Oral methotrexate in the treatment of Hailey‒Hailey disease: a case report.

Hailey‒Hailey disease is a rare chronic autosomal-dominant blistering disease characterized by erosions, fissures, and vegetations occurring in intertriginous regions. To date, there is no specific treatment and there are no therapeutic guidelines, which makes management of the disease challenging. We present the case of a 43-year-old man unsuccessfully treated for Hailey‒Hailey disease with topical and systemic corticosteroids, antibiotics, and surgical debridement. At presentation he had erosions, vegetations, and infection in the axillae and groin. We introduced oral methotrexate, 10 mg weekly, and complete remission was achieved in 3 weeks. After 8 weeks, we decided to discontinue methotrexate due to lesion absence. Over 3 years of follow-up, mild flares were effectively managed with topical miconazole or mild steroid creams. We conclude that oral methotrexate is safe and effective for achieving long-term remission in Hailey‒Hailey disease.

The Impact of the IKBKG Gene on the Appearance of the Corpus Callosum Abnormalities in Incontinentia Pigmenti.

Incontinentia pigmenti (IP) is a rare skin disease combined with anomalies of the teeth, eyes, and central nervous system (CNS). Mutations of the IKBKG gene are responsible for IP. Among the most frequent CNS abnormalities found in IP using magnetic resonance imaging (MRI) are corpus callosum (CC) abnormalities. The aim of the study was to determine the presence of CC abnormalities, their relationship with the IKBKG mutations, and the possible presence of mutations of other genes. A group of seven IP patients was examined. Analyses of the IKBKG gene and the X-chromosome inactivation pattern were performed, as well as MRI and whole exome sequencing (WES) with the focus on the genes relevant for neurodegeneration. WES analysis showed IKBKG mutation in all examined patients. A patient who had a mutation of a gene other than IKBKG was excluded from further study. Four of the seven patients had clinically diagnosed CNS anomalies; two out of four had MRI-diagnosed CC anomalies. The simultaneous presence of IKBKG mutation and CC abnormalities and the absence of other mutations indicate that IKBKG may be the cause of CC abnormalities and should be included in the list of genes responsible for CC abnormalities.

Effectiveness and safety of topical calcipotriol in the treatment of flat seborrheic keratosis on the face.

Seborrheic keratosis is the most common slow-growing, benign epithelial tumour, usually appearing on sun-exposed areas. Treatment modalities for seborrheic keratosis may be uncomfortable and/or time-consuming. We present a case series of 12 patients with solitary seborrheic keratosis localized on the face treated with 0.005% calcipotriol ointment. The treatment lasted 3-8 months and resulted in complete regression of the lesions. Remission (follow-up period) lasted from 6 to 10 years. We conclude that topical calcipotriol may be a useful treatment option for seborrheic keratosis.

Mastocytosis in children: a single-center long-term follow-up study.

BACKGROUND: Mastocytosis is a heterogeneous group of rare disorders characterized by the accumulation of clonal mast cells in organs such as the skin and bone marrow. The diagnosis of cutaneous mastocytosis (CM) is based on clinical findings, positive Darier's sign, and histopathology, if necessary. METHODS: Medical records of 86 children with CM diagnosed during a 35-year long period were reviewed. Most patients (93%) developed CM during the first year of life (median age 3 months). Clinical features at presentation and during the follow-up period were analyzed. Baseline serum tryptase level was measured in 28 patients. RESULTS: A total of 85% of patients had maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), 9% had mastocytoma, and 6% had diffuse cutaneous mastocytosis (DCM). Boy to girl ratio was 1.1:1. Fifty-four of 86 patients (63%) were followed from 2 to 37 years (median 13 years). Complete resolution was registered in 14% of mastocytoma cases, 14% of MCPM/UP, and in 25% of DCM patients. After the age of 18, skin lesion persisted in 14% mastocytoma, 7% MCPM/UP, and 25% children with DCM. Atopic dermatitis was diagnosed in 9.6% of patients with MPCM/UP. Three of 28 patients had elevated serum tryptase. Prognosis in all patients was good, and there were no signs of progression to systemic mastocytosis (SM). CONCLUSION: To the best of our knowledge, our results represent the longest single-center follow-up study of childhood-onset CM. We found no complications of massive mast cell degranulation or progression to SM.

