research could therefore focus on treatment for other manifestations of systemic sclerosis, such digital vasculopathy, pulmonary arterial hypertension, or systemic sclerosis-related gastrointestinal disease.New guidelines and recommendations, which are expected to be published soon, will have increasing complexity due to the high number of new medications citing strong evidence for efficacy.This will challenge their implementation in clinical practice.It is to be noted that the Swiss EUSTAR database has proven useful in monitoring this process.

Table S2:
A comparison of demographic and clinical characteristics between the total number of patients in the Swiss systemic sclerosis cohort and Swiss patients with recorded haematopoietic stem cell transplantation at baseline visit (seven in total).Definitions of items and organ manifestation align with EUSTAR.Data are presented as number (n)/total valid cases (N) (%).Disease duration was calculated as the difference between the dates of the baseline visit and the first non-Raynaud's symptom of the disease, per patient reports.Pulmonary hypertension was judged based on RHC.Active disease was defined as a score >3, which was derived by calculating European Scleroderma Study Group disease activity indices for systemic sclerosis, as proposed by Valentini [48].

Figure 1 :
Figure 1: Patient selection overview.Of the 17,212 patients in the EUSTAR database at the time of export, 812 were from Swiss EUSTAR centres (Aarau, Basel, Bern, Geneva, Lausanne and Zurich).Because recording extended therapy data began in 2013, only data collected after 2013 were considered for analysis.Finally, patients not meeting the 2013 ACR/EULAR classification criteria were excluded.ACR: American College of Rheumatology; EULAR: European league Against Rheumatism; EUSTAR: European Scleroderma Trial and Research Group.

Figure 2 :
Figure 2: Treatment with potentially disease modifying agents in Swiss systemic sclerosis patients, illustrated alphabetically as drugs per patient at baseline visit.Numbers and percentage refer to Switzerland's total patient population.Exact numbers are listed in table S1 in the appendix.

Figure 3 :
Figure 3: Treatment differences among SSc patients according to severity of skin fibrosis and interstitial lung disease, compared to the average baseline treatments of the study's cohort.CRX: Chest X-Ray; HRCT: High-resolution computed tomography; mRSS: modified Rodnan skin score; TNF: Tumor necrosis factor.

Figure 4 :
Figure 4: Percentages of patients treated according to the EULAR/BSR Guidelines.For systemic sclerosis-related skin fibrosis, the recommendation is either methotrexate, mycophenolate mofetil, or rituximab; for systemic sclerosis-related lung fibrosis, the recommendation is cyclophosphamide, mycophenolate mofetil, tocilizumab, or rituximab.Patients with gastrooesophageal reflux disease, for whom proton pump inhibitors have been recommended for treatment, have also been listed.CRX: Chest X-Ray; HRCT: High-resolution computed tomography; mRSS: modified Rodnan skin score; BSR: British Society of Rheumatology.

Table 2 :
Fibrotic manifestations of systemic sclerosis patients in Switzerland (total Swiss cohort n = 590).Classification according to severity of skin and interstitial lung disease.Data of listed variables are presented as number (n)/total cases with available data (N) (%).Skin fibrosis was defined as mRSS >0, and more advanced skin fibrosis as mRSS ≥7.The presence of interstitial lung disease was determined by either chest X-Ray or high-resolution computed tomography.Advanced interstitial lung disease was defined by the parameters shown above.