RESUMO
BACKGROUND: Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. OBJECTIVES: To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. METHODS: Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. RESULTS: In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. CONCLUSIONS: Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.
Assuntos
Pênfigo , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia , Autoanticorpos , Humanos , Pênfigo/tratamento farmacológico , PrednisonaRESUMO
BACKGROUND: Apremilast is an oral phosphodiesterase-4 inhibitor indicated for patients with moderate-to-severe chronic plaque psoriasis and active psoriatic arthritis. OBJECTIVES: To examine the effectiveness of apremilast on Dermatology Life Quality Index (DLQI), Psoriasis Area and Severity Index (PASI) and nail, scalp and palmoplantar involvement, when administered prior to biologics. METHODS: This 52-week real-world study included biologic-naive adults with moderate psoriasis (psoriasis-involved body surface area 10% to <20%, or PASI 10 to <20 and DLQI 10 to <20). Apremilast was initiated ≤7 days before enrolment. Data from the first 100 eligible patients who completed 24 weeks (W24) of observation (or were prematurely withdrawn) are presented in this interim analysis using the last-observation-carried-forward imputation method. RESULTS: Eligible patients (mean age: 49.9 years; 71.0% males; median disease duration: 8.0 years) were consecutively enrolled between April and October 2017, by 18 dermatology specialists practising in hospital outpatient settings in Greece. Baseline DLQI (median: 12.0) and PASI (median: 11.7) scores improved (P < 0.001) at all postbaseline timepoints (Weeks 6, 16 and 24; W24 median decreases: 9.0 and 9.4 points respectively). At W24, DLQI ≤5, DLQI 0 or 1, and PASI-75 response rates were 63.0%, 25.0% and 48.0% respectively. The Nail Psoriasis Severity Index score in patients with baseline nail involvement (n = 57) decreased at all postbaseline timepoints (P < 0.001; W24 median decrease: 20.0 points). At W24, 50.0% and 51.7% of patients with baseline scalp (n = 76) and palmoplantar (n = 29) involvement respectively achieved postbaseline Physician's Global Assessment (PGA) score of 0 or 1 if baseline score was ≥3, or 0 if baseline score was 1 or 2. The adverse drug reaction rate was 21.0% (serious: 2.0%). CONCLUSIONS: These interim results indicate that through 24 weeks, apremilast improved quality of life and reduced disease severity in biologic-naive patients with moderate plaque psoriasis, while demonstrating safety consistent with the known safety profile.
Assuntos
Produtos Biológicos , Psoríase , Adulto , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Qualidade de Vida , Índice de Gravidade de Doença , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
Psoriasis is a multifactorial skin disease affecting ~2% of world's population, causing a dramatic decrease in patients' quality of life and a significant increase in health-care expenses. Biological agents such as the anti-TNFα ones had an enormous impact in patients' therapy; however, a significant proportion of them do not respond well, an outcome attributed mainly to genetic factors. Recently, in a large European cohort of rheumatoid arthritis patients we have shown association with variation in the receptors that correspond to the Fc portion of the biological agents. As both diseases share common immunological fingerprints, we examined the hypothesis that they share common pharmacogenetic markers. Analysis of FCGR2A-H131R and FCGR3A-V158F polymorphisms in 100 psoriasis patients showed association only with respect to FCGR3A-V158F and response to etanercept (P=0.018). Interestingly, no association was found between FCGR2A-H131R and response to anti-TNFα therapy (P=0.882). This study suggests a role for FCGR3A-V158F polymorphism unique for psoriasis.
Assuntos
Anti-Inflamatórios/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Etanercepte/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Psoríase/tratamento farmacológico , Receptores de IgG/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anti-Inflamatórios/efeitos adversos , Resistência a Medicamentos/genética , Etanercepte/efeitos adversos , Feminino , Genótipo , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Testes Farmacogenômicos , Fenótipo , Psoríase/diagnóstico , Psoríase/genética , Psoríase/imunologia , Estudos Retrospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Psoriasis affects 2-3% of the population, causing significant morbidity and financial burden. Immunosuppressive drugs such as cyclosporine are first line systemic therapies for moderate-to-severe forms. However, patients exhibit heterogeneity in their response to therapy, possibly due to genetic factors. The aim of the present study was to assess the ABCB1 T-129C, G1199A, C1236T, G2677T and C3435T single-nucleotide polymorphisms (SNPs) as candidate predictive markers of response to cyclosporine treatment in 84 psoriasis patients. 62% of the patients were defined as responders and 38% as nonresponders. All SNPs complied with Hardy-Weinberg equilibrium. SNP and haplotype analyses were performed to access responsiveness to treatment. Association analysis revealed statistically significant association of SNP 3435 T with negative response (P=0.0075), a result that was further validated in haplotype analysis. This study is the first in the field of the pharmacogenetics of cyclosporine in psoriasis whose results merit further exploitation in larger independent cohorts.