Poikilodermatous mycosis fungoides with CD30-positive large cell transformation successfully treated by brentuximab vedotin.

We present a patient with a 33-year history of poikilodermatous mycosis fungoides (MF) who subsequently developed CD30-positive large cell transformation. After 6 years of conventional MF treatment, side effects of therapy and/or concomitant diseases prevented the previously applied treatment modalities. The CD30-directed antibody-cytotoxic drug conjugate (brentuximab vedotin) was introduced and followed by quick and excellent therapeutic response.

Pemphigus vulgaris and pemphigus foliaceus determined by CD86 and CTLA4 polymorphisms.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare autoimmune blistering diseases with presumed T-cell-dependent pathology. Activation of naïve T cells is dependent on antigen recognition, subsequent signaling through the T-cell receptor complex (signal 1), and various other interactions of T cells with antigen presenting cells that may be collectively designated as signal 2, which is unconditionally required for T-cell activation both in response to infection and to autoantigens. Among the best described interactions contributing to signal 2 are those mediated by B7 family molecules, such as CD80 and CD86 with their ligands; CD28, providing activation signals; and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), conferring inhibition. Single nucleotide polymorphisms (SNPs) within genes encoding those molecules may alter the signaling process. It is not known whether functional genetic polymorphisms within genes encoding the aforementioned proteins may increase risk for developing PV and PF and, if so, whether they might serve as biomarkers for susceptibility to these diseases. To address those questions, we examined functional single nucleotide polymorphisms within CD86 (rs1129055) and CTLA4 (rs733618 and rs5742909) genes in 61 pemphigus patients and 486 healthy controls. We found statistically significant differences in allele and genotype frequencies between PV patients and controls for rs1129055, as well as for rs5742909 among PV and PF patients. Namely, the rs1129055 A allele was significantly more common in PV patients compared with controls (35.4% versus 25.7%, respectively; P = .040), whereas the rs5742909 T allele was significantly more common in PF compared with PV patients (19.2% versus 5.2%, respectively; P = .035). The frequency of the rs5742909 T allele did not, however, differ significantly in PF or in PV compared with controls (10.5%; P = .187 and P = .100, respectively). We report a novel association of SNPs within CD86 and CTLA4 genes with pemphigus. The CD86 rs1129055 A allele appears to confer susceptibility to PV but not to PF. © 2016 Elsevier Inc. All rights reserved.

Inzidenz von bullösen Autoimmunerkrankungen in Serbien: eine retrospektive Studie über 20 Jahre.

HINTERGRUND UND ZIELE: Die meisten früheren Arbeiten zu den klinisch-epidemiologischen Merkmalen von bullösen Autoimmunerkrankungen (AIBD) konzentrierten sich vor allem auf eine einzige Krankheitsentität oder nur eine Krankheitsgruppe; nur in wenigen Studien wurde die Inzidenz verschiedener AIBD untersucht. Bei der vorliegenden Studie war es unser Ziel, das gesamte Spektrum der AIBD zu betrachten, die Inzidenz der häufigsten AIBD zu ermitteln und die zeitlichen Trends ihres Auftretens in Zentralserbien über einen Zeitraum von 20 Jahren zu untersuchen. METHODEN: Wir rekrutierten retrospektiv 1161 AIBD-Fälle, die in Zentralserbien von Januar 1991 bis Dezember 2010 neu diagnostiziert wurden. Die Diagnose stützte sich auf eine strikte klinische, histologische und immunhistologische Beurteilung. ERGEBNISSE: Folgende Inzidenzraten wurden für die einzelnen Erkrankungen ermittelt: 4,35 pro eine Million Einwohner/Jahr (pME/Jahr) für Pemphigus, 4,47 pME/Jahr für Pemphigoid, 1,42 pME/Jahr für Dermatitis herpetiformis (DH), 0,25 pME/Jahr IgA-Dermatose und 0,08 pME/Jahr für Epidermolysis bullosa acquisita. Im betrachteten Zeitraum stieg die altersbereinigte Inzidenzrate für Pemphigus und insbesondere für Pemphigoid signifikant an, während sie für DH, allerdings nicht signifikant, abnahm. SCHLUSSFOLGERUNGEN: Unsere Studie befasst sich zum ersten Mal mit den Inzidenzraten des gesamten Spektrums der AIBD in Serbien und untersucht die zeitlichen Trends ihres Auftretens über einen Zeitraum von 20 Jahren. Nach unserem besten Wissen wurde ein ähnlicher Befund wie der unsere, dass nämlich die Inzidenzraten von Pemphigus und Pemphigoid vergleichbar sind, bisher noch nicht publiziert.

