EARLY SCLERODERMA

Sustavna skleroza (SSc) kronična je autoimuna bolest obilježena visokim stupnjem heterogenosti i povezana s visokim morbiditetom, kao i s najvišim mortalitetom specifičnim za samu bolest, u odnosu na sve druge autoimune bolesti vezivnog tkiva. SSc moguće je jednostavno dijagnosticirati u uznapredovaloj fazi, dakle kad se već razvila obliterativna vaskulopatija te fibroza kože i unutrašnjih organa, ali teško je postaviti dijagnozu u ranoj fazi bolesti. Ta činjenica ograničuje mogućnost ranog liječenja i potencijalnog preveniranja razvoja bolesti i oštećenja tkiva. Raynaudov fenomen (engl. skr. RP) predložen je kao jedno od definirajućih kliničkih obilježja za dijagnozu „rane“ SSc te stoga pozornost valja poglavito usmjeriti na taj simptom, čak i u slučaju odsustva drugih znakova bolesti. Na temelju prethodnih dijagnostičkih kriterija dijagnoza SSc može biti postavljena nakon više godina od početka RP, pa i nakon pojave prvih simptoma nevezanih za RP. Ovaj je vremenski raskorak između pojave simptoma i postavljanja dijagnoze, ponajprije temeljen na fibrozi kože i unutrašnjih organa, „prozor mogućnosti“ koji bi mogao biti vrijeme za intervenciju u ranoj fazi bolesti te time potencijalno prevenirati oštećenje organa. Prijedlog definicije vrlo rane SSc jest stanje obilježeno RP-om, difuznom oteklinom prstiju, pozitivnim protutijelima specifičnima za bolest i patognomoničnim mirkovaskularnim promjenama vidljivima na kapilaroskopiji, a bez zahvaćenosti kože i unutrašnjih organa. U bolesnika s navedenim simptomima, radi otkrivanja pretkliničkih promjena na unutarašnjim organima u SSc, mogu se provesti i pretrage kao što su ezofagealna manometrija, ehokardiografija u B-modu i funkcijski testovi pluća. Nedavno su predloženi novi klasifikacijski kriteriji radi identificiranja bolesnika u najranijoj fazi bolesti. Međutim, prediktori tijeka bolesti i dalje su nepoznati te je stoga potrebno redovito praćenje, iako idealna učestalost kontrolnih pregleda nije utvrđena.Systemic sclerosis (SSc) is a chronic autoimmune disease, characterized by a high level of clinical heterogeneity and associated with a high morbidity along with the highest disease-specific mortality of all autoimmune connective tissue diseases. SSc is quite easy to diagnose in the advanced phase, i.e., when it has already evolved to obliterative vasculopathy and skin and internal organ fibrosis, but it is difficult to establish a diagnosis in the early phase. This limits the possibility to start early treatment, as well as the potential for prevention of disease evolution and tissue damage. Raynaud’s phenomenon (RP) has been proposed as one of the defining clinical features for the diagnosis of “early” SSc, so that particular attention should be paid to this symptom, even in the absence of other signs of the disease. Based on previous diagnostic criteria, the diagnosis of SSc can be delayed for several years after the onset of RP, and even after the onset of the first non-RP symptom. This time gap between symptoms and diagnosis, mainly based on dermal or internal organ fibrosis, is a ‘‘window of opportunity’’ that could represent a chance to intervene earlier in the disease course, thus potentially preventing organ damage. The definition of Very early SSc has been proposed as a state characterized by RP, puffy fingers, disease-specific autoantibodies, and pathognomonic microvascular alterations at capillaroscopy, without skin and internal organ involvement. In patients with the above symptoms further investigations such as esophageal manometry, B-mode echocardiography, and lung function tests are recommended to detect preclinical alterations of internal organs in SSc. Recently, new classification criteria have been proposed with the goal to identify patients in the earliest phase of the disease. However, as predictors of the future course of the disease are still unknown, patients must be followed up regularly, even though the ideal frequency of visits has not yet been established

