C. Pfeiffer

Frequency of disease-associated and other nuclear autoantibodies in patients of the German network for systemic scleroderma: correlation with characteristic clinical features

IntroductionIn the present study, we analysed in detail nuclear autoantibodies and their associations in systemic sclerosis (SSc) patients included in the German Network for Systemic Scleroderma Registry.MethodsSera of 863 patients were analysed according to a standardised protocol including immunofluorescence, immunoprecipitation, line immunoassay and immunodiffusion.ResultsAntinuclear antibodies (ANA) were detected in 94.2% of patients. In 81.6%, at least one of the autoantibodies highly associated with SSc or with overlap syndromes with scleroderma features was detected, that is, anti-centromere (35.9%) or anti-topoisomerase I (30.1%), followed in markedly lower frequency by antibodies to PM-Scl (4.9%), U1-ribonucleoprotein (U1-RNP) (4.8%), RNA polymerases (RNAPs) (3.8%), fibrillarin (1.4%), Ku (1.2%), aminoacyl-transfer RNA synthetases (0.5%), To (0.2%) and U11-RNP (0.1%). We found that the simultaneous presence of SSc-associated autoantibodies was rare (1.6%). Furthermore, additional autoantibodies were detected in 55.4% of the patients with SSc, of which anti-Ro/anti-La, anti-mitochondrial and anti-p25/p23 antibodies were most frequent. The coexistence of SSc-associated and other autoantibodies was common (43% of patients). SSc-associated autoantibodies disclosed characteristic associations with clinical features of patients, some of which were previously not acknowledged.ConclusionsThis study shows that five autoantigens (that is, centromere, topoisomerase I, PM-Scl, U1-RNP and RNAP) detected more than 95% of the known SSc-associated antibody responses in ANA-positive SSc patients and characterise around 79% of all SSc patients in a central European cohort. These data confirm and extend previous data underlining the central role of the determination of ANAs in defining the diagnosis, subset allocation and prognosis of SSc patients.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis

Background Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. Objectives To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). Methods The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Results Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often ‘other antibodies’ (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. Conclusions These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients.

Objective. Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. Methods. The data of 3248 patients with SSc were analyzed. Results. Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. Conclusion. These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

Diagnostics of autoimmune bullous diseases in German dermatology departments.

Background: No consistent data are available on the currently employed diagnostic tools for autoimmune bullous diseases in Germany. The aim of this survey was to describe currently performed diagnostic methods for bullous autoimmune diseases in German dermatology departments.

An open, multicenter, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone

Current treatment of bullous pemphigoid (BP) is based on the long‐term use of topical and/or systemic corticosteroids, which are associated with a high rate of adverse events and increased mortality.

The Predict Study: low risk for digital ulcer development in patients with systemic sclerosis with increasing disease duration and lack of topoisomerase‐1 antibodies

DEAR EDITOR, Digital ulcers (DUs) pose a significant clinical problem in systemic sclerosis (SSc), having a major impact on patients’ quality of life and ability to work. DUs are extremely painful, slow to heal and difficult to treat. The conditions for the development of DUs, including both risk factors and protective factors, are only partially understood. It is known that among patients with SSc, 15–25% have active DUs. The percentage of patients with SSc who have or have had DUs in the past varies considerably, from 35% to 65%. Most of the clinical studies that have investigated clinical risk factors for DU development have used a cross-sectional design, in which a considerable number of patients (25–35%) did not have current DUs or a history of prior DUs. Of interest, in the cohort of the German registry the prevalence of DUs during follow-up did not change, whereas the prevalence of other organ involvement increased substantially over time (Moinzadeh et al. and unpublished observation). To date it is not known what percentage of patients with SSc will develop DUs during further disease evolution. The current study had a multicentre, observational design. All of the patients met the classification criteria as having limited cutaneous SSc or diffuse cutaneous SSc (dcSSc) according to the American College of Rheumatology (ACR) criteria of SSc and the LeRoy criteria. A small number of patients had symptoms compatible with overlap SSc. Patients had either current active DU (cohort 1), reliably documented SSc-related DU in the past (cohort 2) or no current active DU and no prior history of DU (cohort 3). Patients in cohort 3 were followed up at months 6, 12, 18 and 24 for the development of DU. Active DUs were defined as a loss of both epidermis and dermis in an area of at least 2-mm diameter at the distal phalanx of the fingers but not over bony prominences, encompassing the palmar (volar) area. The study was planned to be concluded

