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Clinical and epidemiological research
Concise report
Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database
  1. Florian M P Meier1,
  2. Klaus W Frommer1,
  3. Robert Dinser1,
  4. Ulrich A Walker2,
  5. Laszlo Czirjak3,
  6. Christopher P Denton4,
  7. Yannick Allanore5,
  8. Oliver Distler6,
  9. Gabriela Riemekasten7,
  10. Gabriele Valentini8,
  11. Ulf Müller-Ladner1,
  12. EUSTAR Co-authors
  1. 1Department of Internal Medicine and Rheumatology, Justus-Liebig-University Gießen, Kerckhoff-Klinik, Bad Nauheim, Germany
  2. 2Department of Rheumatology, Basle University, Felix Platter Spital, Basel, Switzerland
  3. 3Department of Rheumatology and Immunology, University of Pecs, Pecs, Hungary
  4. 4Department of Rheumatology, RFH, London, UK
  5. 5Department of Rheumatology A, Paris Descartes University, Cochin Hospital, Paris, France
  6. 6Department of Rheumatology, University Hospital, Zurich, Switzerland
  7. 7Department of Rheumatology and Clinical Immunology, Charité University Hospital, German Rheumatism Research Centre, a Leibniz Institute, Berlin, Germany
  8. 8Department of Rheumatology, Second University of Naples, Naples, Italy
  1. Correspondence to Ulf Müller-Ladner, Department of Internal Medicine and Rheumatology Justus-Liebig-University Gießen Kerckhoff-Klinik, Benekestraße 2-8 D-61231, Bad Nauheim, Germany; u.mueller-ladner@ kerckhoff-klinik.de

Abstract

Objectives Systemic sclerosis (SSc) is a rare disease requiring multicentre collaboration to reveal comprehensive details of disease-related causes for morbidity and mortality.

Methods The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group initiated a database to prospectively gather key data of patients with SSc using a minimal essential dataset that was reorganised in 2008 introducing new items. Baseline visit data of patients who were registered between 2004 and 2011 were analysed using descriptive statistics.

Results In June 2011, 7655 patients (2838 with diffuse cutaneous (dc) and 4481 with limited cutaneous (lc) SSc who fulfilled the American College of Rheumatology diagnostic criteria had been registered in 174 centres, mainly European. The most prominent hallmarks of disease were Raynaud's phenomenon (96.3%), antinuclear antibodies (93.4%) and a typical capillaroscopic pattern (90.9%). Scleroderma was more common on fingers and hands than on any other part of the skin. Proton pump inhibitors (65.2%), calcium channel blockers (52.7%), and corticosteroids (45.3%) were most often prescribed. Among the immunosuppressant agents, cyclophosphamide was used more often in dcSSc than in lcSSc.

Conclusions The EUSTAR database provides an abundance of information on the true clinical face of SSc that will be helpful in improving the classification of SSc and its subsets and for developing more specific therapeutic recommendations.

https://doi.org/10.1136/annrheumdis-2011-200742

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    Introduction

    The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group was officially founded in June 2004 and defined its major aims as follows: (1) to foster the study and care of systemic sclerosis (SSc) and (2) to achieve a consensus on evidence-based standards for the management of patients with SSc.1 SSc is a rare and heterogeneous disease with a prevalence of around 5/105.2 Sometimes patients progress to a severe state and are at high risk of death, sometimes patients only present with painful Raynaud's phenomenon (RP) and skin sclerosis confined to fingers (limited scleroderma). The minimal essential dataset (MEDS) online database is one of the key efforts of EUSTAR and collects data on patients with SSc in yearly follow-ups. The MEDS includes basic demographics, disease characteristics and treatment details of patients with SSc; in addition, it hosts a biobank.3

    As of June 2011, 115 of 174 centres, mainly European, are participating in entering information online (available since 2008, http://www.eustar.org), but interested researchers and doctors from around the world can contribute in entering data, collecting biosamples, or by submitting clinical or basic research projects that run under the patronage of EUSTAR. To reveal the profile of the EUSTAR cohort, baseline visit data from all patients with SSc registered in the database to date were analysed.

    Methods

    Data sample

    A complete data export of all patients registered in the EUSTAR database as of June 2011 was reviewed using the baseline visit data. The structures of the database, the MEDS, and the inclusion criteria have been described previously.2 Approval of the local ethics committee was obtained by each participating centre and informed consent was given by registered patients. Only patients who have been classified according to the American College of Rheumatology (ACR) criteria4 were analysed. Subset classification according to the leRoy criteria is given.5 The subset ‘other’ was defined as skin sclerosis distal from the metacarpophalangeal joints.

