Małgorzata Michalska-Jakubus

Atherosclerotic risk among children taking antiepileptic drugs

Epilepsy is a common chronic neurological disorder that requires long-term or sometimes lifetime therapy. Recent evidence indicates that prolonged use of antiepileptic drugs (AEDs) might modify some vascular risk factors; however, the influence of AED therapy on the development of atherosclerosis has been the subject of controversy. Some epidemiological studies have reported a higher prevalence of ischemic vascular disease among epileptic patients on AEDs, while in other studies the mortality due to atherosclerosis-related cardiovascular disease in treated epileptics has been observed to be lower than in the general population. The etiology of atherosclerosis-related vascular diseases in epileptic patients has not been fully clarified. Since atherosclerotic vascular alterations may start early in life, this review focuses on major atherogenic risk factors among epileptic children, including altered metabolism of homocysteine, disordered lipid profiles, and increased lipoprotein (a) serum levels, as well as thyroid hormone deficiency with special concern for clinical implications.

High serum sCD163/sTWEAK ratio is associated with lower risk of digital ulcers but more severe skin disease in patients with systemic sclerosis

IntroductionSystemic sclerosis (SSc) is an autoimmune disease characterized by chronic inflammation, vascular injury and excessive fibrosis. CD163 is a scavenger receptor which affects inflammatory response and may contribute to connective tissue remodelling. It has recently been demonstrated that CD163 can bind and neutralize the TNF-like weak inducer of apoptosis (TWEAK), a multifunctional cytokine which regulates inflammation, angiogenesis and tissue remodelling. We aimed to investigate the relationships between serum levels of soluble CD163 (sCD163) and soluble TWEAK (sTWEAK) in relation to disease manifestations in SSc patients.MethodsThis study included 89 patients with SSc who had not received immunosuppressive drugs or steroids for at least 6 months and 48 age- and sex-matched healthy controls (HC) from four European centres. Serum concentrations of sTWEAK and sCD163 were measured using commercially available ELISA kits.ResultsThe mean serum concentrations of sTWEAK were comparable between SSc patients (mean +/- SD: 270 +/- 171 pg/mL) and HC (294 +/- 147pg/mL, P >0.05). Concentration of sCD163 and sCD163/sTWEAK ratio were significantly greater in SSc patients (984 +/- 420 ng/mL and 4837 +/- 3103, respectively) as compared to HC (823 +/- 331 ng/mL and 3115 +/- 1346 respectively, P <0.05 for both). High sCD163 levels and a high sCD163/sTWEAK ratio (defined as > mean +2SD of HC) were both associated with a lower risk of digital ulcers in SSc patients (OR, 95%CI: 0.09; 0.01, 0.71, and 0.17; 0.06, 0.51, respectively). Accordingly, patients without digital ulcers had a significantly higher sCD163 concentration and sCD163/sTWEAK ratio as compared to SSc patients with digital ulcers (P <0.01 for both) and HC (P <0.05 for both). A high sCD163/sTWEAK ratio, but not high sCD163 levels, was associated with greater skin involvement.ConclusionsThe results of our study indicate that CD163-TWEAK interactions might play a role in the pathogenesis of SSc and that CD163 may protect against the development of digital ulcers in SSc. Further studies are required to reveal whether targeting of the CD163-TWEAK pathway might be a potential strategy for treating vascular disease and/or skin fibrosis in SSc.

The transcription factor GLI2 as a downstream mediator of transforming growth factor-β-induced fibroblast activation in SSc

Objectives Hedgehog signalling plays a critical role during the pathogenesis of fibrosis in systemic sclerosis (SSc). Besides canonical hedgehog signalling with smoothened (SMO)-dependent activation of GLI transcription factors, GLI can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). Here, we aimed to evaluate the role of non-canonical hedgehog signalling in SSc and to test the efficacy of direct GLI inhibitors that target simultaneously canonical and non-canonical hedgehog pathways. Methods The GLI inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signalling, while the SMO inhibitor vismodegib was used to selectively target canonical hedgehog signalling. Furthermore, GLI2 was selectively depleted in fibroblasts using the Cre-LoxP system. The effects of pharmacological or genetic of GLI2 on transforming growth factor-β (TGF-β) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-β receptor I. Results TGF-β upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBRact-induced fibrosis. Combined targeting of canonical and non-canonical hedgehog signalling with direct GLI inhibitors exerted more potent antifibrotic effects than selective targeting of canonical hedgehog signalling with SMO inhibitors in experimental dermal and pulmonary fibrosis. Conclusions Our data demonstrate that hedgehog pathways and TGF-β signalling both converge to GLI2 and that GLI2 integrates those signalling to promote tissue fibrosis. These findings may have translational implications as non-selective inhibitors of GLI2 are in clinical use and selective molecules are currently in development.