SAT0440 New Data on Renal Crisis and Predictive Markers from More Than 3000 Patients

Background To improve detection and follow-up of patients with systemic sclerosis, the German Network for Systemic Scleroderma (DNSS) was founded 2003 and comprise rheumatologists, dermatologists, pulmonologists and nephrologists from more than 40 medical centers. Renal crisis is rare but still a medical emergency in patients with SSc. Objectives Up to date, more than 3000 patients have been grouped into four descriptive disease subsets, i.e. limited cutaneous disease (lcSSc), diffuse cutaneous disease (dcSSc), overlap-syndrome and undifferentiated connective tissue disease (UCTD) with scleroderma features. Methods In this analysis, we have focused on renal crisis within the three main subsets, e.g. lcSSc, dcSSc and overlap-syndromes to identify baseline aspects, which are predictive for future SSc associated renal crisis. Results Recent analyses of up to now 3180 patients revealed that 56% of patients suffer from limited SSc (lcSSc), 34% from diffuse SSc (dcSSc) and 11% of patients were diagnosed with an overlap-syndrome. Eighteen patients developed a renal crisis (1.4%, 18/3180), while 10% (315/3180) were classified with kidney involvement and 8% (257/3180) with proteinuria. Of these, 66.7% (12/18) were diagnosed with the diffuse form of SSc, while just 27.8% (5/18) were diagnosed with lcSSc and 5.6% (1/18) with SSc-overlap syndromes. Predictive factors for renal crisis in our patient cohort included the diffuse form of SSc (odds ratio (OR) 4.6, p=0.005, 95%>confidence interval (CI) 1.6-13.5), a modified Rodnan skin score (mRSS) of more than 15 (OR 4.7; p=0.002, 95%>CI 1.7-13), positive anti-RNA polymerase (RNAP) autoantibodies (OR 24.6, p<0.0001, 95%>CI 6.1-99.5), tendon friction rubs (OR 5.4, p=0.004, 95%>CI 1.7-16.9), hypertension (OR 6.1, p<0.0001, 95%>CI 2.3-16.5), proteinuria (OR 11.8, p<0.0001, 95%>CI 4.3-32.1) and elevated CK-levels (OR 5.1, p=0.01, 95%>CI 1.4-18.9). Interestingly, positive anti-topoisomerase autoantibodies did not predict a higher risk for renal crisis. Patients diagnosed with renal crisis were significantly more frequent on ACE-inhibitors (61.1%, 11/18, p=0.001). Of these, 5 patients also suffered from proteinuria and 7 patients from hypertension. Patients on systemic glucocorticoids had also an increased risk to develop a renal crisis (OR 5.1, p=0.002, 95%>CI 1.8-14.3), independent of the dosage (> or <7.5mg/day). Conclusions Renal crisis has become a rare complication in SSc. The highest risk was associated with the detection of RNAP antibodies, followed by proteinuria, hypertension, tendon friction rubs, elevated CK-levels and a modified Rodnan skin Score above 15. Close monitoring of patients at high risk for SSc associated renal crisis is mandatory. Disclosure of Interest None declared

FRI0244 Assessing organ involvement and current symptoms as indicators for disease progression in 3047 patient cohort

