Genetic polymorphism in psoriasis and its meaning for the treatment efficacy in the future.

The concept of personalized medicine is a new individualized approach which helps application of the targeted therapy. In fact, tailored medicine is mostly present in the field of life-threatening diseases such as oncology. However, skin diseases as such might be regarded as a potential area of implementation of this approach in the future. Stratified medicine in polygenetic and heterogeneous diseases, such as psoriasis, is more complex. Rapid development of science and novel molecular techniques led to better understanding of molecular pathogenetic pathways of many diseases including psoriasis. Identification of the particular immunopathogenetic pathways led to further development of targeted therapies such as biologic drugs. Actually the goal of individualized therapy is to determine the identical homogenous subgroups of patients, according to a biomarker, in which the response to that therapy will be the best and will carry the lowest risk of side effects. This review attempts to analyze the associations between polymorphisms of certain genes and the increased risk of developing psoriasis or psoriatic arthritis. The review of literature has also included the studies investigating the associations between gene polymorphisms and response to biologic therapy in psoriasis and psoriatic arthritis patients.

Acute-phase response and its biomarkers in acute and chronic urticaria.

INTRODUCTION: Since urticaria is a persisting inflammatory disease it is important to establish the prognostic factors for the duration and severity of the disease. AIM: To evaluate serum concentrations of selected acute-phase proteins (APP) in patients with various forms of urticaria as compared to healthy volunteers and also to analyze these concentrations in different types of urticaria. Additionally, to evaluate the correlation between serum levels of selected APP and disease activity. MATERIAL AND METHODS: Serum concentrations of C-reactive protein (CRP), α1-acid glycoprotein (AGP), α1-antichymotrypsin (ACT), α1-antitrypsin (AT), ceruloplasmin (Cp), transferrin (Tf), α2-macroglobulin (α2M) and haptoglobin (Hp) were measured. Quantitative measurement was conducted using the rocket immunoelectrophoresis. Disease activity was assessed with the use of total symptom score. RESULTS: Analysis of serum APP concentrations revealed statistically higher serum concentrations of CRP, AGP and ACT in the entire group of patients with urticaria in comparison with the control group. In the entire group of patients with urticaria, CRP, AGP, ACT, Cp and Hp correlated positively with disease activity, intensity of pruritus and the number and size of urticarial wheals. Statistically lower serum concentrations of CRP, ACT, Cp and Hp were detected in the group of patients with acute urticaria (AU) and angioedema together, compared to the patients suffering from AU only. CONCLUSIONS: Patients with symptoms of various forms of urticaria present a distinct profile of serum APP concentrations. A significant correlation observed between CRP, AGP, ACT, Cp, Hp and clinical activity score points to the potential role of APP as markers of the urticarial activity.

Expression of selected genes of dendritic and Treg cells in blood and skin of morphea patients treated with UVA1 phototherapy.

INTRODUCTION: Morphea is a chronic autoimmune disease characterized by fibrosis of the skin. Dendritic cells (DC) and regulatory T cells (Tregs) play a significant role in development of autoimmune and tolerance mechanisms. The aim of the study was to establish the expression of selected genes of plasmacytoid and myeloid DC, Treg cells, and the microenvironment of cytokines (interleukin-17A (IL-17A), transforming growth factor ß (TGF-ß)) in blood and skin of morphea patients. In addition, the effect of UVA1 phototherapy on expression of the aforementioned genes was evaluated. MATERIAL AND METHODS: The study was performed on 15 blood and 10 skin samples from patients with morphea. The evaluation included expression of CLEC4C (C-type lectin domain family 4, member C receptor), Lymphocyte antigen 75 (LY75), Forkhead box p3 (foxp3) transcription factor, IL-17A and TGF-ß genes in peripheral blood mononuclear cells (PBMC) and in skin samples both before and after UVA1 phototherapy using real-time polymerase chain reaction. RESULTS: The study revealed lower expression of CLEC4C before (p = 0.010) and after (p = 0.009) phototherapy and lower expression of IL-17A before (p = 0.038) phototherapy in PBMC of patients with morphea vs. the control group. Expression of CLEC4C in PBMC correlated negatively (rho = -0.90; p = 0.001) with activity of disease after phototherapy. No significant differences were found between expression of analysed genes before and after UVA1 therapy in PBMC and skin of morphea patients. CONCLUSIONS: The results do not confirm the involvement of analysed subsets of DC and Tregs in UVA1 phototherapy in morphea, but point to CLEC4C as a possible biomarker associated with the disease activity.

