The Association of Telangiectasias with Other Peripheral Vascular Lesions of Systemic Sclerosis.

Purpose: Systemic sclerosis (SSc) is a relatively rare collagenosis manifested as microvasculopathy, excessive cutaneous and visceral fibrosis in a background of autoimmune alteration. Autoimmune vasculopathy in SSc occurs early and begins with endothelial cell activation followed by blood vessel intimal proliferation in a context of defective angiogenesis. The alteration of peripheral micro and macrocirculation in SSc is evident through vascular lesions, such as Raynaud's phenomenon, telangiectasias, acrocyanosis, digital ulcers, gangrene, peripheral pulse deficiency. Our paper details the results of the study on the association between telangiectasias and other types of immune-mediated peripheral vascular lesions that can be identified in SSc. The presence of these peripheral vascular lesions can provide information about the magnitude of the peripheral vasculopathy. Patients and Methods: A total of 37 patients diagnosed with SSc, recruited from a university clinic in Bucharest between February 2019 and March 2020, were enrolled in an observational study. We evaluated the presence of telangiectasias, as a stigma of autoimmune microvasculopathy, and their association with other immune-mediated peripheral vascular lesions that may be present in SSc. Results: The presence of telangiectasias was identified in the absence, but especially in the presence of acrocyanosis and digital ulcerations, and patients with peripheral pulse deficiency almost always had telangiectasias. Less than a quarter of the patients with digital ulcers progressed unfavorably to gangrene, and only one required amputation, telangiectasias being present not only in the patient with amputation but in all patients with gangrene. Conclusion: We appreciate that telangiectasias may be the clinical expression of peripheral vasculopathy characteristic of SSc, they can often be present in association with other peripheral vascular lesions and may represent a valuable indicator for the gangrene risk of digital ulcerations in SSc.

Pathogenesis of Musculotendinous and Fascial Injuries After Physical Exercise - Short Review.

Purpose: The identification of sports and physical exercises with injury risk is necessary to preserve the capacity of athletes and people who perform physical education and also to prevent the installation of functional deficiencies. Methods: We have selected the articles related to the pathogenic mechanisms involved in musculotendinous and fascial injuries produced as a result of physical exercise. Results and Discussions: The lesional pathogenesis is complex and incompletely clarified. Recent theories put in a new light the mechanisms of muscle pain and tendinopathy production. The accumulation of lactate anion, known to be a residue that induces fatigue and muscle pain, has been reconsidered by some authors. It appears that lactate anion is an excellent fuel for the myocardial fiber. Moreover, the accumulation of lactic acid after intense physical exercise could prevent the inexcitability of the sarcolemma induced by the increased concentration of interstitial K+. Most of the time, overuse injuries are not limited to muscles. They can cause myofascial, myotendinous or purely muscular injuries. The muscular fascia is more susceptible to injuries produced under the action of large external forces. Also, fascia is more sensitive to pain compared to muscle when external forces act eccentrically. Overloading the tendon and putting it under tension repeatedly is followed by ruptures of the tendon fibers. The regeneration of the degenerated tendon is defective in the context of the inflammation produced by the injury. Tendon fibers undergo a process of fibrosis, scarring, adhesion and heterogeneous calcification. Oxidative stress is responsible for inflammation, degeneration and apoptosis of tenocytes. Conclusion: The benefits brought by physical education and sports are indisputable, but their practice requires a coordinated program to prevent possible traumatic and overuse injuries.

Immunologic and nonimmunologic sclerodermal skin conditions - review.

Scleroderma-like cutaneous lesions have been found in many pathological conditions and they have the clinical appearance of sclerotic or scleroatrophic lesions. Affected skin biopsies described histopathological changes similar to those of scleroderma located strictly on the skin or those of systemic sclerosis. These skin lesions can be found in inflammatory diseases with autoimmune substrate (generalized morphea, chronic graft versus host disease, eosinophilic fasciitis), tissue storage diseases (scleredema, scleromyxedema, nephrogenyc systemic fibrosis, systemic amyloidosis), metabolic diseases (porphyrya cutanea tarda, phenylketonuria, hypothyroidism, scleredema diabeticorum), progeroid syndromes. Given the multiple etiologies of sclerodermal lesions, a correct differential diagnosis is necessary to establish the appropriate treatment.

