M. Frerix

Update of EULAR recommendations for the treatment of systemic sclerosis

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment 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 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

Endocardial and myocardial involvement in systemic sclerosis – is there a relevant inflammatory component?

OBJECTIVES Myocardial manifestations of systemic sclerosis are mainly due to fibrotic remodeling. We report on two cases, where an endocardial and myocardial inflammation may be a relevant component of cardiac disease. CASE SERIES Case 1 presented with fulminant tricuspid failure in the absence of pulmonary hypertension and with newly developing systemic sclerosis. Myocardial biopsy and MRI supported endocardial and myocardial inflammation. Treatment with cyclophosphamide resulted in stabilization of cardiac function and normalization of cardiac enzymes. The patient died due to infectious complications. Case 2, also newly developed systemic sclerosis, presented with renal crisis and pulmonary alveolitis. Elevated cardiac troponin T persisted in the presence of cyclophosphamide treatment, subsequent MRI suggested myocardial inflammation. After stepping up treatment by addition of rituximab cardiac enzymes normalized and cardiac function stabilized. CONCLUSION We hypothesize that low-grade endocardial and myocardial inflammation may be more relevant in systemic sclerosis than appreciated previously.

The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis: Derivation and validation of a preliminarily revised EUSTAR activity index

Background Validity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised. Methods Three investigators assigned an activity score on a 0–10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate–multivariate linear regression analyses were used to define variables predicting the ‘gold standard’, their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0–10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS). Results A weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) >18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein >1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted <70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease. Changes in the index paralleled those of MSS (p=0.0001). Conclusions A preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies.

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.

Achenbach's Syndrome (Paroxysmal Finger Hematoma) With Capillaroscopic Evidence of Microhemorrhages

tracing and genetic ablation of ADAM12 perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med 2012;18:1262–70. 42. Bochet L, Lehuede C, Dauvillier S, Wang YY, Dirat B, Laurent V, et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res 2013;73:5657–68. 43. Desai VD, Hsia HC, Schwarzbauer JE. Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells. PloS One 2014;9:e86865. 44. Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Ann Rev Pathol 2013;8: 241–76. 45. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 2011;108:E1475–83. 46. Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J. A pericyte origin of spinal cord scar tissue. Science 2011;333: 238–42. 47. LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 2013;19:1047–53.

[The road to early diagnosis of systemic sclerosis : the evolution of diagnostic and classification criteria in the past decades].

Increasing knowledge about the rare disease systemic sclerosis (SSc) and improved diagnostic methods in recent decades has led to the possibility of diagnosing systemic sclerosis in earlier disease stages. In this review, we describe the evolution of diagnostic and classification criteria for SSc, beginning with the preliminary ARA criteria for the classification of SSc in 1980, then presenting the criteria for limited and diffuse cutaneous SSc by LeRoy et al. in 1988 and 2001, and finishing with a discussion of the recently published new ACR-EULAR classification criteria in 2013. In addition, we seize the ongoing discussion about the intermediate subtype of SSc and highlight whether the two special subtypes CREST syndrome as well as SSc sine scleroderma are similar or different from the limited cutaneous SSc subtype. Finally, we address the question when a patient should be referred to the rheumatologist and discuss potential red flags for early diagnosis of systemic sclerosis.ZusammenfassungDank der vielen neuen Erkenntnisse über das Erkrankungsbild der systemischen Sklerose und den Fortschritten in der Diagnostik der vergangenen Jahre kann die Diagnose in immer früheren Krankheitsstadien gestellt werden. In diesem Artikel möchten wir die Entwicklung der Diagnose- und Klassifikationskriterien über die letzten Jahrzehnte darstellen, beginnend bei den vorläufigen ARA-Klassifikationskriterien 1980 über die Kriterien von LeRoy et al. 1988 und 2001, bis hin zu den neuen ACR/EULAR-Kriterien 2013. Des Weiteren greifen wir die Diskussion über den sog. Intermediärtyp der systemischen Sklerose auf und behandeln die Sonderformen CREST-Syndrom und systemische Sklerose ohne Sklerodermie. Abschließend blicken wir auf die Entwicklung der Kriterien zur „very early diagnosis“ der systemischen Sklerose (VEDOSS), behandeln die Frage des richtigen Zuweisungszeitpunkts zum Rheumatologen und erläutern mögliche Frühwarnsymptome in der täglichen Praxis.AbstractIncreasing knowledge about the rare disease systemic sclerosis (SSc) and improved diagnostic methods in recent decades has led to the possibility of diagnosing systemic sclerosis in earlier disease stages. In this review, we describe the evolution of diagnostic and classification criteria for SSc, beginning with the preliminary ARA criteria for the classification of SSc in 1980, then presenting the criteria for limited and diffuse cutaneous SSc by LeRoy et al. in 1988 and 2001, and finishing with a discussion of the recently published new ACR-EULAR classification criteria in 2013. In addition, we seize the ongoing discussion about the intermediate subtype of SSc and highlight whether the two special subtypes CREST syndrome as well as SSc sine scleroderma are similar or different from the limited cutaneous SSc subtype. Finally, we address the question when a patient should be referred to the rheumatologist and discuss potential red flags for early diagnosis of systemic sclerosis.