Effects of UVA1 Phototherapy on Expression of Human Endogenous Retroviral Sequence (HERV)-K10 gag in Morphea: A Preliminary Study.

BACKGROUND Morphea, also known as localized scleroderma, is a rare autoimmune connective tissue disease characterized by skin fibrosis. UVA1 phototherapy is an important asset in the reduction of clinical manifestations in morphea. There are studies claiming that UV light modulates the expression of some human endogenous retroviral sequences. The aim of this study was to determine if the expression of HERV-K10 gag element is lowered by UVA1 phototherapy in morphea, a disease in which such irradiation has a soothing effect. MATERIAL AND METHODS The expression levels of the HERV-K10 gag were assessed by real-time PCR (polymerase chain reaction) in peripheral blood mononuclear cells (PBMC) and skin-punch biopsies of healthy volunteers and 9 morphea patients before and after phototherapy. Additionally, correlations between the HERV-K10 gag expression and age, disease duration, the Localized Scleroderma Skin Severity Index (LoSSI), and antinuclear antibody (ANA) titers were assessed. RESULTS In PBMC, HERV-K10 gag mRNA was significantly elevated after UVA1 phototherapy compared to healthy controls. Most of the patients responded with an increased expression level of this sequence. However, we found no statistical evidence at this point that phototherapy indeed has an effect on the HERV-K10 gag expression (there were no statistical differences in PBMC of morphea patients before and after phototherapy). Similarly, there was no statistically relevant effect of the UVA1 on the expression of HERV-K10 gag in skin. CONCLUSIONS At this point, the effect of UVA1 phototherapy on the expression of HERV-K10 gag cannot be statistically confirmed.

Vesicular Contact Reaction May Progress into Erythema Multiforme.