Bullous pyoderma gangrenosum associated with pancytopenia of unknown origin.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis of unknown origin. Clinically it starts with a pustule, nodule or bulla that rapidly progresses and turns into a painful ulcer with raised, undermined borders. The etiopathogenesis of PG remains unknown. However it is frequently associated with systemic diseases such as inflammatory bowel disease (IBD), haematological disorders or arthritis. The latest multicentric retrospective analysis published by Ghazal et al. shows that anaemia has been observed very often in German patients suffering from PG (in 45.6% of 259) so this disorder is supposed to be a possible cofactor in the pathogenesis of PG. According to its progressive course, patients require intensive diagnostic procedures and rapid initiation of the treatment. In this article, we report a case of bullous pyoderma gangrenosum in association with pancytopenia of unknown origin, according to its diagnostic and therapeutic difficulties.

Evaluation of serum concentrations of the selected cytokines in patients with localized scleroderma

Introduction Localized scleroderma is an autoimmune disease primarily affecting the skin. The cause of disease remains unexplained although environmental factors are implicated, which are likely to be responsible for activation of the endothelium and subsequent inflammation leading to excessive synthesis of collagen and extracellular matrix components. Aim To determine concentrations of interleukin (IL)-27, transforming growth factor (TGF)-β1, TGF-β2, IL-6, and sIL-6R in patients with localized scleroderma compared to controls and to assess the relations between their levels and laboratory markers. Material and methods The study encompassed 17 females with localized scleroderma (aged 25–67). The control group consisted of 30 age-matched healthy women. The blood was sampled from the basilic vein. Serum levels of cytokines were determined using ELISA. Results The TGF-β2 levels were found to be significantly lower in patients with localized scleroderma compared to controls. Concentrations of TGF-β1 were decreased in scleroderma patients when compared to controls but without statistical significance. There were no significant differences in serum IL-6, sIL-6R and IL-27 levels between patients and the control group; however, we found a significant positive correlation between the level of sIL-6 and ESR among subjects with localized scleroderma. Conclusions The findings of decreased serum levels of TGF-β1 and TGF-β2 in patients with localized scleroderma demonstrate a possible association of these cytokines with pathogenesis of the disease. The results suggest also that sIL-6R is likely to be involved in inflammation in patients with localized scleroderma.

Plasma endothelial microparticles reflect the extent of capillaroscopic alterations and correlate with the severity of skin involvement in systemic sclerosis

INTRODUCTION AND AIM Endothelial microparticles (EMPs) are membrane-coated vesicles shed from endothelial cells and are considered markers of the endothelial state. It has been shown that total numbers of circulating EMPs are increased in patients with systemic sclerosis (SSc), but their clinical correlations have not yet been investigated in detail. We aimed to assess possible relationships between circulating EMPs and clinical as well as laboratory features among SSc patients with special attention to possible association with alteration in microvascular morphology objectified on nailfold videocapillaroscopy and clinical signs of microvascular complications. MATERIALS AND METHODS The study included 47 SSc patients and 27 age- and sex-matched healthy controls. EMPs were identified with flow cytometry after staining platelet-poor plasma with combinations of fluorescent cell-specific monoclonal antibodies (anti-CD31, -51, -42b, -62E and Annexin V). The following types of EMPs were evaluated: total EMPs (CD31+/CD42b-), activated EMPs (CD62E+/AnnV-,) and apoptotic EMPs (CD62E+/AnnV+ or CD51+). Clinical evaluation of patients was obtained, including nailfold videocapillaroscopy. RESULTS All types of EMPs were significantly elevated in SSc patients as compared with healthy controls. We found significant inverse correlation between severity of skin involvement and values of total EMPs (r=-0.32; p=0.02) and their levels tended to be lower in SSc patients with digital ulcers when compared to those without ischaemic skin lesions (p=0.09). Total EMPs and activated EMPs showed correlations with the number of ramified capillaries (r=-0.40 and r=0.37, respectively, p<0.05 for both). Moreover, total EMPs inversely correlated with the severity of capillary loss (r=-0.35, p<0.05) and their levels were significantly lower in patients with late NVC pattern with respect to those with early microangiopathy (p<0.05). On the other hand, active NVC pattern was characterized by strongly elevated levels of activated EMPs when compared to an early vascular alteration (p<0.05). CONCLUSIONS Our results suggest that quantity and phenotype of circulating EMPs might indicate on molecular vascular damage with endothelial dysfunction and to reflect progressive loss of capillaries consequencing in microvascular insufficiency in SSc patients.