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.

Is osteonecrosis of the lunate bone an underestimated feature of systemic sclerosis? A case series of nine patients and review of literature

Osteonecrosis of the lunate bone, also known as Kienböcks disease, is a very rare disease of unknown cause. Until today, only six cases of osteonecrosis of the lunate bone in patients with systemic sclerosis (SSc) have been reported in the literature. It is unknown whether these few cases reflect only a coincidence of two rare diseases or whether osteonecrosis of the lunate bone is a potential currently underestimated disease-associated feature of SSc. In this study, we report the clinical course of nine SSc patients with magnetic resonance imaging proven osteonecrosis of the lunate bone and discuss associated disease characteristics and potential underlying pathophysiological mechanisms. Overall, our observations suggest that osteonecrosis of the lunate bone is a frequent and so far under-recognized manifestation of SSc which might be linked to SSc-related vasculopathy. It is important to distinguish osteonecrosis of the lunate bone from wrist arthritis in SSc patients because the clinical treatment is different. In general, the clinical progression of osteonecrosis of the lunate bone seems to be slow in SSc patients. As most of the patients have only minor complaints, watchful waiting in combination with analgesic therapy seems to be a feasible treatment approach in most patients whether an operative intervention might be necessary in rapid progressive cases.

SAT0467 The Five Prospective Observational Trials of the International Systemic Sclerosis FP7-Health Research Project Desscipher: A Interim Report

Background Due to lack of adequate clinical research data, drug treatment of the rare disease systemic sclerosis (SSc) is commonly off-label. The international EC-funded research project DeSScipher (acronym for “to decipher the optimal management of systemic sclerosis”) was designed to increase the evidence-based treatment strategies for SSc patients and subsequently to improve their long-term quality-of-life. Objectives The primary objective is to compare the outcomes of different treatments with respect to efficacy and safety of currently used off-label drugs from the early to the advanced phases of the main SSc-associated organ dysfunctions in a routine rheumatology in- and outpatient setting. Methods Five prospective observational trials (OTs), carried out within the EULAR Scleroderma Trials and Research (EUSTAR) group, have been designed to analyze current treatment approaches of early functionally relevant manifestations such as digital ulcers (OT1) and hand arthritis (OT2) to the morbidity and mortality-driving manifestations such as interstitial lung disease (OT3), pulmonary hypertension (OT4) and severe heart disease (OT5). The study protocols are accessible at clinicaltrials.gov Identifiers NCT01836263, NCT01834157, NCT01858259, NCT01840748, NCT01829126. Results Between April 2013 and January 2015, 1781 SSc patients have been screened at 27 contributing EUSTAR centers. 1577 (89%) patients have been enrolled into at least one of the five OTs. In particular, 1179, 127, 981, 237 and 716 patients have been enrolled into OT1-5, respectively (3240 in total; a given patient could be enrolled into multiple OTs), which represents a baseline patient recruitment rate of 79% of the target number of 4098 patients (accordingly 226%, 79%, 59%, 25% and 91% of the required number of 522, 160, 1670, 960, 786 patients for OT1-5, respectively). The completion of 1-year (OT3, OT5) and 2-year follow-up visits (OT1, OT2, OT4) are pending. Conclusions DeSScipher is currently the largest prospective observational research project ever for SSc. While patient recruitment is still ongoing, preliminary results of the five OTs are expected in late 2015 and the final results depending on the completion of follow-up visits are expected between 2017 and 2018. Acknowledgements The DeSScipher project was funded by the European Communitys Framework Programme 7 (FP7-HEALTH-2012.2.4.4-2 - Observational trials in rare diseases) under grant agreement N° 305495. We acknowledge the contribution of the following EUSTAR centers: Wuppertal (member N°192), Lille (93), Bad Bramstedt (187), Moscow (78), Assiut (168), Moscow (190), Bucharest (100), Monserrato (142), Iasi (162), Cluj-Napoca (16), Frankfurt (124), Salford/Manchester (80), Tübingen (56), Ancona (34), Zagreb (51) and Roma (94). Disclosure of Interest None declared