Dear Editor, Erythema multiforme is considered an acute skin condition, characterized by a self-limiting and sometimes recurrent course. It is regarded as a type IV hypersensitivity reaction associated with certain infections, medications, and other various triggers. Allergic contact dermatitis is in turn a delayed type of induced allergy as a result of cutaneous contact with a specific allergen to which the patient develops specific sensitivity. This type of cutaneous reaction is associated with inflammation manifesting with erythema, edema, and vesicles. A 27-year old female patient presented with a 3-day history of erythematous and vesicular lesions which developed 24 hours after cesarean section. Initially the lesions were localized in the area of surgery (mainly the abdomen and upper thighs) and on the next day progressed to the buttocks and lumbar area. The patient was referred to the Outpatient Clinic and was treated with antihistamines, but her dermatological state deteriorated rapidly. At the day of admission to the Department of Dermatology, numerous erythematous and vesicular lesions were present on the skin of the abdomen, thighs, and back (Figure 1, a), but the skin of the neck, chest, and extremities was also covered with erythematous and edematous patches. On the second day of hospitalization, we observed the evolution of lesions localized within the chest and extremities into an erythema multiforme-like targetoid eruption (Figure 1, b). Initially the patient was treated with intravenous injections of dexamethasone and ceftriaxone and orally with second-generation antihistamines (in four-fold doses), followed by intravenous metyloprednisolone pulse-therapy (total dose of 3 g). As the new vesicobullous lesions started to appear on the face and arms, we introduced cyclosporine A orally 400 mg daily. We could then observe gradual remission, but on the seventh day of hospitalization the patient developed a massive labial herpes simplex infection and had to be treated with acyclovir intravenously. Eight days after admission, we switched from intravenous metyloprednisolone to its oral formula. Diagnostic methods included: laboratory analyses (leukocytosis, neutrophilia, lymphopenia could be observed, and also serum CRP elevation). Pemphigoid gestationis was excluded on the basis of a direct immunofluorescence from perilesional skin and on the basis of indirect immunofluorescence and also serum analysis using ELISA for serum IgG antibodies to BP180-NC16A (courtesy of Prof. Marian Dmochowski). Histopathological examination revealed: massive edema of dermal papillae, leading to the formation of sub-epidermal vesicles; individual cell necrosis was observed in the upper epidermis. Within the dermis, a dense, perivascular inflammatory infiltrate was detected: the clinical picture suggested erythema multiforme. Another histopathological examination was performed at the University Clinic of Dermatology and Venereology in Magdeburg, courtesy of Prof. Dr. Harald Gollnick and Dr. Med. I. Franke; it also suggested the bullous form of erythema multiforme (dermal type). Three months after remission, the patient was hospitalized again to perform allergological diagnostics. Patch tests were performed with the European Baseline Series (Chemotechnique Diagnostics) supplemented with disinfectants and textiles used during surgical procedure. For patch testing, Finn Chambers on Scanpor were used. Results were recorded at 48 and 72 hour time points. According to the ICDRG (International Contact Dermatitis Research Group), reactions evaluated as ++ and +++ pluses were considered as positive and reaction evaluated as + plus was considered as doubtful. Patch testing revealed polyvalent contact allergy (Table I), (Figure 2a). The patient also reacted to Kodan Tinctur forte used as a skin disinfectant (contains brown dye LF 1889 - mixture of quinoline yellow, sunset yellow, brilliant black) (Figure 2b). It has to be emphasized, that patch test reading procedure was difficult due to patient's skin reactivity toward a plaster mounting Finn chambers. Literature data suggests that erythema multiforme may occasionally occur in conjunction with allergic contact dermatitis to various non-related substances including chemicals (epoxy-based compound, fragrances, epichlorydrine, bromofluorene), medications (antibiotics, acetaminophen, triamcinolone, bufexamac), plant-derived allergens (poison ivy, tea tree oil, red cedar essential oil), but also rubber ingredients and nickel. The severity of the reaction varies from mild erythema to generalized erythema multiforme or even toxic epidermal necrolysis (1,2,3,4). Lesions characteristic for erythema multiforme may appear during the episode of acute contact dermatitis or may follow a nearly resolving vesicular eczematous eruption. The pathomechanism Patomechanism of an erythema multiforme-like eruption developing in association with allergic contact dermatitis still remains unclear. Immune complex-mediated and T-cell-mediated reactions have been proposed as the cause. However, T-cell-mediated cellular mechanisms seems to be more likely, since generalized erythema multiforme often follows contact dermatitis, which is a type IV allergic reaction mediated by T cells (5,6). According to Bushkell et al. (7), an allergen penetration through the skin may result in a type III hypersensitivity reaction, with involvement of circulating immune complexes, and to confirm that, IgM, IgA, C3, and fibrin deposits are detected in some cases of targetoid lesions in erythema multiforme. On the other hand, Wiedemeyer et al. (8) suggest that contact allergens (i.e. paraphenylenodiamine) may be transported in peripheral blood mononuclear cells from the area of initial skin contact even to distant sites. According to Shiohara et al. (9) and Gonzalez-Delgado et al. (10), epidermal expression of adhesion molecule - 1 (ICAM-1) and the number of CD4+ T cells is increased within the iris lesions of erythema multiforme. Thus, it is possible that adhesion molecules may facilitate epidermal invasion of lymphocytes in these lesions, which is also the place of the expression of maintained allergen molecules. In conclusion, in the described case the causative factor also remained uncertain. The patient was found to have contact allergy to six haptens included in the European Baseline Series and also to a disinfectant used during cesarean section. Among these, both colophonium and formaldehyde are used in adhesives and glues or surface coatings. However, formaldehyde is mainly associated with this type of the reaction - in fact, hapten description supplied by Chemotechnique Diagnostics includes the information that "formaldehyde may produce erythema multiforme-like eruptions".

The role of dendritic cells and regulatory T cells in the pathogenesis of morphea.

