SLCO1B1 variants as predictors of methotrexate-related toxicity in children with juvenile idiopathic arthritis.

Objectives: Methotrexate (MTX) administered at the dose 10-15 mg/m2 is currently recommended as the first line therapy in most juvenile idiopathic arthritis (JIA) subtypes. Gastrointestinal side effects and hepatotoxicity are the most prevalent manifestations of MTX intolerance, frequently leading to discontinuation of otherwise effective treatment. Genetic variability within solute carrier organic anion transporter family member 1B1 (SLCO1B1), encoding a hepatic MTX membrane transporter, has been associated with high-dose MTX efficacy and toxicity in paediatric patients with acute lymphoblastic leukaemia. The aim of our study was to determine the association between single-nucleotide polymorphisms in the SLCO1B1 gene (rs4149056, rs2306283) on the disease activity and presence of side effects of MTX therapy in patients with JIA.Method: The study recruited 100 children with JIA of all subtypes treated with MTX. Demographic and clinical parameters were collected at the baseline of MTX therapy and on a control visit 4-6 months after starting MTX. Genotyping was performed using genomic DNA isolated from peripheral blood samples.Results: In comparison to wild-type allele, SLCO1B1 rs4149056 CT/CC variant was significantly associated with higher odds ratio of MTX gastrointestinal side effects occurrence (OR=4.55, 95%CI 1.37-15.13; p=0.013). SLCO1B1 rs4149056 TT subjects were more likely than CT/CC individuals to develop hepatotoxicity (17.86% vs 4.76%, p = 0.046).Conclusion: SLCO1B1 rs4149056 may serve as a determinant of MTX treatment toxicity in children with JIA.

Superiority of ivermectin 1% cream over metronidazole 0·75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial.

BACKGROUND: Few therapeutic alternatives currently exist in the treatment of papulopustular rosacea (PPR). OBJECTIVES: To demonstrate superiority of once-daily ivermectin 1% cream (IVM 1%) once daily vs. twice-daily metronidazole (MTZ 0·75%) cream, regarding percentage reduction of inflammatory lesions in subjects with moderate to severe PPR. METHODS: In this Phase 3, investigator-blinded, randomized, parallel-group study, subjects received IVM 1% once daily, or MTZ 0·75% twice daily over 16 weeks. Efficacy assessments were inflammatory lesion counts and Investigator's Global Assessment (IGA). Safety assessments included incidence of adverse events (AEs) and local tolerance parameters. Subjects evaluated their disease following a 5-grade scale and completed questionnaires. RESULTS: A total of 962 subjects were randomized to receive IVM 1% (n = 478) or MTZ 0·75% (n = 484). At week 16, IVM 1% was significantly superior to MTZ 0·75% in terms of reduction from baseline in inflammatory lesions (83·0% vs. 73·7%; P < 0.001), observed as early as week 3 (Last Observation Carried Forward, LOCF). IGA results (subjects 'clear' or 'almost clear') also favoured IVM 1%: 84·9% vs. 75·4%, respectively (P < 0.001). Incidence of AEs was comparable between groups and local tolerability was better for IVM 1%. More subjects receiving IVM rated their global improvement as 'excellent' or 'good.' CONCLUSIONS: Ivermectin 1% cream was significantly superior to MTZ 0·75% cream and achieved high patient satisfaction.

Association of psoriasis with the VEGF gene polymorphism in the northern Polish population.

