Ulf Mueller-Ladner

Items for developing revised classification criteria in systemic sclerosis: Results of a consensus exercise

Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated. Our objective was to select a set of items potentially useful for the classification of SSc using consensus procedures, including the Delphi and nominal group techniques (NGT).

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.

Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria

OBJECTIVES Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc. STUDY DESIGN AND SETTING A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs). RESULTS Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90). CONCLUSIONS Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.

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.

Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis

Objective To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest–specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation. Methods Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3−/−) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase–PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3−/− and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells. Results Tyro3−/− mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3−/− mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-κB and in vitro osteoclastogenesis were impaired in Tyro3−/− mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner. Conclusions These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.

Cerebral lesions in patients with connective tissue diseases and systemic vasculitides: are there specific patterns?

This study was performed to evaluate whether specific patterns of cerebral lesions can be identified in different rheumatic disease entities. In 132 patients with different connective tissue diseases and vasculitides (systemic lupus erythematosus [SLE], systemic sclerosis [SSc], mixed connective tissue disease [MCTD], Wegeners granulomatosis [WG], immunocomplex vasculitides, antiphospholipid antibody syndrome [APS]), cerebral magnetic resonance imaging scans were performed. Patients were examined clinically, and laboratory parameters including autoantibodies were determined. Distinct distibution patterns could be identified; in WG, most lesions were seen in the cortex, the periventricular region, basal ganglia, and pons. In both SSc and MCTD, highest numbers of lesions could be detected in the corticomedullary junction. In APS, basal ganglia and periventricular white matter were involved predominantly. Generally, the maximum score of cerebral lesions correlated significantly with patients’ age. Pathological values for antinuclear antibodies and increased levels of antiphospholipid antibodies were significantly correlated with the presence of cerebral lesions. WG patients and patients with other vasculitides most frequently showed neurological abnormalities. This study in patients with different rheumatic diseases showed distinct distribution patterns of cerebral lesions, which might help to differentiate between them.

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

OP0061 Update of Eular Recommendations for the Treatment of Systemic Sclerosis

Objectives The aim was to update the 2009 EULAR recommendations for the treatment of systemic sclerosis (SSc) [1] with a distinct focus on new therapeutic aspects. Methods Revision and update of the previous recommendations were performed according to the EULAR standard operating procedures. The task force consisted of 30 SSc experts from Europe and USA, two patients nominated by the pan-European patients association FESCA, a clinical epidemiologist and 3 fellows for systematic literature research. All centers from the EULAR Scleroderma Trials and Research (EUSTAR) group were invited to submit and select research questions concerning SSc treatment using a Delphi approach. A set of 46 research questions addressing 26 different interventions was selected for systematic literature research. The new recommendations were developed in a meeting, based on the available evidence while using a consensus procedure. Results Sixteen recommendations were developed (instead of 14 in 2009) which address treatments of several SSc-related organ complications: Raynauds phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement. Compared with the 2009 recommendations, the 2015 recommendations include phosphodiestase-5 (PDE5) inhibitors in the treatment of SSc-related RP and DUs, riociguat and new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE5 inhibitors for SSc-related PAH. The new recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressing SSc were added. In addition, the statement regarding sitaxentan for PAH was removed, because it was withdrawn from the market. A web-based internal evaluation of the new recommendations revealed high level of approval among task force members (average score >7 out of maximum 9) for all statements except the one regarding fluoxetine for RP (average score of 6,1). In addition, several comments regarding other treatments addressed in research questions and suggestions for the future SSc research agenda were formulated by the experts. Conclusions These updated and improved, data- and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations will also facilitate the directions for future clinical research in SSc. References Kowal-Bielecka et al. Ann Rheum Dis 2009;68:620) Acknowledgements The project is funded by a research grant of EULAR to the EUSTAR SSc recommendation group. All contributing experts will be listed as full coauthors on the respective presentations and publications. Disclosure of Interest O. Kowal-Bielecka Speakers bureau: Abbvie, Actelion, Pfizer, Roche, J. Fransen: None declared, J. Avouac: None declared, M. Becker Consultant for: Actelion, A. Kulak: None declared, Y. Allanore Consultant for: Bayer Pharma, Actelion, Pfizer, Sanofi-Aventis, CSL Behring, Roche, O. Distler Consultant for: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation., L. Czirjak Consultant for: MSD, Pfizer, Roche, Abbvie, UCB, BMS, Servier, Medac, Richter, Egis, C. Denton Grant/research support from: Actelion, CSL Behring, Novartis, Consultant for: Actelion, GSK, Bayer, Inventiva, Takeda, K. Fligelstone: None declared, J. Welling: None declared, U. Mueller-Ladner Grant/research support from: EULAR grant

Systemic sclerosis associated interstitial lung disease - individualized immunosuppressive therapy and course of lung function: results of the EUSTAR group

BackgroundInterstitial lung disease in systemic sclerosis (SSc-ILD) is a major cause of SSc-related death. Imunosuppressive treatment (IS) is used in patients with SSc for various organ manifestations mainly to ameliorate progression of SSc-ILD. Data on everyday IS prescription patterns and clinical courses of lung function during and after therapy are scarce.MethodsWe analysed patients fulfilling American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2013 criteria for SSc-ILD and at least one report of IS. Types of IS, pulmonary function tests (PFT) and PFT courses during IS treatment were evaluated.ResultsEUSTAR contains 3778/11,496 patients with SSc-ILD (33%), with IS in 2681/3,778 (71%). Glucocorticoid (GC) monotherapy was prescribed in 30.6% patients with GC combinations plus cyclophosphamide (CYC) (11.9%), azathioprine (AZA) (9.2%), methotrexate (MTX) (8.7%), or mycophenolate mofetil (MMF) (7.3%). Intensive IS (MMF + GC, CYC or CYC + GC) was started in patients with the worst PFTs and ground glass opacifications on imaging. Patients without IS showed slightly less worsening in forced vital capacity (FVC) when starting with FVC 50–75% or >75%. GC showed negative trends when starting with FVC <50%. Regarding diffusing capacity for carbon monoxide (DLCO), negative DLCO trends were found in patients with MMF.ConclusionsIS is broadly prescribed in SSc-ILD. Clusters of clinical and functional characteristics guide individualised treatment. Data favour distinguished decision-making, pointing to either watchful waiting and close monitoring in the early stages or start of immunosuppressive treatment in moderately impaired lung function. Advantages of specific IS are difficult to depict due to confounding by indication. Data do not support liberal use of GC in SSc-ILD.

Variable intrafamilial expressivity of the rare tumor necrosis factor-receptor associated periodic syndrome-associated mutation I170N that affects the TNFR1A cleavage site

We report on a 33-year-old female patient with a relatively mild clinical case of TNF-receptor associated periodic syndrome (TRAPS) and her 58-year-old father in whom end-stage renal disease due to TRAPS-related AA-amyloidosis has already developed. TRAPS was caused by a I170N mutation that has previously not been associated with amyloidosis. It remains unclear if an only mildly affected patient such as ours would benefit from treatment considering her father’s severe course of disease. The relevant literature on this problem is reviewed.