Coexistence of pemphigus foliaceus and acquired hemophilia A: A case report

Pemphigus foliaceus (PF) is an autoimmune bullous dermatosis with anti‐desmoglein‐1 autoantibodies. Acquired hemophilia A (AHA) is a rare coagulation disorder with a high mortality rate, caused by anti‐factor VIII immunoglobulin G antibodies leading to spontaneous severe hemorrhages into skin, muscles or soft tissues. This coagulopathy may be associated with malignancies, drug reactions and autoimmune disorders including bullous dermatoses. Herein, we demonstrate a first report of AHA in the course of pemphigus foliaceus. A 55‐year‐old woman presenting with extensive, erosive, crusted, scaly skin lesions was diagnosed with PF based on histopathological and immunofluorescent examination, confirmed by the presence of anti‐desmoglein‐1 antibodies on enzyme‐linked immunoassay. She developed extensive internal hemorrhages and prolonged external bleeding after laparotomy. Based on coagulation tests, AHA was diagnosed. Simultaneous remission of pemphigus and coagulopathy occurred with immunosuppressants and recombinant activated factor VII.

Clinical associations of serum leptin and leptin/adiponectin ratio in systemic sclerosis

Introduction Leptin and adiponectin have recently received the attention of researchers as attractive biomarkers in systemic sclerosis (SSc) because of their role in the inflammatory process, vascular function and fibrosis. We hypothesized that leptin and adiponectin may be associated with disease activity and severity in patients with SSc. Aim To compare serum leptin, adiponectin and leptin/adiponectin levels in patients with SSc and healthy controls and to evaluate their possible relationship with frequently used laboratory markers and clinical findings. Material and methods The study included 48 Caucasian female patients with SSc and 38 healthy controls. Serum concentrations of leptin and adiponectin were measured in patients and controls using commercially available ELISA Kits (Quantikine ELISA Kit R&D Systems, Minneapolis, MN, USA). The results were assessed by the Mann-Whitney U-test and Spearman’s correlation test. Results Leptin and adiponectin levels correlated with body mas index in SSc patients (r = 0.495, p = 0.000398 and r = –0.306; p = 0.0342) in contrast to healthy controls (p = 0.070 and p = 0.256, respectively), and, in SSc patients only, a strong negative correlation was observed between leptin and adiponectin serum levels (r = –0.314; p = 0.0312). Diffuse form of the disease (dcSSc) was associated with significantly lower serum adiponectin levels (8638.62 ±10382.62). Active disease was associated with significantly lower leptin concentration (13700.49 ±18293.32) and there was a significant negative correlation between leptin serum level and activity index score (r = –0.342; p = 0.0185). Conclusions The results of our study indicate that leptin levels might correlate with disease activity and subtype in SSc patients.

Anti-endothelial cell antibodies do not correlate with disease activity in systemic sclerosis

Introduction Anti-endothelial cell antibodies (AECA) recognize endothelial cell proteins and are thought to play an important role in vascular damage observed in systemic scleroderma (SSc) and many other autoimmune diseases. In SSc, AECA were found to be more common in patients with pulmonary hypertension, digital ulcers and nailfold capillaroscopic changes. Until now, there have been no studies examining the association between AECA positivity with the activity and duration of the disease. Aim To evaluate associations between the presence of AECA in sera of patients with SSc and internal organs involvement as well as disease activity. Material and methods Sera of 58 patients with SSc (50 with localized subtype and 8 with diffuse subtype) were examined for AECA presence using an indirect immunofluorescence technique. Several clinical and laboratory features were also evaluated as well as disease activity and disease duration. Results A significant association between positive AECA and a subtype of SSc (p = 0.021) was found, as well as between presence of digital ulcers and digital scars (p = 0.001), calcinosis (p = 0.02), acroosteolysis (p = 0.028) and a nearly significant association between AECA and lung fibrosis (p = 0.47). No association between disease duration, disease activity and AECA (p = 1.000 and 0.191, respectively) was present. Conclusions Anti-endothelial cell antibodies are not associated with the activity of SSc. Digital ulcers, calcinosis and acroosteolysis are more common among AECA-positive patients suggesting that the presence of AECA might be an indicator of vascular complications development in SSc. Positive AECA among patients with lung fibrosis indicate their possible role in the development of lung disease. Further prospective studies including a greater number of patients are required.

Occupational exposure as a presumable cause of subcutaneous sarcoidosis in a tannery worker – case report and review of the literature

Address for correspondence: Małgorzata M. Michalska-Jakubus, Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, 13 Radziwiłłowska St, 20-080 Lublin, Poland, phone: +48 693 549 654, e-mail: mjm@poczta.onet.eu Received: 4.02.2016, accepted: 10.08.2017. Occupational exposure as a presumable cause of subcutaneous sarcoidosis in a tannery worker – case report and review of the literature