Principles of Treatment and Clinical-Evolutionary Peculiarities of Deep Cervical Spaces Suppurations-Clinical Study.

As medical-surgical emergencies, regardless of the causal agent, deep cervical space suppurations are not only a diagnostic challenge, but also a therapeutic one. In some cases, in spite of proper therapeutic measures, extremely severe complications can develop. A 5-year retrospective study (2016-2020) was conducted on a group of 107 patients suffering from cervical suppurations, being hospitalized and treated in the ENT Clinic of the "Sf. Apostol Andrei" Emergency County Hospital of Galați. This research is a clinical-statistical study based on the experience of this ENT clinic and was carried out based on the analysis of the patients' medical records. Descriptive analysis' statistical methods of the data series collected from the clinical observation sheets were used, with the patients' informed consent for the processing of the aforementioned data, with the agreement of the Ethics Commission of the Emergency Clinical Hospital "Sf. Apostol Andrei" Galați and the College of Physicians Galați, România. The patients' clinical and multidisciplinary treatment features included in the study group are presented. The results highlight the clinical particularities of deep cervical space suppurations treatment, including under COVID-19 impact, or with other comorbidities, having consequences on the case mix index increase or directly on the costs, admittance duration and the clinical status of the patient at discharge. The conclusions of the clinical study are based on the fulfillment of the research objectives in terms of treatment and symptomatology of deep cervical space suppurations and under the impact of comorbidities (global health crisis and pandemic, triggering of comorbidities due to health care access difficulty in the context of anti-COVID-19 government-implemented measures and the infection-rate that overburdened the medical system in the early period of the pandemic). Individualized treatment of deep cervical space suppurations is recommended to be approached multidisciplinary. Of particular importance is early diagnosis combined with prompt and correctly instituted multidisciplinary treatment. In this context, an appropriate medical measure that we recommend is patient health education, as it was observed in the clinical study: most times, patients address medical services with advanced disease, hence the generally unfavorable prognosis and outcome (about 25% of patients develop unfavorable prognosis and 4% die).

Multimodal Considerations Concerning Basal Cell Carcinoma Clefting - Profile of Structural and Aggressive Traits - Perspectives.

Although basal cell carcinoma is a well-known tumor with confirmed clinical and histopathology traits, prognosis factors and treatment options, new facets of this tumor emerge as innovative approach methods develop. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) allow a basal cell carcinoma's in vivo analysis of its depth of invasion, tumor margins prior to surgical approach and the tumor's response to a non-invasive treatment, evaluating simultaneously the tumor's vasculature. By RCM and OCT analysis, basal cell carcinoma has registered a groundbreaking discovery regarding a small (but with predictive factor potential) trait - the cleft, developing in between the tumor islands/nodules/chords and the surrounding tumor stroma; it was considered to date as a consequence of the tissue's histopathology processing. RCM and OCT revealed that the "clefting artifact", as it is frequently found in the medical literature, is not actually an artifact of laboratory processing, but a tumor trait found in vivo, with apparent mucin deposits. This review aims at merging the methods of evaluating basal cell carcinoma, both non-invasive (dermoscopy, RCM, OCT) and invasive ones (histopathology - with newly proposed classification), with special emphasis on the cleft issue - its assessment with the aforementioned techniques, with potential implications in the patient's prognosis.

Hearing Loss Secondary to Systemic Sclerosis Vasculopathy: Case Study with a Short Review.

Systemic sclerosis (SSc) is a collagenosis with a substrate of chronic inflammation, which is determined by autoimmunity. The pathogenesis of this disease involves microvasculopathy (small vessel pathology) followed by excessive cutaneous and visceral fibrosis. Although acoustic and vestibular impairment is not classified as being a secondary pathology of SSc, several studies have identified cases of SSc that associate hearing loss and especially vertigo and tinnitus. This paper presents data from the medical literature that have identified vestibular and auditory symptoms among patients with SSc, associating the clinical case presentation of a patient suffering from SSc, which is associated with hearing loss. The need for additional studies on larger groups of patients is underlined, in order to clarify the impact of vasculopathy and fibrosis on the acoustic and vestibular analyzer in patients with SSc.

CREST Syndrome in Systemic Sclerosis Patients - Is Dystrophic Calcinosis a Key Element to a Positive Diagnosis?