Incidence of autoimmune bullous diseases in Serbia: a 20-year retrospective study.

BACKGROUND AND OBJECTIVES: While most previous surveys on the clinico-epidemiological features of autoimmune bullous diseases (AIBDs) have predominantly focused on a single disease entity or just one disease group, there have been only few studies examining the incidence of various AIBDs. In the present study, we set out to determine the spectrum of AIBDs, to estimate the incidence of the most common AIBDs, and to examine their temporal trends in Central Serbia over a period of 20 years. METHODS: We retrospectively recruited 1,161 new AIBD cases diagnosed in Central Serbia during the period from January 1991 to December 2010. The diagnosis was based on strict clinical, histological, and immunohistological evaluation. RESULTS: The incidence rates were: 4.35 per million population/year (pmp/year) for pemphigus, 4.47 pmp/year for pemphigoid, 1.42 pmp/year for dermatitis herpetiformis (DH), 0.25 pmp/year for linear IgA disease, and 0.08 pmp/year for epidermolysis bullosa acquisita. In the period observed, age-adjusted incidence rates significantly increased for pemphigus and particularly for pemphigoid, whereas they decreased, albeit not significantly, for DH. CONCLUSIONS: For the first time, our study evaluates the incidence rates of the entire spectrum of AIBDs in Serbia, and examines their temporal trends over a 20-year period. To the best of our knowledge, our finding of similar incidence rates for pemphigus and pemphigoid has previously not been reported.

TNF, IL12B, and IFNG Gene Polymorphisms in Serbian Patients with Psoriasis.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease with a strong genetic basis. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (ILs) such are IL-12 and IL-23, and interferon gamma (IFN-γ) are released from various inflammatory and resident cells, and have been implicated in the initiation/maintenance of inflammation. Certain alleles of the aforementioned cytokines may be associated with disease susceptibility/severity. OBJECTIVE: To investigate the association of three common functional gene polymorphisms, namely TNF -308 G/A (rs1800629), IL12B (encoding the p40 subunit of IL-12/23) +1188 A/C (rs3212227), and IFNG +874 T/A (rs2430561) with psoriasis development and severity in Serbian patients. METHODS: We genotyped 130 patients with psoriasis (26 of whom also had psoriatic arthritis) and 259 controls; rs1800629 and rs3212227, and rs2430561, by real-time PCR assay. RESULTS: The TNF GG genotype was detected at a higher frequency in patients with psoriasis compared to control subjects (OR, 1.420; 95% CI, 0.870~2.403) without statistical significance (p=0.191). Lack of the TNF G allele was associated with lower psoriasis severity (p=0.007). The IL12B AC genotype was underrepresented in the patients with psoriatic arthritis compared to healthy subjects (OR, 0.308; 95% CI, 0.090~1.057; p=0.049). The distribution of the rs2430561 allele and genotype frequencies was similar between patients with psoriasis and controls. CONCLUSION: Our study demonstrates an effect of the rs1800629 on psoriasis severity, and a marginal impact of the rs3212227 on susceptibility to psoriatic arthritis. Collectively, our results obtained in a Serbian cohort expand current knowledge regarding individual predisposition to psoriatic disease.

Pustular psoriasis in childhood and adolescence: a 20-year single-center experience.

