The burden of systemic sclerosis in Switzerland – the Swiss systemic sclerosis EUSTAR cohort

DOI: https://doi.org/10.4414/smw.2021.20528

Introduction

Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disorder, characterised by vasculopathy and extensive tissue fibrosis with multiple organ involvement [1, 2]. With estimates of prevalence from 3 to 50 per 100,000, SSc is an orphan disease, and is associated with high morbidity and disease-related mortality [3, 4]. At present, there is no licensed therapy that can prevent overall disease progression [5].

The aetiology of the disease is still unclear, but genetic and environmental factors have been implicated [6]. There is a higher susceptibility in females as well as in Afro-Americans, and geographical variations with higher prevalence of SSc in the USA and Australia than in Japan and Europe [7, 8]. Within Europe, a north-south gradient with higher prevalence in southern countries and higher prevalence of more severe organ manifestations in eastern centres has been described. However, differences between European countries might be due to referral-and investigator-related bias in the specific healthcare systems rather than true differences in prevalence and severity [3, 6].

The American College of Rheumatology (ACR) classification criteria from 1980 have been the most widely used in epidemiological studies of SSc [3, 9]. However, as the ACR criteria 1980 were developed for patients with longstanding SSc, they show insufficient sensitivity for early/mild and very early / very mild SSc patients [10–12]. The lack of early diagnostic criteria and predictors of disease progression are important limiting factors for identification and treatment in the early and very early stages of the disease [13]. Especially as internal organ involvement occurs early and is often subclinical, detection of disease in the so-called “window of opportunity”, which refers to the time between first manifestations to development of irreversible organ damage, is of great interest [13–16]. In 2013, the new ACR / European Alliance of Associations for Rheumatology (EULAR) classification criteria including immunological, vascular and fibrotic features of the disease were published. These criteria were validated as highly sensitive and specific for SSc, and allow inclusion of more patients into clinical studies [17–19]. Further, the European Scleroderma Trials and Research (EUSTAR) group defined preliminary criteria for diagnosis of very early SSc. These included puffy fingers, (SSc-specific) antinuclear antibodies, and microvascular alterations detected by nailfold capillaroscopy in addition to Raynaud’s phenomenon [20]. These criteria aim to identify patients with a predisposition to develop SSc fulfilling the classification criteria SSc [21, 22].

In Switzerland, a national strategy for the management of rare diseases offering prospects of improved medical care and government-funded support has been developed and approved [23]. In this context, it is essential to have a good understanding of the specific needs of SSc patients in Switzerland. The EUSTAR database was formed in June 2004, and since then has prospectively followed SSc patients in most European countries. It provides a unique opportunity to assess Swiss and European SSc patients. Further, a comparison of Swiss with European SSc patients leads to a better understanding of the geographical epidemiology of SSc and to identification of specificities of clinical manifestations of SSc patients. To date, no characterisation of Swiss SSc patients has been published.

In this study, we aimed to address this unmet need. This analysis could represent a valuable asset to set priorities in the clinical management strategy of SSc and thus guide the direction of medical efforts and resources towards the best care of patients.

Patients and methods

For this observational study, all SSc patients from the EUSTAR centres in Switzerland (Zurich, Basel, Geneva, Aarau, Bern, Lausanne) and Europe (excluding Swiss centres, all included centres are listed in supplementary table S1 in appendix 2) with visits entered into the EUSTAR or the associated VEDOSS database (for patient with very early / very mild SSc) between 01 January 2009 and 30 October 2017 (date of data export) were analysed cross-sectionally. The first visit after 01 January 2009 was used to characterise patients. This date was chosen because by then the online documentation was introduced and more complex clinical data, including detailed information on therapies, were available. Collection of the data from the VEDOSS cohort started in July 2010 with participation of all EUSTAR centres including patients with a predisposition to develop early SSc according to recently developed criteria [20].

All patients agreed to participate in the EUSTAR/VEDOSS database by signing informed consent forms approved by the local ethics committees. Ethics approval has been obtained from the local ethics committees by all participating EUSTAR and VEDOSS centres and the corresponding ethics committee in Zurich gave approval for our study (KEK-BASEC-Nr. 2017-02102). The study was conducted in accordance with the principles of the Declaration of Helsinki, local laws and guidelines for Good Clinical Practice.