BACKGROUND: Neovascularization plays an important role in pathogenesis of psoriasis and vascular endothelial growth factor (VEGF) seems to be the main angiogenic factor involved in this disease. Published studies which analysed the role of VEGF gene polymorphism in psoriasis were limited and they received controversial results. Objective The aim of our study was to evaluate the association between -1154 G/A, -460 T/C and +405 G/C polymorphisms and the psoriasis susceptibility and to determine whether this genetic variation influence levels of VEGF protein expression. MATERIALS AND METHODS: One hundred and eighty-nine patients with psoriasis and 215 ethnically matched controls were genotyped using ARMS-PCR and PCR-RFLP methods. VEGF serum levels were assessed in 47 patients and 40 controls using ELISA test. RESULTS: We noted that an increased risk of Type I psoriasis is associated with -1154 G allele (OR = 1.9; P = 0.04), +405 CC (OR = 2.86; P = 0.03) and -460 TT (OR = 1.56; P = 0.05) genotypes and demonstrated that a significantly increased risk of developing disease is related to presence of haplotype GTC among all patients (OR = 1.97; P = 0.001), patients with Type I (OR = 1.87; P = 0.005) and Type II psoriasis (OR = 2.37, P = 0.01). We have found significantly increased serum levels of VEGF in patients with psoriasis compared with those in healthy controls (P = 0.008). Serum levels of VEGF significantly correlated with PASI: r = 0.72, P < 0.00001. Patients with elevated levels of VEGF in the serum showed more frequently: GC genotype (P = 0.04), C allele (P = 0.02) at the locus +405 and TT genotype (P = 0.03) at the locus -460. CONCLUSION: Our results strongly support the role of VEGF gene polymorphism in the pathogenesis of psoriasis.

Relationship between serum levels of interleukin-18, IgE and disease severity in patients with atopic dermatitis.

BACKGROUND: Interleukin (IL)-18 is a pleiotropic cytokine. Synergistically with IL-12, IL-18 promotes immune responses of the T helper type, by enhancing synthesis of interferon-γ and inhibiting IgE production. IL-18 can also enhance production of IL-4 and IL-13 production, and stimulate synthesis of IgE. Moreover, in the presence of IL-3, IL-18 can directly stimulate basophils and mast cells to produce their mediators in an IgE-independent manner. These results indicate a role for IL-18 in the pathogenesis of atopic dermatitis (AD). AIM: To examine the association of serum IL-18 with IgE levels and disease severity in patients with AD. METHODS: ELISA was used to measure IL-18 and total IgE levels in the sera of 67 patients with AD and 50 healthy volunteers. The SCORing Atopic Dermatitis (SCORAD) tool was used to determine the severity of this disease. RESULTS: The mean serum level of IL-18 in study group (155.68 pg/mL) was significantly higher than that of controls. IL-18 was also significantly higher in the sera of the patients with severe AD than in those with milder disease. There was a correlation with IgE and IL-18 levels, as patients who had high IgE levels also had high IL-18 levels, compared with controls. CONCLUSION: IL-18 seems to play an important role in the pathogenesis of AD, but this requires further study. IL-18 could be a useful clinical marker of disease severity in AD.

Interleukin-13 promoter gene polymorphism -1112C/T is associated with the systemic form of mastocytosis.

BACKGROUND: Mastocytosis is a heterogenous disease involving mast cells (MC) and their progenitors. Cutaneous and systemic variants of the disease have been reported. In contrast to cutaneous mastocytosis (CM), patients with systemic mastocytosis (SM) are at risk to develop disease progression or a nonMC-lineage haematopoietic neoplasm. Little is known, however, about factors predisposing for the development of SM. One factor may be cytokine regulation of MC progenitors. METHODS: We examined the role of the interleukin-13 (IL-13) promoter gene polymorphism -1112C/T, known to be associated with increased transcription, in mastocytosis using allele-specific polymerase chain reaction method. Serum tryptase and IL-13 levels were determined by immunoassay, and expression of the IL-13 receptor in neoplastic MC by reverse transcription-polymerase chain reaction and flow cytometry. RESULTS: The frequency of the -1112T allele of the IL-13 promoter was significantly higher in patients with SM compared with CM (P < 0.008) and in mastocytosis patients compared with healthy controls (P < 0.0001). Correspondingly, the polymorphism was found to correlate with an elevated serum tryptase level (P = 0.004) and with adult-onset of the disease (P < 0.0015), both of which are almost invariably associated with SM. Serum IL-13 levels were also higher in SM patients compared with CM (P = 0.011), and higher in CT- than in CC carriers (P < 0.05). Finally, we were able to show that neoplastic human MC display IL-13 receptors and grow better in IL-13-containing medium. CONCLUSIONS: The -1112C/T IL-13 gene polymorphism and the resulting 'hypertranscription' may predispose for the development of SM.