Pustular psoriasis (PP) is rare in children. The small number of reported cases makes deciding on treatment and follow-up challenging. The current study was an evaluation of treatment approaches and courses of PP in 18 children diagnosed and followed over a 20-year period. From 1992 to 2011 we treated 1,447 children with psoriasis, 18 of whom had PP. Follow-up was 2 to 19 years. At the time of initial manifestation of PP, our patients were 1.5 months to 16 years old. Seven patients had a previous history of psoriasis vulgaris. Three children entered long-term remission after one pustular attack, 10 developed psoriasis vulgaris, 2 are currently under treatment, and 3 were lost to follow-up. Treatment with acitretin, cyclosporine, or methotrexate was efficacious and well tolerated. PP is rare, but according to our experience, it has a good prognosis in children.

Direct immunofluorescence of the outer root sheath in anagen and telogen hair in pemphigus vulgaris and pemphigus foliaceus.

Direct immunofluorescence of peri-lesional skin is the gold standard in the diagnosis of pemphigus. A specific immunofluorescence pattern may also be demonstrated in the outer root sheath of anagen and telogen hair. We demonstrated an intercellular reticular deposition of immunoglobulin G in the outer root sheath of plucked anagen and telogen hair in all pemphigus vulgaris patients with active disease and for the first time in all patients with active pemphigus foliaceus. Moreover, we demonstrated for the first time that plucked hair samples may be kept at -20°C for at least 2 weeks before immunofluorescent staining and analysis.

Aloe-emodin inhibits proliferation of adult human keratinocytes in vitro.

Aloe-emodin (AE) is a plant-derived hydroxyanthraquinone with several biological activities. It is present in a variety of skin-conditioning agents containing aloe extracts, but its influence on keratinocyte growth was not examined so far. We investigated the influence of AE on human keratinocyte proliferation and apoptosis in vitro. AE significantly inhibited proliferation of cultivated human keratinocytes at 5 µM concentration, as revealed by incorporation of radioactive thymidine. The antiproliferative effect of AE was accompanied with induction of apoptosis, but not necrosis, as demonstrated by flow cytometric analysis and lactate dehydrogenase release assay. Based on the half maximal inhibitory concentration values, we demonstrated that AE may impair proliferation of keratinocytes at concentrations far below the industry standards for commercial products containing aloe extracts. Therefore, further research of AE effects on the human skin and proper labeling of products are necessary for maximizing benefits from aloe extracts and to avoid undesired responses.

Congenital self-healing histiocytosis presenting as blueberry muffin baby: a case report and literature review.

Congenital self-healing Langerhans cell histiocytosis (CSHLCH), also called as Hashimoto-Pritzker disease, is a rare, benign variant of histiocytosis. Despite the initial dramatic clinical presentation, affected infants are otherwise healthy and skin lesions disappear spontaneously within several weeks to months. We present a case of CSHLCH presenting as blueberry muffin baby. The lesions appeared in the first week of life and lasted 6 months. The follow-up period was 24 months, without any signs of relapse. At the pediatric dermatology unit of our clinic, during the last 20 years, we had 10 children with Langerhans cell histiocytosis and among them only one with CSHLCH. In the literature, we found only 5 newborns with Langerhans cell histiocytosis presenting as blueberry muffin baby, among them only 4 with self-healing CSHLCH. The early recognition of CSHLCH may spare children from redundant and potentially toxic systemic treatment.

Widespread scleredema associated with paraproteinemia and generalized osteoarthritis in an HLA-B39 positive patient.

Scleredema adultorum (SA) is a rare sclerotic disorder characterized by non-pitting induration of the neck with acral progression, sparing hands and feet. We report on a 57-year-old male with severe SA associated with paraproteinemia, treated with methotrexate. Such widespread skin thickening followed by severe movement restriction and inability to function on daily basis, as in our patient, has never been described. Severe osteoarthritis and finding of HLA-B39 allele in association with SA has not been previously described either. To the best of our knowledge, up to 40 patients with SA associated with paraproteinemia has been reported so far, and currently, there is no established effective treatment protocol. In our patient, low-dose methotrexate resulted in stiffness reduction, increased motility of the trunk and extremities, and ability to function on daily basis. We believe that any information about treatment outcome in SA patients should be disseminated in order to establish consensual treatment protocol for this rare disease.