The database covers demographic aspects, disease duration, organ involvement, and laboratory and therapy data, which have been described in detail previously [7, 24]. For the present analysis, patients were grouped into late/established (patients fulfilling the ACR 1980 classification criteria), early/mild (patients fulfilling only the ACR/EULAR 2013, but not the ACR 1980 classification criteria) and very early / very mild patients (patients not fulfilling any of the classification criteria, but with evidence for SSc based on the VEDOSS criteria) [9, 17, 20]. Patients from non-European centres and patients with missing information for the classification criteria were excluded from the analysis.

First, a descriptive analysis from the Swiss cohort with EUSTAR and VEDOSS patients including disease characteristics, organ involvement, antibody profile and laboratory parameters was performed. Skin fibrosis was assessed by the modified Rodnan skin score [25]. Presence of organ involvement was defined as follows: interstitial lung disease (by low‐dose high‐resolution computed tomography [CT] and/or X-ray), kidney involvement (presence of renal crisis), conduction blocks (by electrocardiography), heart involvement on echocardiography (any of the following: pericardial effusion, diastolic dysfunction or left ventricular ejection fraction <50%), and clinical diagnosis of joint synovitis. The New York Heart Association (NYHA) functional classification was used to determine cardiac insufficiency. Clinical experts in the respective EUSTAR centres determined the presence of organ involvement or certain SSc parameters based on EUSTAR definitions [26, 27].

In a second step, characteristics of the Swiss EUSTAR patients were compared with European EUSTAR patients. Disease characteristics, organ involvement, antibody profile and survival were compared between the Swiss and European cohort by the subgroups diffuse cutaneous (dcSSc) and limited cutaneous SSc (lcSSc), according to the Le Roy criteria 1988 [28].

Statistical analysis

For this cross-sectional study and longitudinal survival analysis, continuous variables were tested for normal distribution with the Kolmogorov-Smirnoff test, and mean and standard deviation (SD) or median and interquartile range (IQR) were calculated. Categorical variables were presented as frequencies (percentages). Statistical evaluation between two groups was performed using the chi-square or Fisher’s exact test for categorical variables and the t-test or Mann-Whitney U test as appropriate for continuous variables. To address multiple testing, a Bonferroni correction (α/number of tests) was applied and only p-values ≤0.0011 (0.05/45) were considered statistically significant and marked as p*-values. Vital status was obtained at the latest follow up. Survival curves were computed with Kaplan-Meier analysis and survival estimates were statistically tested with the log-rank test. Statistical analysis was performed in IBM SPSS Statistics v. 23 software.

Results

Study population

Figure 1 Disease characteristics and organ involvement Switzerland and Europe.

Peripheral vasculopathy: digital ulcers ever; joint involvement: any of joint contracture, joint synovitis or tendon friction rubs; muscular involvement: any of muscle weakness or muscle atrophy; GIT (gastrointestinal tract) involvement: any of oesophageal (dysphagia, reflux), stomach or intestinal symptoms; ILD (interstitial lung disease): lung fibrosis on x-ray or HRCT; PAH (pulmonary artery hypertension): PAPsys >40 mm Hg by echo; heart involvement: left ventricular ejection fraction <45%; kidney involvement: renal crisis.

At the time of data export, the EUSTAR registry comprised a total of 10,863 European SSc patients (EUSTAR: 529 Swiss / 8036 European; VEDOSS: 150 Swiss / 757 European) with at least one available visit after 01 January 2009. Excluded were 383 patients with missing data for classification criteria (EUSTAR: 7 Swiss / 192 European; VEDOSS: 1 Swiss / 183 European) and 1008 Patients from EUSTAR fulfilling neither the ACR 1980 classification criteria nor ACR/EULAR 2013 (80 Swiss / 928 European). Thus, the final number of patients included in the analysis were 679 patients from Switzerland and 8793 patients from other European countries.

Analysis of the Swiss cohort

Of 679 Swiss patients, we found 401 (59.1%) established, 177 (26.1%) early/mild and 101 (14.9%) very early / very mild cases. Demographics and disease characteristics, organ involvement and antibody status are summarised in table 1 and table 2. There were 66% female patients among the established group and 88% in the early/mild and very early / very mild group. Age was similar in the established and early/mild groups (56.81 ± 13.61 and 57.46 ± 14.72 years, respectively) and lower in very early / very mild patients (47.70 ± 14.75 years). Over 94% in all groups were Caucasian and over 95% had Raynaud’s phenomenon. Age at onset of Raynaud’s phenomenon was again similar between established and early/mild (46.76 ± 16.53 and 47.23 ± 17.73 years, respectively) and lower for very early / very mild patients (39.93 ± 16.55 years). Age at onset of first non-Raynaud’s phenomenon symptom (disease onset) was lower in established (47.81 ± 15.2 years) than in early/mild patients (51.02 ± 16.4 years).