    Data analysis

    Variables were chosen for descriptive analysis and data were checked for plausibility (online supplementary text S1). Each variable examined refers to the defined subset5 listed in each column (tables 1–3). In 2008, the database was restructured using online documentation instead of a paper version and new items were introduced. These are highlighted in the tables. The value of missing data for new items was calculated on basis of a subgroup (online supplementary table S2, see notes of tables).

    View this table:
    Table 1

    Patient characteristics of the European League Against Rheumatism Scleroderma Trials and Research cohort

    View this table:
    Table 2

    Disease characteristics of the European League Against Rheumatism Scleroderma Trials and Research cohort

    View this table:
    Table 3

    Treatments in the European League Against Rheumatism Scleroderma Trials and Research cohort

    Statistical analysis

    Variables were categorised as categorical or continuous. Categorical variables were analysed using χ2 or Fisher's exact test, as appropriate. For continuous data, median and IQR or mean value±SD were calculated. Gaussian distribution was tested using the normality test. Two-group comparisons between limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) were performed for non-categorical distributions using the Mann–Whitney U test or Student t test, when appropriate. p Values were considered statistically significant for p<0.05. All calculations were performed using SPSS 15.0.

    Results

    Patient characteristics

    At the time of complete data export from the EUSTAR database (June 2011), 7655 of 9165 patients (83.5%) included in the registry fulfilled the ACR criteria4 (for comparison between patients fulfilling and patients not fulfilling the ACR criteria see online supplementary table S1, inclusions per year available as online supplementary figure S1). In the remaining patients the diagnosis was made based on constellations of symptoms, signs, laboratory and functional studies. A total of 58.5% were classified as lcSSc,5 37.1% as dcSSc5 and 4.0% as ‘others’. Patients of the dcSSc group were significantly younger. Although female subjects were affected more often by dcSSc and lcSSc than men, the relative proportion of male subjects was higher in dcSSc than in lcSSc (sex ratio female/male 4:1 in dcSSc and 10:1 in lcSSc). Regarding ethnicity, the largest proportion consisted of Caucasian patients (89.2%); while Asian (6.2%) and African (2%) ethnicities represented only a minority in the registry. Of note, the mean body mass index was low in all patients (24.1±4.4 kg/m2).

    Disease characteristics

    The duration between the onset of RP and the onset of first non-RP symptoms differed between the SSc groups. The onset of the first non-RP symptom of the disease followed the occurrence of RP in patients with dcSSc on average in 1.8±5.5 and in lcSSc in 5.1±9.1 years. The mean age at onset of RP in all subsets was 42.2±14.9 years. The occurrence of RP (ever) was very high in all forms of SSc (96.3%). Characteristics that can occur during the course of the disease—for example, digital ulcers, scleroderma, joint synovitis, contractures, tendon friction rubs, muscle weakness and/or atrophy were significantly more common in the dcSSc group (table 2).

    As expected, the extent of skin thickening measured by the modified Rodnan skin score was higher in dcSSc (median of 16) than in lcSSc and ‘others’ (median of 6 and 3; p<0.001, table 2). Of note, the median of skin involvement of the upper extremity was higher than that of the lower extremity (6 vs 0, data not shown).

    Antinuclear antibodies were observed in more than 90% of the individuals. Positivity of anticentromere autoantibodies was more frequent in the limited form, whereas positivity of anti-Scl70 autoantibodies was more prevalent in the diffuse form, but both were also seen in each subset. About one-third of patients with dcSSc had raised levels of C-reactive protein. On average, erythrocyte sedimentation rate was increased in patients with dcSSc to 28±23 mm versus 23±20 mm in patients with lcSSc (p<0.001; table 2).

    Nailfold capillaroscopy revealed a scleroderma pattern in more than 90% of the patients. While the ‘active pattern’ as defined by Cutolo et al6 occurred more often in lcSSc and other forms (43.2% and 45.5%), the ‘late pattern’ was more common in dcSSc (46.5%; table 2).

    Organ involvement

    Lung

    Of all patients, 35.3% presented with dyspnoea either due to lung fibrosis (39.5%), suspected pulmonary arterial hypertension (PAH) by echocardiography7 (21.1%), both of them or for other reasons. Lung fibrosis on plain x-ray examination occurred significantly more often in patients with dcSSc (52%, p<0.001). Carbon monoxide transfer factor was significantly reduced in patients with lung fibrosis (58.6±20.4%), PAH (57.3±22.1%) or both (51.3±20.1%, data not shown) compared with the overall cohort (68.3%). Patients with PAH had a mean systolic pressure of the pulmonary artery of 46.8±15.5 mm Hg (data not shown). Oxygen was supplied in 2.8% of the cases (table 3).

    Gastrointestinal tract

    Symptoms of the gastrointestinal tract (GIT) were very common in all SSc groups. Manifestations of upper compared with lower GIT symptoms appeared more frequently.