Immunosuppression for interstitial lung disease in systemic sclerosis

The efficacy of immunosuppressors in the treatment of systemic sclerosis-interstitial lung disease is still matter of controversy. In this review we will analyse the evidence that immunosuppressors, despite not being able to reverse fibrotic changes, may help in slowing disease progression. Induction treatment with cyclophosphamide should be started as soon as possible in patients at risk for progression. Mycophenolate mofetil and rituximab have to be considered in patients who are unable to tolerate cyclophosphamide. After remission, maintenance treatment with mycophenolate mofetil or azathioprine should be started in order to preserve the benefits achieved during the induction treatment

Critical finger ischemia and myocardial fibrosis development after sudden interruption of sildenafil treatment in a systemic sclerosis patient.

Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud’s Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment

In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case–control study

Dermatomyositis; Polymyositis; Systemic sclerosisDermatomiositis; Polimiositis; Esclerosis sistémicaDermatomiositis; Polimiositis; Esclerosi sistèmicaBackground Some myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM). Objectives To assess the significance of DH/BS in patients with IM. Methods Practitioners from five IM networks were invited to report patients with IM suffering from DH/BS (without other known cause than IM). IM patients without DH/BS, randomly selected in each participating centre, were included as controls at a ratio of 2 to 1. Results 49 DH/BS-IM patients (DH: 57.1%, BS: 42.9%) were compared with 98 control-IM patients. DH/BS-IM patients were older (65 years vs 53 years, p<0.0001) and the diagnosis of IM was delayed (6 months vs 3 months, p=0.009). Weakness prevailing in the upper limbs (42.9% vs 15.3%), dysphagia (57.1% vs 25.5%), muscle atrophy (65.3% vs 34.7%), weight loss (61.2% vs 23.5%) and loss of the ability to walk (24.5% vs 5.1%) were hallmarks of DH/BS-IM (p≤0.0005), for which the patients more frequently received intravenous immunoglobulins (65.3% vs 34.7%, p=0.0004). Moreover, DH/BS-IM patients frequently featured signs and/or complications of systemic sclerosis (SSc), fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for this disease in 40.8% of the cases (vs 5.1%, p<0.0001). Distribution of the myopathy, its severity and its association with SSc were independently associated with DH/BS (p<0.05). Mortality was higher in the DH/BS-IM patients and loss of walking ability was independently associated with survival (p<0.05). Conclusion In IM patients, DH/BS is a marker of severity and is associated with SSc (scleromyositis)

Systemic Sclerosis Sera Impair Angiogenic Performance of Dermal Microvascular Endothelial Cells: Therapeutic Implications of Cyclophosphamide

In systemic sclerosis (SSc), dermal capillaries are progressively lost with consequent chronic tissue hypoxia insufficiently compensated by angiogenesis. Clinical studies reported that intravenous cyclophosphamide (CYC) may improve SSc-related peripheral microvascular damage. Recently, we showed that CYC treatment may normalize SSc sera-induced abnormalities in endothelial cell-matrix interactions. Our objective was to evaluate in vitro the effects of sera from treatment-naïve or CYC-treated SSc patients on dermal blood microvascular endothelial cell (dMVEC) angiogenesis, migration, proliferation and apoptosis. dMVECs were challenged with sera from 21 SSc patients, treatment-naïve (n = 8) or under CYC treatment (n = 13), and 8 healthy controls. Capillary morphogenesis on Geltrex matrix was significantly reduced upon challenge with sera from naïve SSc patients compared with healthy controls. When dMVECs were challenged with sera from CYC-treated SSc patients, their angiogenic capacity was comparable to that of cells treated with healthy sera. Wound healing capacity and chemotaxis in Boyden chamber were both significantly decreased in the presence either of naïve or CYC-treated SSc sera compared with healthy sera. WST-1 assay revealed that cell proliferation was significantly decreased in dMVECs challenged with sera from naïve SSc patients compared with healthy sera. Conversely, dMVEC proliferation was not impaired in the presence of sera from CYC-treated SSc patients. Accordingly, the percentage of TUNEL-positive apoptotic dMVECs was significantly higher in the presence of sera from naïve SSc patients than healthy controls, while CYC-treated SSc sera did not induce dMVEC apoptosis. Levels of the angiostatic mediators endostatin, pentraxin 3, angiostatin and matrix metalloproteinase-12 were all significantly elevated in sera from naïve SSc patients compared with sera from both healthy controls and CYC-treated SSc patients. In SSc, CYC treatment might boost angiogenesis and consequently improve peripheral microangiopathy through the normalization of the endothelial cell-matrix interactions, reduction of endothelial cell apoptosis and rebalance of dysregulated angiostatic factors