Specific analysis of the subgroups revealed certain characteristics: the very early / very mild patients showed typical early/mild disease features: abnormal nailfold capillaroscopy pattern in 58.4% patients, followed by presence of SSc-specific anti-centromere antibodies (ACA) in 42.6%, oesophageal involvement in 27%, puffy fingers (20.8%) and telangiectasia (13%). Presence of anti-Scl70 antibodies, anti-RNA polymerase antibodies (RNAP) III and digital ulcers was very low (4.0%, 7.4% and 4.0%, respectively). Creatine kinase and the inflammation markers C-reactive protein and erythrocyte sedimentation rate were elevated in a small number of the very early / very mild patients (9.1%, 7.0% and 5.3%, respectively).

In the early/mild group, an abnormal scleroderma pattern on nailfold capillaroscopy was present in 80.3% of the patients, followed by ACA antibodies (73.7%), puffy fingers (70.7%) and telangiectasia (50.9%), a typical feature of lcSSc [29]. As expected, organ involvement was more frequent than in very early / very mild patients: oesophageal involvement 50.0%, lung fibrosis 17.4%. Similarly, early/mild patients had more cardiovascular, gastrointestinal and vascular manifestations, as well as higher inflammation markers (table 2).

As expected, in established SSc, organ manifestations became even more frequent (table 2). Although the appearance of organ manifestations increased with disease severity, features that characterise early/mild SSc, such as puffy fingers and ACA, were less frequent in established patients. The number of males was more than two-fold higher in established SSc in comparison with early/mild and very early patients, consistent with previous studies in SSc [30–36]. Dyspnoea NYHA II was similar in all groups, but with more severe cases (NYHA III/IV) in established patients. As expected, lung involvement was highest in established patients with 44.5% of the patients having interstitial lung disease based on chest CT or X-ray.

Cardiovascular involvement with diastolic dysfunction and palpitation occurred often in established (33.8% and 16.6%) as well as early/mild patients (33.1% and 14.4%). Left ventricular ejection fraction (LVEF) <45% was rare in established (0.9%) and absent in early/mild and very early / very mild patients.

Gastrointestinal symptoms were very common in all groups and oesophageal symptoms were most often reported. Renal crisis was rare and only present in established patients. ANA (anti-nuclear antibodies) were found in all groups, in from 93–98%. Similarly, joint synovitis had a stable distribution among the groups, as did creatine kinase elevation.

Comparison of Swiss and European patients

Demographic information of all included Swiss and other European patients are listed in table 3. There was no difference found in age (55.7 ± 14.5 years Swiss / 55.4 ± 14.2 years European), and over 95% in both cohorts were Caucasian. There were more male patients in Switzerland (25% vs 16% European, p = 0.005). A significant difference in disease classification was found, with a higher prevalence of established patients in other European countries (84.7% vs 59.1% Swiss, p <0.0001) and consequently higher prevalence of early/mild (26.1% vs 8.5% European, p <0.0001) and very early / very mild patients (14.9% vs 6.7% European, p <0.0001) in Switzerland. Disease subsets according to Le Roy were similar: dcSSc 37.8% Swiss / 35.4% European and lcSSc 62.2% Swiss / 64.6% European [28].

Univariable comparison of Swiss and European established patients summarised in figures 1 and 2 revealed no major differences after correction for disease subsets. (Details in supplementary tables S2 and S3 in appendix 2.)