Background To improve detection and follow-up of patients with systemic sclerosis, the German Network for Systemic Scleroderma (DNSS) was founded and initiated a registry gathering information on diagnosis, clinical symptoms and therapy of SSc patients. Methods Up to date, more than 3000 patients have been grouped into four descriptive disease subsets, i.e. limited cutaneous disease (lcSSc), diffuse cutaneous disease (dcSSc), overlap-syndrome and undifferentiated connective tissue disease (UCTD) with scleroderma features. Disease progress between initial patient registration (year 0) and fourth follow-up (year 4) was measured using organ involvement and present symptoms as indicators. Results Recent analyses revealed that 49% of patients suffer from limited SSc (lSSc), 31% from diffuse SSc (dSSc) and 10% of patients were diagnosed with an overlap-syndrome. 8% had an undifferentiated form while Scleroderma sine scleroderma was present in 0.7% of patients. Follow-up data are available from 1595 patients after one year, from 901 patients followed for two years, 573 patients followed for three years and 386 followed for at least four years. After four years a significant increase was detected in the frequency of pulmonary hypertension (PAH) (14.4% to 24.2%, p=0.001), lung fibrosis (38.8% to 47.6%, p=0.006), oesophagus involvement (58.5% to 74.8%, p=0.0001), bowel involvement (13.6% to 19.9%, p=0.03), Kidney (10.7% to 15.8%, p=0.03) and Heart (13.4% to 24.0%, p<0.0001) involvement. Disease subsets were associated with different organs being more frequently involved, i.e. lcSSc with PAH (13.5% to 25.0%, p=0.007), oesophagus (60.7% to 77.0%, p=0.0001) and colon involvement (7.3% to 11.6%, p=0.002); dcSSc with PAH (19.0% vs. 25.9%, p=0.035), lung fibrosis (63.5% vs. 71.4%, p=0.02) and heart involvement (19.1% vs. 27.7%, p=0.007). Interestingly, patients with overlap syndrome showed no significant change in organ involvement over time. Conclusions After four years of follow-up in a large well defined SSc cohort, a significant increase in frequency of organ involvement was observed, particularly with respect to the lung, GI-tract and heart. Patients with SSc should be followed at least annually for organ involvement, the frequency of follow-ups being increased depending on the disease activity. Disclosure of Interest None Declared

SAT0191 Disease Progression in SSC-Overlap Syndromes is Significantly Different from Limited and Diffuse Cutaneous SSC

Background Overlap syndromes are a very heterogeneous and remarkable group of patients, who present at least two connective tissue diseases (CTDs) at the same time, usually with a specific autoantibody status. Currently it is still debated, whether SSc patients showing signs of overlaps to other connective tissue diseases should be regarded as a specific disease subset. Objectives To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc). Methods We here present the data of a prospective study, involving well-defined 3323 patients, registered (with yearly follow-up informations) in a database of the German network for systemic sclerosis (DNSS). The following statistical methods were used: Kaplan-Meier analysis, cox regression, logistic regression, McNemar test as well as א2test/Fisher’s exact test. Results Among 3323 registered patients, 10% (325/3240) were diagnosed as SSc-overlap syndrome. Of these, 82.5% (268/325) were female with a mean age of 49, 2 ± 1.2 years. Significantly more of them developed musculoskeletal involvement, compared to lcSSc and dcSSc patients (37.8 %, 47.8%; p<0.0001) and carried significantly more often other antibodies (71.1%; p<0.0001), which were separated into U1RNP- (22.7%), Ro- (16.8%), PmScl- (11.5%) antibodies, followed by 10.8% with rheumatoid factors, 7.5% with La-, 5.8% with dsDNA- and 2.8% with Jo-1- and 2.6% with Ku-antibodies. The Kaplan-Meier analysis of the onset of organ involvement revealed a clear inclined position of overlap patients between patients suffering from lcSSc and dcSSc, especially regarding lung fibrosis and heart involvement. Patients suffering from PAH, oesophagus involvement and kidney involvement, overlap and lcSSc patients showed nearly similar curve progression (log rank<0.0001). Furthermore musculoskeletal involvement was significantly more frequent and more progressive in patients with overlap disease, followed by patients with dcSSc and lcSSc (log rank<0.0001). Conclusions These data support the current concept, that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different course of the disease, different proportional distribution of specific autoantibodies and skin/organ involvement. Disclosure of Interest None Declared