Introduction: CREST syndrome is a clinical entity associated with systemic sclerosis, which meets at least three of the five clinical features: calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. Three of these clinical features (Raynaud's phenomenon, sclerodactyly and esophageal dysmotility) are often present in classical subsets of SSc: limited and diffuse, and their presence in association does not define CREST syndrome. Calcinosis seems to be less common in SSc and its association with other clinical features is characteristic of CREST syndrome. Therefore, it can be appreciated that calcinosis is the key element of CREST syndrome. Methods: This study included a number of 37 candidates with SSc, diagnosed with the help of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2013 criteria. Results and Discussions: These three elements (calcinosis, Raynaud's phenomenon, esophageal dysmotility) were recorded both in the limited subset of SSc, but especially in the subset of diffuse SSc, contrary to the data in the literature. Conclusion: We appreciate that CREST syndrome is a clinical entity that can overlap with both subsets of SSc. Given the divergent views of the authors on the classification of CREST syndrome, future studies may contribute to a reassessment of SSc classification.

Paraclinical Aspects in Systemic Sclerosis.

Systemic sclerosis (SSc) is a chronic inflammatory disease with an autoimmune substrate that affects the skin and a large number of internal organs. The chronic inflammatory process is sustained by a wide range of cytokines and chemokines, which are discharged by inflammatory cells, with fibrosis and nail bed vascular changes (disorganized vasculature architecture with microhemorrhages, megacapillaries and areas without capillaries). Confocal microscopy contributes to the understanding of the molecular mechanism involved in chronic inflammation and mainly targets the field of research. Coherent optical tomography, capillaroscopy, and skin biopsy are useful for the differential diagnosis of SSc with other sclerodermoid syndromes. The immunological profile is a classification criterion for SSc and directs the diagnosis to the two subsets of the disease. Multisystemic damage requires evaluation with the help of a set of investigations specific to each affected organ, such as: diffusing capacity for carbon monoxide, forced vital capacity, 6-minute walk test, high-resolution computed tomography standard and reduced sequential, cardiac ultrasound and right cardiac catheterization. The current possibilities of diagnosis, treatment and monitoring are permanently adapting to new medical discoveries.

Old and new therapeutic strategies in systemic sclerosis (Review).

Systemic sclerosis (SSc) is a chronic inflammatory disease with autoimmune determinism having an incompletely known pathogenesis. Although not all links in the pathogenic chain are known, studies have shown that vasculopathy is the initial event and is followed by extensive fibrosis of the skin and internal organs. New therapeutic strategies have been developed in recent years, thanks to innovative research which has increased understanding of the disease mechanisms. No curative treatment for SSc is currently known. Therefore, the therapeutic target in SSc is its symptomatology. Peripheral vasculopathy can be improved by administering vasodilators. Endothelin receptor antagonists and 5-phosphodiesterase inhibitors have a double benefit, both on peripheral and on pulmonary vasculopathy. Several molecules with antifibrotic effects are currently available; however, further studies are needed to confirm their beneficial effects. Immunosuppressants manage to control the cutaneous and visceral fibrotic process, thereby remaining as first-line drugs in the treatment of SSc. Although biological therapy using rituximab and tocilizumab has shown promising results in pulmonary fibrosis, ongoing studies are needed to determine their exact impact. The authors have differing views on the triggering role of glucocorticoids and the benefits of angiotensin-converting enzyme inhibitors in renal scleroderma. Some aspects of this disease such as calcinosis and pruritus, asthenia, or joint and muscle damage, remain difficult to manage.

Basal cell carcinoma: Comprehensive clinical and histopathological aspects, novel imaging tools and therapeutic approaches (Review).