Figure 2 Skin fibrosis in Switzerland and Europe. dcSSc = diffuse cutaneous systemic sclerosis; lcSSc = limited cutaneous systemic sclerosis; mRSS = modified Rodnan skin score

Consistent differences were found for disease duration, which was significantly shorter in established Swiss patients: 5.0 years (1–12) vs 7.0 years (3–13) European, p* <0.0001). However, as only visits after 2009 were included in this analysis, this difference might be caused by a higher recruitment of patients into the database after 2009 in Switzerland without true differences in disease duration. To correct for this potential bias, we performed a subanalysis including only patients who had their first visit after 2009. In this subanalysis (82.1% of Swiss established SSc patients and 62.4% of European established SSc patients) there was still a shorter disease duration in the Swiss patients, but without reaching statistical significance: 5.0 years (1–12) vs 6.0 years (2–12) European, p = 0.055). Still, when looking at the whole cohort, disease duration was shorter in Swiss patients across subgroups: in dcSSc 4.0 years (1–9) Swiss / 5.0 years (2–11) European, p = 0.003; in lcSSc 6.0 years (2–13) years Swiss / 8.0 (4–15) years European, p = 0.015) and in Swiss early/mild patients (3.0 (1–9) Swiss / 5.0 years (2–11) European, p = 0.016). However, it did not reach statistical significance after conservative correction for multiple testing using the Bonferroni method (p-values ≤0.0011, marked as p*).

Despite the shorter disease duration, Swiss patients showed overall evidence of a more severe disease, particularly in the lcSSc subset. In patients with lcSSc, significantly higher percentage had tendon friction rubs (10.2% Swiss / 3.9% European, p* <0.0001), and diastolic dysfunction (39.0% Swiss / 21.7% European, p* <0.0001). Similarly, joint involvement (31.4% Swiss / 22.8% European, p = 0.002), gastro-intestinal tract involvement (76.6% Swiss / 67.7% European, p = 0.003) and renal crisis (2.4% Swiss / 0.9% European, p = 0.037) were more prevalent in Swiss lcSSc patients, but without reaching statistical significance after Bonferroni correction. In Swiss dcSSc patients, significant differences were found only for more prevalent RNA pol III antibodies (20.2% Swiss / 7.9% European, p* <0.0001). However, Swiss dcSSc patients did not show a milder disease than European dcSSc patients, despite of their shorter disease duration (table S2).

Survival analysis

During the median follow up (duration from disease onset to last visit / death) of 8.0 years (4–13) Swiss / 9.0 years (4–14) European for dcSSc and 10 years (5–16) Swiss / 12.0 years (6–18) European for lcSSc patients, 13/151 (8.6%) Swiss / 250/2526 (9.5%) European dcSSc and 16/248 (6.5%) Swiss / 295/4787 (6.1%) European lcSSc patients died. As illustrated in figures 3 and 4 , there was no significant difference of survival between Switzerland and Europe in either dcSSc or lcSSc patients. The 10-year survival estimate (standard error) in dcSSc was 91.8% (3.2%) Swiss / 93.1% (0.6%) European, and 15-year survival was 88.6% (4.5%) / 88.1% (1.0%), respectively. In lcSSc patients, 10-year survival was 92.2% (2.2%) Swiss / 97.1% (0.3%) European and 15-year survival was 91.1% (2.5%) / 94.0% (0.5%), respectively.

Figure 3 Kaplan-Meier survival analysis dcSSc patients. dcSSc = diffuse cutaneous systemic sclerosis; RP = Raynaud’s phenomenon.

Figure 4 Kaplan-Meier survival analysis lcSSc patients. lcSSc = limited cutaneous systemic sclerosis; RP = Raynaud’s phenomenon

Discussion

This is the first description of the Swiss EUSTAR cohort. Our cross-sectional analysis provides a detailed overview of the clinical profile of the Swiss SSc patients. Application of ACR 1980 classification criteria, the ACR/EULAR 2013 classification criteria and inclusion of patients from the VEDOSS database with very early / very mild and early/mild disease allowed us to include a wide range of SSc patients.

The current analysis showed that the Swiss EUSTAR/VEDOSS registry includes a larger part of the Swiss SSc population. Considering that the published prevalence estimates for Europe are 3 to 50 per 10⁵ [3, 4], the Swiss EUSTAR registry covers, with 8 per 10⁵, a remarkable part of the expected number of patients in Switzerland [37]. In general, prevalence numbers have to be interpreted with caution because they strongly depend on the definition of SSc and on the quality of the epidemiological data. In addition, prevalence data do not exist for Switzerland and are thus estimated from other European countries. However, even considering these limitations, the calculated 8 per 10⁵ lies within the expected range and allows us to assume a remarkable coverage of SSc patients in Switzerland. Still, one has to realise that the EUSTAR Swiss cohort does not cover all SSc patients, as registration is not mandatory. A centre effect with registration of more severe patients into the EUSTAR SSc expert centres can therefore not be excluded.

