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

DOI: https://doi.org/https://doi.org/10.57187/s.3630

Introduction

Systemic sclerosis is an autoimmune connective tissue disease characterised by increased deposition of extracellular matrix, resulting from fibroblast dysfunction, microvasculopathy, and autoimmunity [1–5]. The organ manifestations and clinical course of systemic sclerosis vary greatly, and this complicates its monitoring and treatment [4, 6].

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 [16–19].

In the two trials, it was observed that randomised placebo-controlled trials with tocilizumab indicated a trend of improving skin fibrosis and had a strong effect on stabilizing interstitial lung disease [20–22]. 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, 27–30]. 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.

Patients and methods

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%.

Treatment analysis

Potentially disease-modifying medications prescribed for each patient at the baseline visit were recorded. These medications, DMARDs, included immunomodulatory medications (hydroxychloroquine, intravenous immunoglobulins), conventional immunosuppressives (azathioprine, cyclosporin A, cyclophosphamide, D-penicillamine, leflunomide, methotrexate, mycophenolate mofetil, and glucocorticoids [e.g., prednisone, sulfasalazine]), and biological DMARDs (abatacept, rituximab, TNF-alpha antagonists, and tocilizumab). Prednisone was considered a DMARD in doses >10 mg/d [35].

In addition, haematopoietic stem cell transplantation lung transplantation, oxygen supplementation and proton-pump inhibitor usage were recorded, the latter because gastro-oesophageal 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 above-mentioned 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.

Results

Study population

Patient selection is summarised in figure 1.

Figure 1Patient 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.

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.

Treatment

All treatments with potentially disease modifying agents per patient are depicted in figure 2. Regarding non-biologic DMARDs, the most frequently prescribed medication was methotrexate, in 97 (16.4%) patients, followed by hydroxy-/chloroquine, in 67 (11.4%), and mycophenolate mofetil in 55 (9.3%) patients. Among biologic DMARDs, rituximab and tocilizumab were administered most frequently, each in 23 (3.9%) patients. Additionally, 124 (21%) patients were treated with low-dose prednisone (≤10 mg/d). Seven (1.2%) underwent haematopoietic stem cell transplantation and two (0.3%) lung transplantation. Furthermore, 378 (64.1%) received proton-pump inhibitors and 20 (3.4%) required oxygen supplementation.

Figure 2Treatment 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.

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. 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.

Figure 3Treatment 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.

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 inhibitors; 80/177(45.2%) received therapy with cyclophosphamide, mycophenolate mofetil, tocilizumab, or rituximab (figure 4).

Figure 4Percentages 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.

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 proton-pump 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, 40–45]. 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 placebo-controlled 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 numeric, 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. There 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 proton-pump 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. Finally, 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.

Acknowledgments

We thank all patients for allowing us to collect their data and for providing informed consent. Primary data are available upon reasonable request, submitted to the corresponding author, following EUSTAR rules.We thank all patients for allowing us to collect their data and for providing informed consent. Primary data are available upon reasonable request, submitted to the corresponding author, following EUSTAR rules.

References

1. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017 Oct;390(10103):1685–99. 10.1016/S0140-6736(17)30933-9 

2. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009 May;360(19):1989–2003. 10.1056/NEJMra0806188 

3. Wollheim FA. Classification of systemic sclerosis. Visions and reality. Rheumatology (Oxford). 2005 Oct;44(10):1212–6. 10.1093/rheumatology/keh671 

4. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013 Nov;65(11):2737–47. 10.1002/art.38098 

5. Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011;6(1):509–37. 10.1146/annurev-pathol-011110-130312 

6. Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al.; EUSTAR Coauthors. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017 Aug;76(8):1327–39. 10.1136/annrheumdis-2016-209909 

7. Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirjak L, et al.; EUSTAR Co-Authors. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009 May;68(5):620–8. 10.1136/ard.2008.096677 

8. Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, et al.; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016 Oct;55(10):1906–10. 10.1093/rheumatology/kew224 

9. Hachulla E, Agard C, Allanore Y, Avouac J, Bader-Meunier B, Belot A, et al.; Collaborators. French recommendations for the management of systemic sclerosis. Orphanet J Rare Dis. 2021 Jul;16(S2 Suppl 2):322. 10.1186/s13023-021-01844-y 

10. Hoffmann-Vold AM (Rheumatology L, editor). Distler O et al. The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements. 2020. pp. E71–83. 10.1016/S2665-9913(19)30144-4 

11.      van den Hoogen FHJ, Boerbooms AMT, Swaak AJG, Rasker JJ, van Lier HJJ, van de Putte LBA. Comparison of Methotrexate with placebo in the treatment of systemic sclerosis: a 24 Week randomized double-blind trial, followed by a 24 week observational trial. 1996;35:364–72. 

12. Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001 Jun;44(6):1351–8. 10.1002/1529-0131(200106)44:6<1351::AID-ART227>3.0.CO;2-I 

13. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006 Dec;54(12):3962–70. 10.1002/art.22204 

14. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al.; Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun;354(25):2655–66. 10.1056/NEJMoa055120 

15. Volkmann ER, Tashkin DP, Sim M, Li N, Khanna D, Roth MD, et al. Cyclophosphamide for Systemic Sclerosis-related Interstitial Lung Disease: A Comparison of Scleroderma Lung Study I and II. J Rheumatol. 2019 Oct;46(10):1316–25. 10.3899/jrheum.180441 

16. Namas R, Tashkin DP, Furst DE, Wilhalme H, Tseng CH, Roth MD, et al.; Participants in the Scleroderma Lung Study I and members of the Scleroderma Lung Study II Research Group. Efficacy of Mycophenolate Mofetil and Oral Cyclophosphamide on Skin Thickness: Post Hoc Analyses From Two Randomized Placebo-Controlled Trials. Arthritis Care Res (Hoboken). 2018 Mar;70(3):439–44. 10.1002/acr.23282 

17. Volkmann ER, Tashkin DP, Li N, Roth MD, Khanna D, Hoffmann-Vold AM, et al. Mycophenolate Mofetil Versus Placebo for Systemic Sclerosis-Related Interstitial Lung Disease: An Analysis of Scleroderma Lung Studies I and II. Arthritis Rheumatol. 2017 Jul;69(7):1451–60. 10.1002/art.40114 

18. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al.; Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun;354(25):2655–66. 10.1056/NEJMoa055120 

19. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al.; Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708–19. 10.1016/S2213-2600(16)30152-7 

20. Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016 Jun;387(10038):2630–40. 10.1016/S0140-6736(16)00232-4 

21. Khanna D, Lin CJ, Furst DE, Goldin J, Kim G, Kuwana M, et al.; focuSSced investigators. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020 Oct;8(10):963–74. 10.1016/S2213-2600(20)30318-0 

22. Distler O, Distler JH. Tocilizumab for systemic sclerosis: implications for future trials. Lancet. 2016 Jun;387(10038):2580–1. 10.1016/S0140-6736(16)00622-X 

23. Kuster S, Jordan S, Elhai M, Held U, Steigmiller K, Bruni C, et al.; EUSTAR collaborators. Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort. RMD Open. 2022 Nov;8(2):e002477. 10.1136/rmdopen-2022-002477 

24. Maher TM, Tudor VA, Saunders P, Gibbons MA, Fletcher SV, Denton CP, et al.; RECITAL Investigators. Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med. 2023 Jan;11(1):45–54. 10.1016/S2213-2600(22)00359-9 

25. Saunders P, Tsipouri V, Keir GJ, Ashby D, Flather MD, Parfrey H, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. Trials. 2017 Jun;18(1):275. 10.1186/s13063-017-2016-2 

26. al SEe. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): open-label extension of a double blind, investigators-initiated, randomised, placebo-controlled trial. Lancet Rheumatology. 2022;Volume 4, Issue 8, E546-E555, August 2022. 

27. Tsukamoto H, Nagafuji K, Horiuchi T, Mitoma H, Niiro H, Arinobu Y, et al. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatology (Oxford). 2011 May;50(5):944–52. 10.1093/rheumatology/keq414 

28. Vonk MC, Marjanovic Z, van den Hoogen FH, Zohar S, Schattenberg AV, Fibbe WE, et al. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. 2008 Jan;67(1):98–104. 10.1136/ard.2007.071464 

29. Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011 Aug;378(9790):498–506. 10.1016/S0140-6736(11)60982-3 

30. van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al.; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun;311(24):2490–8. 10.1001/jama.2014.6368 

31. Hernández J, Jordan S, Dobrota R, Iudici M, Hasler P, Ribi C, et al.; The Eustar Collaborators. The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort. Swiss Med Wkly. 2021 Jul;151(2728):w20528. 10.4414/smw.2021.20528 

32. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000 Mar;132(6):425–34. 10.7326/0003-4819-132-6-200003210-00002 

33. Dobrota R, Maurer B, Graf N, Jordan S, Mihai C, Kowal-Bielecka O, et al.; EUSTAR coauthors. Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis. 2016 Oct;75(10):1743–8. 10.1136/annrheumdis-2015-208024 

34. Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008 Jun;177(11):1248–54. 10.1164/rccm.200706-877OC 

35. Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017 Apr;46(5):625–31. 10.1016/j.semarthrit.2016.10.003 

36. Bandeira CD, Rubin AS, Cardoso PF, Moreira JS, Machado MM. Prevalence of gastroesophageal reflux disease in patients with idiopathic pulmonary fibrosis. J Bras Pneumol. 2009 Dec;35(12):1182–9. 10.1590/S1806-37132009001200004 

37. Qi J, Shang S, Li Z, Kang J, Kong L. [The relationship between idiopathic pulmonary fibrosis and gastroesophageal reflux disease]. Zhonghua Nei Ke Za Zhi. 2015 Aug;54(8):695–8. 

38. Wu W, Jordan S, Becker MO, Dobrota R, Maurer B, Fretheim H, et al. Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model. Ann Rheum Dis. 2018 Sep;77(9):1326–32. 10.1136/annrheumdis-2018-213201 

39. Shenoy PD, Bavaliya M, Sashidharan S, Nalianda K, Sreenath S. Cyclophosphamide versus mycophenolate mofetil in scleroderma interstitial lung disease (SSc-ILD) as induction therapy: a single-centre, retrospective analysis. Arthritis Res Ther. 2016 Jun;18(1):123. 10.1186/s13075-016-1015-0 

40. Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Paliogianni F, Sirinian C, et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012;30(2 Suppl 71):S17–22. 

41. Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, et al.; EUSTAR Rituximab study group. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015 Jun;74(6):1188–94. 10.1136/annrheumdis-2013-204522 

42. Elhai M, Boubaya M, Distler O, Smith V, Matucci-Cerinic M, Alegre Sancho JJ, et al.; for EUSTAR network. Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis. 2019 Jul;78(7):979–87. 10.1136/annrheumdis-2018-214816 

43. Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010 Feb;49(2):271–80. 10.1093/rheumatology/kep093 

44. Ebata S, Yoshizaki-Ogawa A, Sato S, Yoshizaki A. New Era in Systemic Sclerosis Treatment: Recently Approved Therapeutics. J Clin Med. 2022 Aug;11(15):4631. 10.3390/jcm11154631 

45. Sircar G, Goswami RP, Sircar D, Ghosh A, Ghosh P. Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial. Rheumatology (Oxford). 2018 Dec;57(12):2106–13. 10.1093/rheumatology/key213 

46. Maher TM, Tudor VA, Saunders P, Gibbons MA, Fletcher SV, Denton CP, et al. Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med. 2022. 

47. Khanna D, Denton CP, Lin CJ, van Laar JM, Frech TM, Anderson ME, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018 Feb;77(2):212–20. 10.1136/annrheumdis-2017-211682 

48. Khanna D, Lin CJ, Furst DE, Goldin J, Kim G, Kuwana M, et al. A randomised placebo-controlled phase 3 trial of tocilizumab in systemic sclerosis. Lancet Respir Med. 2020. 10.1016/S2213-2600(20)30318-0 

49. Hunzelmann N, Moinzadeh P, Genth E, Krieg T, Lehmacher W, Melchers I, et al.; German Network for Systemic Scleroderma Centers. High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy. Arthritis Res Ther. 2009;11(2):R30. 10.1186/ar2634 

50. Iudici M, Fasano S, Iacono D, Russo B, Cuomo G, Valentini G. Prevalence and factors associated with glucocorticoids (GC) use in systemic sclerosis (SSc): a systematic review and meta-analysis of cohort studies and registries. Clin Rheumatol. 2014 Feb;33(2):153–64. 10.1007/s10067-013-2422-0 

51. Salaffi F, Di Carlo M, Carotti M, Fraticelli P, Gabrielli A, Giovagnoni A. Relationship between interstitial lung disease and oesophageal dilatation on chest high-resolution computed tomography in patients with systemic sclerosis: a cross-sectional study. Radiol Med. 2018 Sep;123(9):655–63. 10.1007/s11547-018-0894-3 

52. Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al.; SENSCIS Trial Investigators. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med. 2019 Jun;380(26):2518–28. 10.1056/NEJMoa1903076 

53. Valentini G, D’Angelo S, Della Rossa A, Bencivelli W, Bombardieri S. European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. IV. Assessment of skin thickening by modified Rodnan skin score. Ann Rheum Dis. 2003 Sep;62(9):904–5. 10.1136/ard.62.9.904 

Appendix