Basal cell carcinoma (BCC) is one of the most common malignant tumors worldwide, involving the skin. It is also part of keratinocyte carcinomas, alongside its squamous counterpart. It has low mortality and extremely low metastatic rates (although when present, it indicates a poor patient prognosis); it also has a high morbidity rate through local destruction and recurrence, particularly when perineural invasion is observed, clinically or histopathologically. BCC development is the result of environmental and patient factors, with genetics and ultraviolet radiation playing major roles. The clinical and histopathological aspects vary according to tumor subtype, being classified as high-risk tumors (nodular, superficial, pigmented and infundibulocystic BCC with adnexal differentiation) and fibroepithelial subtypes, or as high-risk tumors (micronodular, infiltrating, sclerosing/morphoeic and basosquamous subtype or the type with sarcomatoid differentiation). Dermoscopy is now complimented by novel in vivo diagnostic tools (optical coherence tomography, reflectance confocal microscopy, high-resolution ultrasonography, Raman spectroscopy or terahertz pulse imaging), improving the diagnostic accuracy and providing tumor depth and lateral margins without the use of invasive techniques. Novel treatment approaches for the treatment of BCC have recently been investigated with the use of hedgehog pathway inhibitors, such as Vismodegib. These approaches aim for complete resolution, minimal side-effects, high patient satisfaction with the optimal cosmetic results, particularly in key areas, such as the face. The present review article summarizes and discusses the comprehensive clinical and histopathological aspects of BCC, and presents novel imaging tools and therapeutic approaches that have been identified.

Cutaneous adverse reactions in a lung cancer patient treated with pembrolizumab: A case report.

Lung cancer is the main cause of oncological death in the US and worldwide, constituting a significant public health problem. The incidence of lung cancer is on the increase. In the present study, the diagnostic process was carried out and treatment options were considered to determine the therapeutic response of a patient diagnosed with lung cancer. The case of an early stage lung cancer patient who benefited from surgical treatment was presented. The pathology report stated the complete diagnosis to be pleomorphic lung cancer with an adenocarcinoma component, pT2aN0M0, with focal positivity for thyroid transcription factor 1 (TTF1), without epidermal growth factor receptor (EGFR) mutations and ALK recombinations, having an initial clinical stage of IB and programmed death ligand-1 (PD-L1) positivity with a tumor proportion score of over 70%. The patient underwent radiotherapy treatment and was administered osteoclast inhibitors and immunotherapy, with no favorable therapeutic effect and with the presence of secondary cutaneous adverse effects to pembrolizumab. As a main cause of death, lung cancer registers a low general survival rate even in patients with targeted therapies or immunotherapy. By better identifying the patients at risk, one can establish a more efficient personalized treatment; the future objective of scientific studies is the follow-up of adverse effects of new therapies.

Clinical, histological and therapeutical aspects in the management of uterine and extrauterine stromal sarcomas: Case reports.

Endometrial stromal sarcoma (ESS) is a rare tumor, predominantly occurring as a primary tumor of the uterus. Rare cases of primary extrauterine ESS (EESS) have been reported. Low-grade ESS (LG-ESS) is more common than high-grade ESS (HG-ESS). We present five cases of ESS and one case of EESS. All cases received external radiotherapy (EBRT) at the Radiotherapy Department of the Emergency Clinical Hospital 'Sfantul Apostol Andrei' Galati, during 2004-2020. Five cases underwent EBRT in two-dimensional (2D) technique and only one patient received EBRT with three-dimensinal conformational radiotherapy (3DCRT) technique with a linear accelerator, Elekta Synergy. Five patients were referred to postoperative radiotherapy after hysterectomy. The median age of the patients was 57.4 years. One patient was referred to radiotherapy with palliative intent. EESS localized in the retroperitoneum, in the para-aortic region, was identified in one 64-year-old patient with a personal history of hysterectomy and bilateral salpingo-oophorectomy in 1997; EESS was complicated with vertebral extension at the L1-L2 level and spinal cord compression syndrome. ESS represents a rare diagnosis and a high- or low-grade tumor profile is distinguished by immunohistochemistry (IHC) tests. Up to 30% of patients have EESS at presentation. The treatment of ESS is multimodal, its management requiring a multidisciplinary team, and it is different according to the primary tumor location and tumor staging. The role of adjuvant radiotherapy remains controversial in high-grade EESS and due to the rarity of these cases there are limited data concerning the efficacy of adjuvant EBRT available from prospective randomized control clinical trials.

Nevi, biologics for psoriasis and the risk for skin cancer: A real concern? (Case presentation and short review).