Auf dem Weg zur Frühdiagnose der systemischen Sklerose

Increasing knowledge about the rare disease systemic sclerosis (SSc) and improved diagnostic methods in recent decades has led to the possibility of diagnosing systemic sclerosis in earlier disease stages. In this review, we describe the evolution of diagnostic and classification criteria for SSc, beginning with the preliminary ARA criteria for the classification of SSc in 1980, then presenting the criteria for limited and diffuse cutaneous SSc by LeRoy et al. in 1988 and 2001, and finishing with a discussion of the recently published new ACR-EULAR classification criteria in 2013. In addition, we seize the ongoing discussion about the intermediate subtype of SSc and highlight whether the two special subtypes CREST syndrome as well as SSc sine scleroderma are similar or different from the limited cutaneous SSc subtype. Finally, we address the question when a patient should be referred to the rheumatologist and discuss potential red flags for early diagnosis of systemic sclerosis.ZusammenfassungDank der vielen neuen Erkenntnisse über das Erkrankungsbild der systemischen Sklerose und den Fortschritten in der Diagnostik der vergangenen Jahre kann die Diagnose in immer früheren Krankheitsstadien gestellt werden. In diesem Artikel möchten wir die Entwicklung der Diagnose- und Klassifikationskriterien über die letzten Jahrzehnte darstellen, beginnend bei den vorläufigen ARA-Klassifikationskriterien 1980 über die Kriterien von LeRoy et al. 1988 und 2001, bis hin zu den neuen ACR/EULAR-Kriterien 2013. Des Weiteren greifen wir die Diskussion über den sog. Intermediärtyp der systemischen Sklerose auf und behandeln die Sonderformen CREST-Syndrom und systemische Sklerose ohne Sklerodermie. Abschließend blicken wir auf die Entwicklung der Kriterien zur „very early diagnosis“ der systemischen Sklerose (VEDOSS), behandeln die Frage des richtigen Zuweisungszeitpunkts zum Rheumatologen und erläutern mögliche Frühwarnsymptome in der täglichen Praxis.AbstractIncreasing knowledge about the rare disease systemic sclerosis (SSc) and improved diagnostic methods in recent decades has led to the possibility of diagnosing systemic sclerosis in earlier disease stages. In this review, we describe the evolution of diagnostic and classification criteria for SSc, beginning with the preliminary ARA criteria for the classification of SSc in 1980, then presenting the criteria for limited and diffuse cutaneous SSc by LeRoy et al. in 1988 and 2001, and finishing with a discussion of the recently published new ACR-EULAR classification criteria in 2013. In addition, we seize the ongoing discussion about the intermediate subtype of SSc and highlight whether the two special subtypes CREST syndrome as well as SSc sine scleroderma are similar or different from the limited cutaneous SSc subtype. Finally, we address the question when a patient should be referred to the rheumatologist and discuss potential red flags for early diagnosis of systemic sclerosis.