Pemphigus vulgaris in three adolescents: the course of the disease.

We report three adolescents with pemphigus vulgaris whose disease started at the age of 13, 15 and 14 years, respectively. The course of the disease and the treatment approaches were reviewed. Pemphigus vulgaris during childhood and adolescence is a very rare disease in this part of Europe. Among 410 pemphigus vulgaris patients that we treated during the 20-year period, only three patients (0.73%) were under the age of 18 years. According to our experience, the course of pemphigus vulgaris in patients before the age of 18 years is comparable with the course of pemphigus vulgaris in adults.

The irritative property of alpha-tricalcium phosphate to the rabbit skin.

The aim of this study was to assess the irritant properties of a new developed calcium phosphate ceramic, alpha-tricalcium phosphate (alpha-TCP) after single application to intact skin of the rabbit. The test substance, alpha-TCP was produced by modified hydrothermal method and prepared in two different forms, as a solid material (disc 5 x 2 mm) and paste. Both, solid material and paste of alpha-TCP were evaluated for primary skin irritation to the ISO 10993-10:2002/Amd 1:2006 Biological Evaluation of Medical Devices - Part 10. At the end of the study macroscopic examination of the skin was performed. In this model, general and local tolerances were good. Score of primary irritation (SPI) and primary irritation index (PII) of alpha-TCP for both, solid material and paste, revealed that there was no significant toxicity/irritability (PII = 0.0) as compared to the negative control (PII = 0.0). Positive control did cause significant skin irritation in acute irritation test using Draize technique in rabbit model (PII = 2.11). Based on present results, it can be concluded that the the irritation potential of the tested material is negligible. However, other procedures for preclinical safety assessments of the alpha-TCP material are needed in order to completely elucidate its toxic potential.

Bullous pemphigoid induced by penicillamine in a patient with Wilson disease.

We report a 47-year-old man with Wilson disease who developed bullous lesions on the trunk and extremities after 20 years of penicillamine treatment. The histologic and immunofluorescence findings were diagnostic of bullous pemphigoid. When penicillamine was replaced by zinc sulfate, the patient's bullous skin lesions improved rapidly. However, after 2 months of zinc sulfate treatment, the patient's skin condition remained improved but his neurologic disease became worse and penicillamine was reinstituted. Bullous lesions recurred within 1 week and the diagnosis of penicillamine-induced bullous pemphigoid was confirmed. This is the first report of penicillamine-induced bullous pemphigoid in a patient with Wilson disease.

Granulomatous rosacea-like leukemid in a patient with acute myeloid leukemia.

INTRODUCTION: Skin findings in leukemias may be divided into specific lesions (leukemia cutis) and non-specific lesions (leukemids) which may be found in up to 80% of all patients with leukemias. The leukemids vary clinically and they are usually a manifestation of bone marrow or immunologic impairment, but also Sweet syndrome, pyoderma gangrenosum, erythroderma, maculopapular exanthema, prurigo-like papules, generalized pigmentation, follicular mucinosis, generalized pruritus may be found during the course of leukemia. CASE REPORT: We report a 70-year-old male with a 3-month history of erythema, papules and pustules on the face, ears and neck and over a month history of refractory anemia, anorexia, weight loss, malaise, and fever. Physical examination revealed symmetric erythematous, violaceous papules, papulo-nodules and plaques with slate scale and sparse, small pustules on the face, earlobes and neck. Histopathologic findings of involved skin showed diffuse mixed inflammatory cell infiltrate with perifollicular accentuation and focal granulomatous inflammation in the papillary and upper reticular dermis. Extensive checkup revealed the presence of acute myeloid leukemia French-American-British (FAB) classification subtype M2, with signs of three-lineage dysplasia. The patient was treated by L6 protocol which led to complete remission, both in bone marrow and skin, but after seven months he had relapse of leukemia with the fatal outcome. CONCLUSION: This case indicates the importance of skin eruptions in the context of hematological malignancies.