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

Objective: Systemic sclerosis (SSc) features multiorgan fibrosis orchestrated predominantly by activated myofibroblasts. Endothelial-to-mesenchymal transition (EndoMT) is a transdifferentiation by which endothelial cells (ECs) lose their specific morphology/markers and acquire myofibroblast-like features. Here, we determined the possible contribution of EndoMT to the pathogenesis of dermal fibrosis in SSc and two mouse models. Methods: Skin sections were immunostained for endothelial CD31 or vascular endothelial (VE)-cadherin in combination with α-smooth muscle actin (α-SMA) myofibroblast marker. Dermal microvascular ECs (dMVECs) were prepared from SSc and healthy skin (SSc-dMVECs and H-dMVECs). H-dMVECs were treated with transforming growth factor-β1 (TGFβ1) or SSc and healthy sera. Endothelial/mesenchymal markers were assessed by real-time PCR, immunoblotting and immunofluorescence. Cell contractile phenotype was assayed by collagen gel contraction. Results: Cells in intermediate stages of EndoMT were identified in dermal vessels of either patients with SSc or bleomycin-induced and urokinase-type plasminogen activator receptor (uPAR)-deficient mouse models. At variance with H-dMVECs, SSc-dMVECs exhibited a spindle-shaped appearance, co-expression of lower levels of CD31 and VE-cadherin with myofibroblast markers (α-SMA+ stress fibres, S100A4 and type I collagen), constitutive nuclear localisation of the EndoMT driver Snail1 and an ability to effectively contract collagen gels. Treatment of H-dMVECs either with SSc sera or TGFβ1 resulted in the acquisition of a myofibroblast-like morphology and contractile phenotype and downregulation of endothelial markers in parallel with the induction of mesenchymal markers. Matrix metalloproteinase-12-dependent uPAR cleavage was implicated in the induction of EndoMT by SSc sera. Conclusions: In SSc, EndoMT may be a crucial event linking endothelial dysfunction and development of dermal fibrosis

The Role of Bronchoalveolar Lavage in Systemic Sclerosis Interstitial Lung Disease: A Systematic Literature Review

The role of Bronchoalveolar Lavage (BAL) in the evaluation of systemic sclerosis (SSc) interstitial lung disease (ILD) is still controversial. The aim of this systematic literature review was to investigate the use of BAL in SSc-ILD, and to focus on the pros and cons of its real-life application. Methods: PubMed, Cochrane, and Embase were questioned from inception until 31 December 2021. Results: Eighteen papers were finally analyzed. A positive correlation was observed between lung function and BAL cytology; in particular, BAL neutrophilia/granulocytosis was related to lower diffusing capacity for carbon monoxide (DLCO) values and lower forced vital capacity (FVC). Moreover, a positive correlation between BAL cellularity and high-resolution computed tomography (HRCT) findings has been reported by several authors. Cytokines, chemokines, growth factors, coagulation factors, and eicosanoids have all been shown to be present, more often and in higher quantities in SSc-ILD patients than in the health control and, in some cases, they were related to more severe pulmonary disease. There was no consensus regarding the role of BAL cellularity as a predictor of mortality