Laura Susok

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.

Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis

Objectives Casein kinase II (CK2) is a constitutively active serine/threonine protein kinase that plays a key role in cellular transformation and tumorigenesis. The purpose of the study was to characterise whether CK2 contributes to the pathologic activation of fibroblasts in patients with SSc and to evaluate the antifibrotic potential of CK2 inhibition. Methods Activation of CK2, JAK2 and STAT3 in human skin and in experimental fibrosis was analysed by immunohistochemistry. CK2 signalling was inhibited by the selective CK2 inhibitor 4, 5, 6, 7-Tetrabromobenzotriazole (TBB). The mouse models of bleomycin-induced and TGFβ receptor I (TBR)-induced dermal fibrosis were used to evaluate the antifibrotic potential of specific CK2 inhibition in vivo. Result Increased expression of CK2 was detected in skin fibroblasts of SSc patients. Inhibition of CK2 by TBB abrogated the TGFβ-induced activation of JAK2/STAT3 signalling and prevented the stimulatory effects of TGFβ on collagen release and myofibroblasts differentiation in cultured fibroblasts. Inhibition of CK2 prevented bleomycin-induced and TBR-induced skin fibrosis with decreased dermal thickening, lower myofibroblast counts and reduced accumulation of collagen. Treatment with TBB also induced regression of pre-established fibrosis. The antifibrotic effects of TBB were accompanied by reduced activation of JAK2/STAT3 signalling in vivo. Conclusions We provide evidence that CK2 is activated in SSc and contributes to fibroblast activation by regulating JAK2/STAT3 signalling. Inhibition of CK2 reduced the pro-fibrotic effects of TGFβ and inhibited experimental fibrosis. Targeting of CK2 may thus be a novel therapeutic approach for SSc and other fibrotic diseases.

Interstitial Granulomatous Dermatitis Associated with Myelodysplastic Syndrome - Complete Clearance under Therapy with 5-azacytidine

Granulomatous skin diseases comprise a heterogenous spectrum of dermatoses that are characterised by a dermal infiltrate of predominantly histiocytes (1). Among this group, interstitial granulomatous dermatitis (IGD) is a term introduced by Ackerman in 1993 (2). It describes a rare form of granulomatous, non-infectious, reactive dermatosis that is frequently associated with rheumatoid arthritis (3, 4). However, several reports of drug-induced IGD and IGD associated with haematological malignan-cies exist as well (5–8). We report a case of IGD with un-derlying myelodysplastic syndrome (MDS). Successful treatment of MDS with 5-azacytidine led to a complete clearance of IGD, which might indicate a pathogenetic relationship of both diseases in this patient. To our know-ledge, only one previous report exists on the coincidence of IGD and MDS (9). Our report further suggests to screen for MDS or other haematologic malignancies in patients with IGD.CASE REPORT

T regulatory cells and other lymphocyte subsets in patients with bullous pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, and is associated with autoantibodies to the hemidesmosomal BP autoantigens BPAG1 and BPAG2.

Val/Val glutathione-S-transferase P1 polymorphism predicts nonresponders in psoriasis patients treated with fumaric acid esters.

Fumaric acid esters (FAE) are beneficial in the treatment of psoriasis. However, about a third of psoriasis patients do not respond to FAE. We aimed to determine whether glutathione-S-transferase (GST) M1 and GSTP1 polymorphisms are associated with treatment outcome in psoriasis patients treated with FAE. We studied 84 psoriasis patients who were treated with FAE for 3 months. FAE nonresponders were defined as having psoriasis area and severity improvement index less than 50% after 3-month therapy. GSTM1 genotyping for gene deletion and GSTP1 exon 5 105 Ile→Val polymorphisms were assessed using a high-resolution melting analysis. A dropout rate of 23.8% (20/84) was found; 25% (16/64) were FAE nonresponders. We observed 42 (84/50%) patients with G 9STM1*0 homozygous alleles and 42 (84/50%) patients with one or two active GSTM1 alleles. The Ile/Ile GSTP1 genotype was observed in 37 (84/44%), the Ile/Val GSTP1 genotype in 38 (84/45.2%) patients and the Val/Val GSTP1 genotype in nine (84/10.7%) patients. There was no significant (P>0.05) association between the GST genotypes assessed and the frequency FAE responder status, except for the Val/Val GSTP1 polymorphism, which was a significant (overall model fit; P=0.0012) predictor for nonresponders with an odds ratio of 43.4 (95% confidence interval: 4.2–511.1). The coefficient of regression was 3.9, with a SE of 1.2 as assessed by logistic regression analysis (P=0.0017). The Val/Val GSTP1 polymorphism predicts nonresponders in FAE treatment of psoriasis patients and may therefore serve as a biomarker that enables a laboratory-based pretreatment selection of patients.

AB0164 Disease Progression in 282 Patients with Undifferentiated SSc – Data from The German Network for Systemic Scleroderma

Background Systemic sclerosis (SSc) is a heterogeneous multisystem connective tissue disease, usually subdivided into the main SSc subsets, e.g. limited (lcSSc), diffuse SSc (dcSSc) and SSc overlap syndromes. However, some patients present with symptoms suggestive of, but not conclusive for a diagnosis of definite SSc. This subset has been referred to as undifferentiated or very early SSc. It was defined as positive RP together with at least one further feature of SSc and/or detectable SSc-specific autoantibodies. Objectives Methods Up to date, more than 3400 patients have been registered within the German network for systemic scleroderma. Disease progress after initial patient registration and further follow-up visits was analysed to determine, whether clinical features in patients with undifferentiated SSc change over time into definite SSc. Results Among 3473 registered patients, 8.1% (282/3473) were diagnosed with undifferentiated SSc. Of these, 87.5% were female with a mean age at onset of 59.9±1.5years. A significant difference was detectable comparing patients with undifferentiated SSc and lcSSc (54.8±0.5years; p<0.001) as well as dcSSc (49.8±0.6years; p<0.001). Positive antinuclear antibodies (ANA) were detectable in 219 (77.7%) patients; of these 40.2% were anti-centromer (ACA) positive and 12.8% anti-topoisomerase antibody (ATA) positive. No substantial difference regarding organ manifestations between patients with or without existing ANAs was found. 34.0% of undifferentiated SSc patients suffered from sicca symptoms, followed by 31.2% with gastrointestinal (GI) involvement, 30.5% with musculoskeletal involvement, 14.5% with lung fibrosis, 6.0% with heart involvement, 5.0% with pulmonary arterial hypertension (PAH) and 0.4% with renal crisis. Musculoskeletal involvement, sicca symptoms and heart involvement were found in a similar percentage in patients with undifferentiated and lcSSc. Lung fibrosis, PAH and GI involvement occurred significantly less in patients with undifferentiated SSc compared to lcSSc. Within a mean follow-up time of 3.6years, the majority of the patients classified initially as undifferentiated SSc, remained within this subset (76.6%), while only 16.3% converted into lcSSc. 4.6% were classified as dcSSc and 3.2% as SSc overlap syndromes. Conclusions Patients classified as undifferentiated SSc, develop clinical features suggestive of SSc at a significantly older age than other subsets (i.e. 5–10 years). During follow up progression into a limited, diffuse or SSc overlap syndrome subset was observed, however, the majority of undifferentiated SSc patients remained stable and did not develop definite SSc. Disclosure of Interest None declared

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