    Cardiovascular system

    Diastolic dysfunction with a frequency of 17.4% was a widespread feature in all SSc groups. Palpitations were also common (23.7%), but conduction blocks could be found in only 11.0% on ECG.

    Kidneys

    Severe renal crisis (SRC) as a feared risk in SSc was documented in 2.1% of the cases (more details in table 2).

    Treatment

    Treatment data were available from a total of 1820 individuals (patient characteristics in online supplementary table S2). The most commonly prescribed drugs were proton pump inhibitors (65.2%), calcium channel blockers (52.7%), prednisone (45.3%, median 8 mg/day), angiotensin-converting enzyme inhibitors (20.8%), cyclophosphamide (15.9%, median 1000 mg per last 4 weeks), iloprost infusions (15.6%), non-steroidal anti-inflammatory drugs (14.7%), methotrexate (13.7%, median 12 mg/week) and diuretics (13.0%). The severe state of health in dcSSc resulted in an aggressive treatment that included more frequent use of immunosuppressant agents, especially prednisone and cyclophosphamide, than in the other subgroups (more details in table 3).

    Discussion

    To our knowledge, this is the largest collection of data describing the clinical profile of patients with SSc. The EUSTAR cohort includes mainly Caucasian patients with SSc (89.2%) with a higher prevalence for lcSSc (58.5%).8 The sex ratio for SSc is strongly shifted towards female subjects (6:1), but the relative proportion of male patients is higher in dcSSc.9 The mean body mass index of all patients in the EUSTAR cohort was low (24.1±4.4 kg/m2), suggesting either an impaired general state of health or reflecting the considerable problems of the GIT due to high prevalence of GIT symptoms.10 ,11 Severe skin affection of the upper extremity, especially of fingers and hands, is the hallmark of the disease, but has not been described in such detail before. More frequent affection of fingers and hands is an observation similarly recorded for the joint involvement in SSc, yet not explained.12

    Eighty-three point five per cent of the registered patients in the EUSTAR cohort correctly fulfilled the ACR criteria, leaving 15.1%, as possible, yet unclassified patients with SSc. This indicates the need to rethink new or altered criteria to include these forms accordingly.13 As the scleroderma pattern was highly prevalent in all SSc forms (90.9%) and only to some extent less frequent than antinuclear antibody positivity (93.4%) or RP (96.3%), all three are likely to play an important role in the early classification of patients with SSc in the future.13 The subset ‘other’, defined as skin sclerosis distal to metacarpophalangeal joints, includes patients with early SSc as well as overlap syndromes14 and stands for a heterogeneous group representing the largest proportion (50.5%) of patients who did not fulfil the ACR criteria (online supplementary table S1). However, the discrimination of lcSSc and dcSSc is well established and supported by the results of these data.

    Interestingly, patients with dcSSc showed increased levels of laboratory acute phase parameters for inflammation such as C-reactive protein or erythrocyte sedimentation rate, reflecting the inflammatory state of this subset. Severity of dcSSc is further underlined by a higher frequency of disease characteristic symptoms (eg, digital ulcers). Detailed analysis of lung involvement showed that lung fibrosis was significantly more common in dcSSc, but PAH was found at equal frequencies in both subsets, which is in accordance with the German scleroderma registry,15 but controversial compared with data from other studies.16 The same distribution was seen for the involvement of the GIT, the cardiovascular system and the kidneys, leading to the conclusion that dcSSc is associated with a higher morbidity than lcSSc.17 Therefore, attending doctors tended to use immunosuppressant agents, notably prednisone and cyclophosphamide, more regularly.

    SRC is a severe but rare complication with high mortality rates in the 1970s, which nowadays is manageable but still clinically challenging.17 Prednisone has been reported to be associated with an increased risk of SRC in SSc.18 As documented in the EUSTAR cohort, prednisone was often used to handle symptoms despite the fact of limited evidence.9 Thus, if truly inevitable, blood pressure and renal function should be regularly monitored in patients receiving steroids as stated in the EUSTAR recommendations for the treatment of SSc.18

    Taken together, this database supplies rheumatologists and related specialties with a body of information on the true clinical face of SSc and will therefore be very helpful in developing appropriate patient care by giving a solid view of the different aspects of this disease.

    Moreover, the collected data will clearly contribute to the next important goals of the EUSTAR initiative such as reclassification, better discrimination of SSc and its subsets as well as more specific therapeutic recommendations.

    Acknowledgments

    The authors and all EUSTAR centres are grateful for the continuing support of the European League Against Rheumatism.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Files in this Data Supplement:

      • Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
      • Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Collaborators EUSTAR Co-authors. (See online supplementary material for list of co-authors).

    • Funding EULAR.

    • Competing interests EUSTAR is supported by EULAR. There are no other competing interests.

    • Ethics approval Approval of the local ethics committee has been obtained by each participating centre

    • Provenance and peer review Not commissioned; externally peer reviewed.