Psoriasis is a systemic inflammatory cutaneous disease that affects approximately 2% of the world's population. Systemic treatments and biologic treatment therapies are a powerful option for patients with moderate to severe psoriasis. Some studies from the literature indicate an overall small, but increased, risk of neoplasia in patients with psoriasis treated with phototherapy or systemic medication. The relationship between psoriasis and malignancy is not very well established; there are few studies with conflicting results. We present the case of a 31-year-old male patient, diagnosed with psoriasis, who was deemed eligible for systemic therapy. Treatment with methotrexate was initiated, but without a satisfactory outcome. Given the patient's resistant disease involving 15% of his body surface, his desire to have a clear skin, besides his being naïve to biologic therapy, he was proposed to start treatment with secukinumab 300 mg monthly. The patient experienced complete clearance of lesions and was followed-up on the basis of clinical and biological parameters. There are limited data concerning the relationship between melanocytic lesions, psoriasis and melanoma. Immunologic pathways implicated in psoriasis induce a reduction in the number of melanocytic nevi. Nevertheless, little is known concerning the association of melanocytic nevi with psoriasis. Thorough skin examination, meaning clinical and dermoscopic evaluation of melanocytic lesions, must be encouraged in patients treated with systemic therapies such as biologic agents.

Predictive value of immunological markers in systemic sclerosis.

Systemic sclerosis (SSc) is a collagenosis characterized by excessive deposition of collagen in the skin and viscera, in a background of immune disorder. The immunological profile of SSc often shows elevated levels of antinuclear antibodies (ANAs). However, many authors have identified cases of SSc having normal ANA levels, framed as paraneoplastic SSc. Among patients with negative ANAs in our group, we did not identify any neoplastic process that could support this hypothesis. The extended detection of autoantibodies is extremely useful in establishing the subset of SSc. Thus, anti-Scl70 antibodies are specific for the diffuse subset of SSc, while anticentromere antibodies (ACAs) have specificity for a limited subset. However, studies have shown the existence of cases of diffuse SSc having high titers of ACAs and cases of limited SSc with high titers of anti-Scl70 antibodies. This indicates an inconsistent association between the disease subset and the autoantibodies specific to each subset. Our study found a more balanced consistency between disease subsets and autoantibodies specific for each subset. Therefore, the percentages of patients having an immunological profile inconsistent with the subset of SSc, are lower than those found by other authors. This observation opens the perspective of larger studies on the immunological profile in SSc.

Multifactorial expression of IL-6 with update on COVID-19 and the therapeutic strategies of its blockade (Review).

Interleukin 6 (IL-6), a cytokine produced by various cells of the human body (macrophages, lymphocytes, astrocytes, ischemic myocytes, endothelial cells) has both pro-inflammatory and anti-inflammatory properties, being a key component in regulating various physiologic and pathological processes. The structure of this molecule and the receptor system it possesses are important due to the different activities that IL-6 can exert; through trans-signaling pro-inflammatory activities are mediated, while through classic signaling, IL-6 is responsible for anti-inflammatory and regenerative activities. IL-6 signaling is involved in coronary artery disease and the global COVID-19 pandemic. This proatherogenic cytokine reaches elevated serum levels in the cytokine storm generated by SARS-CoV-2, and is also associated with smoking or obesity-classic cardiovascular risk factors which promote inflammatory states. IL-6 levels are proportionally correlated with dyslipidemia, hypertension and glucose dysregulation, and they are associated with poor outcomes in patients with unstable angina or acute myocardial infarction. IL-6 targeting for treatment development (not only) in cardiovascular disease and COVID-19 is still a matter of ongoing research, although tocilizumab has proven to be effective in reducing the proatherogenic effects of IL-6 and is suggested to improve COVID-19 patient survival.

Epidemiological profile of systemic sclerosis in the southeast region of Romania.

Systemic sclerosis (SSc) is a collagenosis, in which the microvasculature of the skin and internal organs becomes affected, followed by excessive deposition of connective tissue. It has been included in the group of rare diseases, and it seems to have had an increasing incidence over the last two decades. Statistics show, not only an increase in the incidence of SSc, but that of autoimmune diseases as a whole. The present study aimed to outline the epidemiological profile of SSc in the southeast region of Romania and to identify similarities and differences concerning the epidemiology of this disease in other countries. The current observational study was carried out on a group of 22 patients who were diagnosed with SSc and who were hospitalized at a university clinic in Bucharest. Our research revealed a higher prevalence of women suffering from SSc, with higher numbers suffering from the diffuse subset of this disease. In addition, we found that the majority of patients came from urban areas. SSc has an important impact on the quality of life of patients, thus opening the opportunity for studies to be carried out on larger populations of patients in order to identify epidemiological similarities and differences in various countries, as well as finding new experimental models useful for future research.