Mutations in the EDA gene in three unrelated families reveal no apparent correlation between phenotype and genotype in the patients with an X-linked anhidrotic ectodermal dysplasia.

Anhidrotic ectodermal dysplasia (EDA) is caused by mutations in the EDA gene encoding ectodysplasin A, a member of the TNF ligand superfamily involved in the communication between the cells. The structure of the EDA gene was investigated in three patients exhibiting clinical symptoms of EDA in an attempt to correlate the molecular findings with the phenotype of the patients. Genomic DNA was analyzed by single stranded conformation polymorphism (SSCP) followed by direct sequencing. In one of the patients, as well as in his heterozygous mother and sister, a single T insertion was evidenced in exon 3 between nucleotides 713 and 714 that changed Lys codon (AAA) into a termination codon TAA (Lys158Ter). In the other patient, A1321T transversion was demonstrated. The same mutation was found in his heterozygous mother and resulted in a change of Ileu360Asn that might generate an additional glycosylation site. In the third patient an A1285G transition was revealed. This mutation that originated de novo was localized in a region that is highly conserved in TNF ligand family and caused substitution of Ala349Thr. Localization of the mutations in the extracellular domain of ectodysplasin A suggested that the primary cause of EDA is a defect in communication between the cells responsible for the development of skin appendages. Despite a different character and localization of the mutations, no apparent correlation between phenotype and genotype of the patients was evidenced. Some differences in the patients' phenotype were observed.

Psoriasis vulgaris with the early and late onset--HLA phenotype correlations.

The purpose of the study was to classify psoriasis vulgaris basing on HLA phenotype and the age of onset of the disease. One hundred fifteen psoriatic patients were included into the study and divided into two groups: group I--with early onset (< 40 years) and group II--with late onset (> or = 40 years). Each group was subclassified according to Cw6 antigen expression: IA-Cw(6+)--early onset, IB-Cw(6-)--early onset, IIA-Cw(6+)--late onset, IIB-Cw(6-)--late onset. HLA class I antigen typing was performed in each of 115 subjects using the microlymphocytotoxicity test. HLA class II antigen typing was also performed in 20 randomly selected patients by means of the two-step microlymphocytotoxicity test. The occurrence Cw6, B13, B17 antigens was significantly increased in psoriatic groups in comparison with a control population. No difference between the groups was found with respect to class II antigen frequency. Cw6, B13 and B17 were the most specific markers for psoriasis with the early onset, whereas B27, Cw2, B44 and Cw5 seemed to be associated with the late type of the disease.

Kaposi's sarcoma following long-term immunosuppressive therapy: clinical, histologic, and ultrastructural study.

Multifocal Kaposi's sarcoma in a patient with chronic myeloid leukemia treated with busulfan, a cytostatic and suppressive drug, is reviewed. After five years of treatment, during which temporary remissions occurred, the patient experienced a relapse of leukemia and a considerable immune deficiency. This was expressed by a decrease in the ratio of CD4/CD8 lymphocytes in the peripheral blood. The relation of Kaposi's sarcoma with leukemia, as well as with the state of immunity in this case, does not evoke any doubts. Verification of oncologic treatment brought about a remission of leukemia, an improvement in the patient's immune state, as well as an inhibition of new foci of the Kaposi's sarcoma in the skin in the course of a few months of follow-up evaluation.

Cutaneous T-cell lymphoma at a young age.

A case of cutaneous T-cell lymphoma (CTCL) in a 22-month-old patient is discussed, emphasizing the importance of screening for CTCL even in very young patients with atypical symptoms of eczema, atopic dermatitis, or parapsoriasis. The clinical, histologic, and immunologic diagnostics can now be supported by molecular methods; therefore, patients at the earlier stages of CTCL can be diagnosed and treated with good results.