Morphea is one of diseases characterised by fibrosis of the skin and subcutaneous tissue. It is a chronic disease that does not shorten the life of the patient, yet significantly affects its quality. The group of factors responsible for its pathogenesis is thought to include disturbed functioning of endothelial cells as well as immune disturbances leading to chronic inflammatory conditions, accompanied by increased production of collagen and of other extracellular matrix components. Dendritic cells (DC) are a type of professional antigen-presenting cells and can be found in almost all body tissues. Individual investigations have demonstrated high numbers of plasmacytoid DC (pDC) in morphoeic skin lesions, within deeper dermal layers, around blood vessels, and around collagen fibres in subcutaneous tissue. It appears that DC has a more pronounced role in the development of inflammation and T cell activation in morphea, as compared to systemic sclerosis (SSc). Regulatory T (Treg) cells represent a subpopulation of T cells with immunosuppressive properties. Recent studies have drawn attention to the important role played by Treg in the process of autoimmunisation. Just a few studies have demonstrated a decrease in the number and activity of Treg in patients with SSc, and only such studies involve morphea. This article reviews recent studies on the role of DC and regulatory T cells in the pathogenesis of morphea. Moreover, mechanisms of phototherapy and potential therapeutic targets in the treatment of morphea are discussed in this context.

Itching sensation in psoriatic patients and its relation to body mass index and IL-17 and IL-31 concentrations.

INTRODUCTION: According to available data, pruritus is a common symptom of psoriasis, however its characteristics and pathogenesis are not clearly understood. AIM: The main aim of this study was to assess itching sensation among patients suffering from psoriasis, including its incidence and severity. All factors triggering and worsening pruritic symptoms were also carefully analyzed. The authors assessed the relationship of itch with body mass index (BMI) and severity of disease. Moreover, serum levels of interleukin 17 (IL-17) and IL-31 were analyzed in relation to Psoriasis Activity and Severity Index, BMI and severity of pruritus. MATERIAL AND METHODS: The study group consisted of 60 patients with plaque-type psoriasis. Analysis of impact of pruritus on the quality of life and worsening factors was based on the questionnaire. The severity of pruritus was assessed with the use of two independent scales. Serum IL-17 and IL-31 levels were measured in 30 patients suffering from psoriasis and in 10 healthy controls using immunoassay tests. RESULTS: 88.3% of analyzed patients complained of itch and the most common factor which exacerbated pruritus was stress (39.6%). Pruritus in psoriasis was independent of gender, illness duration and extent of skin lesions. The average intensity of pruritus was assessed as moderate and did not correlate significantly with BMI level, IL-17 and IL-31. CONCLUSIONS: Since the pathogenesis of pruritus in psoriasis is not fully understood, further investigation in this area needs to be conducted. Pruritus may be considered as a characteristic feature of psoriasis and, besides the skin lesions, should be a target in dermatological treatment to improve patient's quality of life.

Biosimilars in dermatology.

Over the last decade the availability of biological drugs for the treatment of psoriasis vulgaris, psoriatic arthritis and many other inflammatory diseases has revolutionized the treatment of these diseases around the world. Due to the high cost of therapy, the search has started for biosimilars. In dermatology the greatest interest in biosimilar medicines concerns inhibitors of tumor necrosis factor a (TNF-α), for use in the treatment of psoriasis vulgaris and psoriatic arthritis (infliximab, etanercept, adalimumab). The most important element of the safety of biologicals is their immunogenicity. Therefore, when discussing biosimilars, attention needs to be paid to the dangers of their immune activity. In view of the fact that the drugs contain and aggregates, produced by living organisms or cultures of living cells, they cannot be compared in any way to low molecular weight synthetic generics (called generics). Biosimilars are authorized for use in patients and treated as equivalent to the reference medicine only after passing a number of studies and assessments. As it is well known, the development of medicine and pharmacology is extremely intense, and the market in biological medicine is developing much faster than that of all other drugs, which underlines their important role in modern medicine. Currently, the subject of biosimilars is one of the most important challenges and topics of discussion around the world, including pharmacovigilance and legal and economic regulatory standards. It seems inevitable that biosimilar products will be introduced for the treatment of diseases with indications corresponding to the original product on which they are based.

Neurogenic markers of the inflammatory process in atopic dermatitis: relation to the severity and pruritus.