Etiological factors of systemic sclerosis in the southeast region of Romania.

Systemic sclerosis (SSc) is a relatively rare autoimmune disease with skin and visceral involvement, having a yet unknown etiopathogenesis. Research has shown that professional exposure to various polluting chemicals such as dyes, aliphatic and aromatic organic solvents, inhalable silica dust or certain heavy metals, can be triggering factors for this disease when they overlap a predisposing genetic profile. Smoking is still a debated factor involved in the etiology of SSc, as authors have divergent opinions on this matter. The present study was designed to analyze the etiological factors identified in the group of 37 patients with diffuse and limited SSc from the southeast region of Romania and the results were compared to the literature data. In the group of patients included in this study, occupational exposure and smoking history were not present in all patients, and a hereditary factor was identified only in an isolated case. The majority of patients suffered from a major negative psychological event or from long-term stressful situations and these factors were associated with smoking history or occupational exposure; this suggests that SSc is initiated in a set of cumulative triggering factors.

Associated risk factors of lower limb lymphedema after treatment of cervical and endometrial cancer.

The scope of the study was to identify the associated risk factors of lower limb lymphedema development in cervical and endometrial cancer patients. We retrospectively analysed 326 patients: 186 cases (57.06%) with cervical cancer and 140 cases (42.94%) with endometrial cancer were treated in Surgery, Radiotherapy, Oncology and Gynaecology Clinics of 'St. Apostle Andrew' Emergency Clinical Hospital Galati over 9 years. Adjuvant radiotherapy was performed in 83.57% of endometrial cancer cases. Adjuvant chemotherapy was performed in 45.16% of cervical cancer cases. Over 10 lymph nodes were removed in 74.73% of cervical cancer patients. Incidence of lymphedema was 15.05% in cervical cancer patients and 10% in endometrial cancer patients, P=0.06. Analysed risk factors for lower limb lymphedema occurrence were: Age, disease stage, radiotherapy, number of invaded lymph nodes (for cervical cancer patients), number of removed lymph nodes (for cervical cancer patients) and obesity. Multivariate analysis for associated risk factors of lower limb lymphedema development in cervical cancer showed that number of removed lymph nodes, OR=2.109 (0.907-4.903), P<0.0001, number of lymph nodes with metastasis, OR=1.903 (0.253-4.332), P=0.004 and obesity, OR=1.713 (0.226-2.967), P=0.006 were found as statistically significant risk factors for lower limb lymphedema onset. For endometrial cancer patients, obesity, OR=1.518 (0.721-2.75), P=0.0003, was the only associated risk factor with statistical significance for the lower limb lymphedema development. Lower limb lymphedema represents one of the adverse reactions of multimodal treatment in gynaecological cancers which affects patient's quality of life. Lower limb lymphedema occurrence is related with number of risk factors, the most important being removed lymph nodes, obesity and radiotherapy.

Erratum: Dynamics of digital ulcers in systemic sclerosis.

[This corrects the article DOI: 10.3892/etm.2020.8572.].

Dynamics of digital ulcers in systemic sclerosis.

Systemic sclerosis (SSc) is a collagenosis with insufficiently known etiopathogenesis, characterized by microvasculopathy and excessive fibrosis in the context of an autoimmune disorder. The incompletely elucidated pathogenesis and limited therapeutic options, disabling aspects, skin lesions and pain determine important functional and psychological deficiencies which affect the quality of life. It is imperative to observe and correlate individual clinical and paraclinical data to optimize disease management. A group of 22 patients diagnosed with SSc, hospitalized in a university clinic in Bucharest was included in an observational study. The evolution of digital ulcers was evaluated as an indicator of vasculopathy and their status and dynamics were correlated with clinical elements reflecting the fibrotic aspect of the disease. The present study shows that the Raynaud phenomenon is almost always present during the course of the disease, but its presence is not always associated with digital ulcers. The existing data in the literature show that fibrosis is subsequent to vasculopathy, but this study did not reveal causality between these two aspects of pathogenesis. The presence of microstomia and digital contracture was identified in the presence of digital ulcers, but also in their absence. The etiopathogenic mechanisms with multiple unknown involved factors open the opportunity to investigate many aspects of SSc for optimal aiming of therapeutic interventions.