[Effectiveness of a micronized purified flavonoid fraction (MPFF) in the healing process of lower limb ulcers. An open multicentre study, controlled and randomized]. / Efficacia della frazione flavonoica purificata micronizzata (FFPM) nell'aumentare la guarigione della ulcere agli arti inferiori. Studio multicentrico in aperto, controllato e randomizato.

OBJECTIVE: To determine the increase in healing rate of venous ulcer in patients receiving a micronised purified flavonoid fraction (MPFF) as supplementation to standard local care. DESIGN: A randomised, open, controlled, multicentre study. SETTING: Departments of Dermatology and University Outpatients Clinics. PATIENTS: One hundred and forty patients with chronic venous insufficiency and venous ulcers. INTERVENTION: PATIENTS received standard compressive therapy plus external treatment alone or 2 tablets of MPFF daily in addition to the above treatment for 24 weeks. MAIN OUTCOME MEASURE: Healing of ulcers and their reduction in size after 24 weeks of treatment. RESULTS: The percentage of patients whose ulcers healed completely was found to be markedly higher in those receiving MPFF in addition to standard external and compressive treatment than in those treated with conventional therapy alone (46.5% vs 27.5%; p<0.05. OR=2.3, 95% CI 1.1-4.6). Ulcers with diameters <3 cm were cured in 71% of patients in the MPFF group and in 50% of patients in the control group, whereas ulcers between 3 and 6 cm in diameter were cured in 60% and 32% of patients (p<0.05), respectively. The mean reduction in ulcer size was also found to be greater in patients treated with MPFF (80%) than in the control group (65%) (p<0.05). The cost-effectiveness ratio (cost per healed ulcer) in the MPFF group was 1026.2 compared with 1871.8 in the control group. CONCLUSIONS: These results indicate that MPFF significantly improves the cure rate in patients with chronic venous insufficiency.

[Psoriatic arthritis--diagnostic criteria]. / Luszczycowe zapalenie stawów--kryteria rozpoznawcze.

Arthritis psoriatica has been known for over 160 years, however, not long ago it became a separate nosologic unit. In 1964 American Rheumatological Society introduced the name arthritis psoriatica, which is obligatory nowadays. It was thought in the beginning that the inflammation may coexist with psoriasis accidentally only, whereas epidemiological studies, clinical observations and serologic data excluded such a simple relation. Since the international diagnostic criteria were established and also the rheumatoid factor was discovered it has been clear there's a direct relation between arthritis psoriatica and dermatologic changes of a psoriasis type. Therefore it is a disease where rheumatology and dermatology meet with each other. The aim of our study was to collect the knowledge about the diagnosis of arthritis psoriatica.

[Fibronectin in the skin of patients with allergic dermatitis]. / Fibronektyna w skórze chorych z wypryskiem.

In the skin of healthy subjects linear deposits were found of fibronectin at the dermoepidermal junction and in the walls of blood vessels, and reticular deposits in the papillary and reticular layers of the skin. In the epidermis of 12 out of 51 patients with allergic contact dermatitis fibronectin deposits were found in relation to Langerhans cells and keratinocytes. This was not observed in the epidermis in healthy subjects. The authors suggest that fibronectin on the surface of Langerhans cells and keratinocytes may play a role in antigen presentation.

[Ultrastructural image of the Langerhans cells in the skin of patients with allergic contact dermatitis]. / Obraz ultrastrukturalny komórek langerhansa w skórze chorych z alergicznym wypryskiem kontaktowym.

The alterations in the ultrastructural feature of Langerhans cells in patients with allergic contact eczema were characterized by significant increase in number of Birbeck granules accompanied by the increase in volume of smooth- and rough-surfaced endoplasmic reticulum. These changes may be regarded as a morphological expression of the increase of the synthetic and secretory activity of the Langerhans cells. In the epidermis the Langerhans cells associated with immediately adjacent precursor cells (the so called indeterminate cells), lymphoid cells and keratinocytes form the morphologically visible and probably functional units.