The patient registry of the German Network for Systemic Scleroderma (DNSS) was founded in 2003 and >4500 patient cases have been recorded as of now. The Network involves >40 clinical centers with different subspecialties including rheumatologists, dermatologists, pulmonologists and nephrologists. The Ethics Committee of the coordinating center, i.e. the Department of Dermatology at the University Hospital Cologne, approved the patient information and consent form of the DNSS registry (approval number, 04–037), which was used by all participating centers to receive the approval of their local ethics committees prior to registering patients. To participate in the study, written informed consent was obtained from all patients.
The four-page disease- and organ-specific questionnaire collects clinical data to determine the current disease status with information on gender, date of birth, onset of organ manifestations as well as current symptoms together with characteristic laboratory findings including antinuclear antibodies and therapies as recently described.[2,19]
Definition for Organ Manifestations and Clinical Signs
RP was defined by repetitive spasms of small digital arterioles/arteries at fingers and/or toes. The first non-RP onset has been defined as the time/age when first skin changes or first organ manifestation (first non-RP symptom) has occurred. For skin manifestation, we used the modified Rodnan Skin Score (mRSS).
PH was defined by an increase of the mean pulmonary arterial pressure (PAPm) of ≥25 mmHg in rest, evaluated by right heart catheterization. Additionally, an estimated right ventricular systolic pressure (RVSP) >35/40 mmHg as determined by echocardiography was used to define likely PH. Lung fibrosis was defined by bilateral fibrosis, confirmed by both X-ray and high-resolution CT scan of the chest together with restrictive pulmonary changes seen in the pulmonary function test [forced vital capacity (FVC) <80%]. Gastrointestinal involvement included gastrointestinal motility disturbance, dysphagia, nausea, malabsorption, oesophageal stenosis, gastroesophageal reflux or intestinal pseudo-obstruction. Heart involvement was defined as one of the following: dyspnea (NYHA), syncope, palpitations, pericarditis, conduction disturbance or diastolic dysfunction on the echocardiogram. Kidney involvement was defined as the presence of renal insufficiency secondary to acute renal crisis (creatinine clearance age-related <80 mL/min). The diagnosis of proteinuria was fulfilled in cases of albuminuria ≥30 mg/24 h or ≥20 mg/l as well as proteinuria ≥300 mg/24 h or ≥200 mg/l. Skeletal muscle involvement was present in case of proximal muscle weakness or atrophy recorded on clinical evaluation and raised serum muscle enzyme levels [creatinkinase (CK) >3 times higher than the upper limit of the reference range]. The diffusing capacity for carbon monoxide (DLCO/SB) was defined as diffusing capacity or transfer factor of the lung for carbon monoxide with a range of 20–95%; the standard value is >75%. Digital ulcers were defined as loss of dermis and epidermis of at least 2 mm of tissue at the fingertips.
Definition of Included SSc Subsets
The registry encompasses five different subsets of SSc including early undifferentiated forms (early and very early SSc), SSc sine scleroderma, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc) and SSc overlap syndromes. Patients included fulfilled the ACR/EULAR 2013 classification criteria. The SSc subset (lcSSc, dcSSc) was based on the classification criteria established by LeRoy et al..[18,21] Follow-up visits were performed at least once per year.
In the present analysis, we focused on patients with lcSSc, dcSSc and SSc overlap syndromes. Furthermore, we excluded patients with missing information on date of disease onset and patients with time since disease onset >20 years at registration. Using this selection, data of 3281 patients registered between 2003 and 2018 with 8079 follow-up visits were reviewed for this analysis.
Patients suffering from lcSSc were defined by skin sclerosis of the extremities distal to the knee and elbow joints and facial skin. The RP usually appeared many years prior to skin involvement and patients were mostly positive for ACA, which is in line with previously published data.[18,19] Patients with dcSSc had a progressive course of disease with an early onset of RP (usually within 1 year prior to the onset of first skin thickening). These patients are defined by rapid skin involvement of the trunk, face, proximal and distal extremities and they most frequently are anti-topoisomerase (ATA) antibody positive.[2,18] SSc overlap syndromes showed clinical features of SSc, according to the ACR criteria, or main SSc-associated symptoms, simultaneously with those typical for other rheumatic diseases.[2,22] These patients, although showing a limited expression of skin sclerosis, are considered as a separate SSc subset, distinct from lcSSc and dcSSc patients.
Age at Disease Onset – Three Main Subgroups
In addition to the assignment to the three main SSc subsets, we assigned the patients to three age groups according to the disease onset [<40 years (early disease onset), 40–60 years (standard disease onset), and >60 years (late disease onset)]. The disease onset was defined as the age of the onset of the first non-RP symptom.
An association of specific age groups with other clinical data was descriptively evaluated comparing patients younger than 40 years, between 40 and 60 years and older than 60 years. To compare demographic and serological parameters, we used data of the initial visit. To compare organ manifestations, clinical symptoms and medication, we used follow-up data on all visits (i.e. organ manifestation at last follow-up visit, and clinical symptoms/medication use ever/never documented at any visit). For group comparisons, we used Pearson's χ 2 test (qualitative data) and Kruskal–Wallis test (quantitative data). To compare the disease progression within the three age subgroups, the onset of different organ involvements is illustrated within the course of the disease. For this purpose, the proportion-free of organ involvement was estimated using Kaplan–Meier method and compared using log rank tests. Results are presented as Kaplan–Meier curves and as rates with corresponding 95% confidence intervals at time points 5 and 10 years after SSc onset (time of first non-RP manifestation, starting-point used for Kaplan-Meier analysis). All reported P-values are two-sided and P-values of <0.05 were considered statistically significant. As the analyses were regarded as explorative, we did not adjust for multiple testing. Calculations and figures were carried out using SPSS (22.214.171.124 64-Bit, IBM Corp., Armonk, NY, USA) and Excel (Microsoft Corp., Redmond, WA, USA) as well as R (version 3.4.0, R Foundation for Statistical Computing, Vienna, Austria).
Rheumatology. 2020;59(11):3380-3389. © 2020 Oxford University Press