INTRODUCTION: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease, characterized by eczematous skin lesions and intensive pruritus. Recent studies have shed light on the role of the nervous system in the pathogenesis of AD. It can influence the course of the disease through an altered pattern of cutaneous innervation and abnormal expression of neuropeptides in the lesional skin. AIM: The aim of the study was to evaluate plasma concentrations of the nerve growth factor (NGF), substance P (SP) and vasoactive intestinal peptide (VIP) in AD patients in comparison to two control groups (healthy volunteers and patients suffering from psoriasis). Correlations between plasma levels of evaluated parameters, severity of the disease and selected clinical parameters (skin prick tests, total and antigen specific IgE levels) were also analysed. MATERIAL AND METHODS: Seventy-five patients with AD, 40 patients with psoriasis and 40 healthy volunteers were included into the study. Patients with AD included 52 persons suffering from an extrinsic and 23 from an intrinsic type of the disease. The severity of skin lesions was assessed with SCORAD index. Pruritus was evaluated on the basis of the questionnaire assessing the extent, frequency and intensity of pruritus. Commercial enzyme-linked immunosorbent assays (SP, NGF: R&D Systems; and VIP: Phoenix Pharmaceuticals) were used to assess the neuropeptide and NGF plasma levels. RESULTS: Nerve growth factor and VIP plasma concentrations were significantly higher in AD patients compared to psoriatic patients and healthy subjects. Substance P plasma concentrations were elevated in the extrinsic type of AD and psoriasis comparing to healthy volunteers. There were no statistically significant differences in NGF, SP and VIP plasma concentrations between the extrinsic and intrinsic type of AD. There was also no correlation between plasma levels of evaluated parameters (NGF, SP, VIP) and SCORAD index in both types of AD. However, plasma SP concentration correlated with intensity of pruritus in AD patients. Plasma VIP concentrations correlated with intensity of pruritus in the intrinsic type of AD and with IgE-mediated sensitization to moulds in the extrinsic type of disease. CONCLUSIONS: Our findings confirm that NGF and VIP play a prominent role in atopic inflammatory reactions and may serve as good alternative biomarkers of AD. The results of this study also suggest a similar important role of neuroimmune interactions in both variants of AD. Increased SP plasma concentrations in both AD and psoriasis point to its possible role in modulating immune-mediated inflammation in different chronic inflammatory skin diseases. Moreover, SP and VIP seem to influence the course of AD by increasing pruritus, whereas an elevated plasma VIP level in AD patients may be related to a risk of developing IgE-mediated sensitization to certain airborne allergens.

A case of diffuse large B-cell lymphoma misdiagnosed as an erysipelas of the face.

We report a case of a woman with diffuse large B-cell lymphoma (DLBCL). Primary cutaneous lymphomas (PCLs) represent distinct clinical and histopathologic subtypes of extranodal T- and B-cell lymphomas. Cutaneous B-cell lymphomas comprise 20-25% of all primary cutaneous lymphomas. The patient presented an erythematous tumour mass of the left nasolabial fold, nose and left cheek as well as disseminated infiltrative plagues on the trunk, arms and left lower leg. Skin biopsy revealed a diffuse infiltrate of lymphocytes around hair follicles and blood vessels within dermis and subcutaneous tissue. An immunohistochemistry showed a diffuse infiltrate of large non-cleaved B-cells, with a high proportion of centroblast-like cells within dermis. Tumor cells expressed CD20, bcl-2 protein and did not express CD10. The patient was misdiagnosed as the erysipelas of the face and unsuccessfully treated with long-term antibiotic therapy by a laryngologist and a dermatologist. The correct diagnosis was delayed and established after 6 months' history of DLBCL lesions. Therefore, we would like to strongly stress the importance of considering diagnosis of cutaneous lymphomas in chronic skin lesions non-responsive to adequate therapies.

[Selected vulvar dermatoses]. / Wybrane dermatozy sromu.

Numerous cutaneous lesions are located in the region of the female genital organs, occasionally presenting a diagnostic and therapeutic challenge. The most common cases include: eczema vulvae, lichen simplex chronius, lichen sclerosus et atrophicus or lichen planus. Clinical presentation of these lesions is not always characteristic for certain dermatoses. Thus, it is important to conduct proper tests, including histopathological or contact allergy examination. Only thorough diagnostics allows to implement correct therapy. This paper shows a detailed description of dermal lesions located in the region of the female genital organs of the allergic and lichenoid origin, together with the literature review on diagnosis and treatment.