EUSTAR centres are requested to include all consecutive patients into the registry to avoid selection biases. Indeed, in the Swiss EUSTAR cohort, the frequencies of organ manifestations for different subsets of the disease, as well as other disease features, are very similar to those in other databases [3, 6, 24]. Accordingly, comparison of Swiss and European patients revealed no major differences after correction for disease subsets in the current analysis. These data support the assumption that the Swiss EUSTAR cohort is a representative cohort for Swiss SSc patients and can be used to further define specific national needs, to monitor the use of certain treatments and treatment responses, document the natural course of the disease over time and possibly even for socioeconomic estimates.

The only remarkable difference between the Swiss and European EUSTAR SSc patients was the shorter disease duration when first registered into the database. Even though the difference did not remain statistically significant after correction for potential confounding factors, a meaningful difference of a 1-year shorter disease duration for Swiss SSc patients remained. The most likely explanation for the difference is that the highly developed Swiss healthcare system allows early referral of patients with rare, orphan diseases such as SSc to expert tertiary centres. Early referral is of high importance for the care of SSc patients, as it provides a window of opportunity for early intervention and risk stratification before irreversible organ damage occurs. Delayed inclusion in the registry after the patient was seen and inclusion of selected rather than consecutive patients in other European SSc centres could also have played a role.

Early intervention has been shown to improve long-term outcome in other chronic inflammatory diseases [38]. However, despite their earlier referral, the Swiss EUSTAR SSc patients did not show a better long-term outcome. Survival was not significantly different in Swiss SSc patients compared with other European patients. Swiss patients with lcSSc even presented with evidence for more severe disease compared with the SSc patients from other European countries. Several possible explanations can be considered:

1. SSc interstitial lung disease is the most frequent cause of death in SSc [39]. Treatments have been implemented only during very recent years, including a more frequent use of mycophenolate mofetil and nintedanib, the first registered targeted therapy for SSc interstitial lung disease [40–45]. These novel treatments possibly affect survival only in the long term, which cannot be analysed when these changes in treatment occurred only recently. Longer-term follow up and re-analyses in several years could address this hypothesis.

2. With the exception of haematopoietic stem cell transplantation [46], which is recommended only for a small subgroup of patients with rapidly progressive SSc at high risk of organ failure [47], treatments modifying the overall disease course of SSc beyond single organ manifestations are not available at present. This does not exclude beneficial effects of early intervention with standard of care on specific organ manifestations and patient well-being, but it might not lead to an overall improvement in survival.

3. Most importantly, earlier referral as seen for the Swiss SSc patients might not be early enough. Indeed, a recent analysis of the EUSTAR database showed that patients who were seen as early as within the first year after onset of Raynaud’s phenomenon already had meaningful and frequent organ involvement [48]. This is further supported by data from the Norwegian national SSc cohort, which showed that SSc interstitial lung disease is already frequently detected at first presentation to the SSc centres, and only a few patients develop interstitial lung disease at follow up [49]. Thus, our and other data indicate that even more efforts are needed to be made to identify patients with SSc as early as possible, before meaningful organ damage occurs, to ensure referral to an expert centre and to initiate very early risk stratification and treatment.

Our study also has limitations: The EUSTAR registry is an observational real-life database. As such, it has missing data, which limited some of the analysis. For example, because of missing data, the ACR/EULAR criteria could not be calculated in 9.1% of EUSTAR patients, who then were not included into the analysis. However, for all key SSc characteristics, the EUSTAR database has a remarkably low amount of missing data (tables 1 and 2 ). After all, the EUSTAR database is run by mostly academic tertiary expert centres. There is no financial compensation for putting patients into the registry, which makes it difficult for smaller centres and private practices to contribute. Thus, while the Swiss SSc EUSTAR cohort covered remarkably a high percentage of the expected Swiss SSc patients, a recruitment bias for more severe patients cared for in tertiary centres cannot be excluded.

Taken together, our study provides the first report on the national Swiss EUSTAR cohort. Clinical profiles for different subforms of the disease were reported. We showed that the recruited patients are representative for a typical European SSc population, which emphasises the high burden of disease for SSc patients in Switzerland. Compared with other European centres, we could show an earlier referral of SSc patients. Despite this early referral, outcomes were not different in the Swiss SSc patients. This indicates that more efforts need to be made to allow referral of SSc patients at risk even before severe organ damage has occurred.

Appendix: Supplementary tables

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