Assuntos
Ciclosporina/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Psoríase/tratamento farmacológico , Psoríase/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Feminino , Grécia , Humanos , Masculino , Psoríase/metabolismoRESUMO
The purpose of this study was to evaluate the efficacy of calcipotriol ointment as monotherapy versus calcipotriol in combination with narrow-band ultraviolet (UV)-B or UVA1 phototherapy and to determine whether calcipotriol in combination with UVA1 is an alternative to calcipotriol with narrow-band UVB phototherapy. Forty-five patients with plaque psoriasis were divided into three treatment groups with no significant differences in Psoriasis Area and Severity Index (PASI) scores, mean age, sex or skin type. The total duration of the treatment was 3 months. Regarding PASI score, psoriasis regression was statistically significant between the groups. The response to UVA1 and narrow band UVB with calcipotriol was superior to calcipotriol monotherapy. UVA1 phototherapy with calcipotriol could be an alternative to narrow-band UVB phototherapy with calcipotriol.
Assuntos
Calcitriol/análogos & derivados , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/radioterapia , Terapia Ultravioleta , Adulto , Idoso , Calcitriol/uso terapêutico , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Tacrolimus is an immunomodulatory agent that inhibits the activation and maturation of T-cells and blocks transcriptional activation of several cytokine genes. It also interferes with the function of Langerhans cells, basophil cells and mast cells. Recent studies have demonstrated the efficacy of topical tacrolimus in inflammatory skin disorders. Our objective was to assess the efficacy of topical treatment with tacrolimus ointment 0.1% in patients with psoriasis on the anogenital region and the face. Included in the study were 10 patients with a long-standing history of genital and facial psoriasis, partially controlled with periodic use of topical corticosteroids. Tacrolimus ointment 0.1% was applied twice daily for 10 days. The patients were followed-up every 3 weeks for a total period of 12 weeks. The severity of psoriasis was evaluated in all patients at baseline (day 0) and at the end of weeks 3, 6, 9 and 12. Clinical severity of erythema, scaling, infiltration and lesional extent were graded using a 0-3 scale indicating none, mild, moderate and severe expression, at baseline and at follow-ups. An overall severity score of 0 (clear), 1-4 (mild), 5-8 (moderate) or 9-12 (severe) was then assigned to each patient by adding the scores for the above parameters. On each visit, every patient was evaluated clinically. The decision to reapply the drug was determined by the clinical response of each patient at each visit. At the end of the study, patients also assessed efficacy, safety and tolerance after topical application of tacrolimus ointment using a 0-5 scale for each parameter: A marked improvement was noticed in all patients at the end of the first week without drug-related adverse effects. There were 15 recurrences during the 12-week period in all patients. In conclusion, tacrolimus ointment 0.1% seems to represent a safe new option for the treatment of genital and facial psoriasis. Further studies are probably needed to specify the therapeutic dosage and maintenance therapy
Assuntos
Face , Doenças dos Genitais Masculinos/tratamento farmacológico , Imunossupressores/uso terapêutico , Psoríase/tratamento farmacológico , Tacrolimo/uso terapêutico , Adulto , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Tacrolimo/administração & dosagemRESUMO
The term sensitive skin has been used to describe a clinical phenomenon of hyperreactivity of the human skin, which develops exaggerated reactions when exposed to external factors. The aim of this study was to determine objective biophysical findings in patients with sensitive skin compared to those individuals with nonsensitive skin. Thirty-two patients with sensitive skin and 30 healthy volunteers with nonsensitive skin were studied. The testing methods included in vivo and in vitro tests: epicutaneous testing (Patch tests); measurement of sebum and hydration of the skin; alkali resistance test; stinging test with lactic acid; reaction to aqueous solution of methyl nicotinate 0.5%, 1.4% and acetyl-b-methylcholine chloride 1:1000; pH measurement; dermographism; and measurement of total and specific IgE. Significant results were observed in the measurement of sebum (p < 0.01) and hydration (p < 0.05) of the skin, in the alkali resistance test (p < 0.05), in the vascular reaction to methyl nicotinate (p < 0.01) and to acetyl-b-methylcholine chloride (p < 0.01) and in the skin response to allergens of the European standard (p < 0.01) and cosmetic series (p < 0.05). In addition, the subjective findings of stinging test produced significant results (p < 0.001) as was anticipated. Patients with sensitive skin possess very dry skin with low fatness, which leads to a disturbance of the protective skin barrier function. They also present a hyperreaction of the skin blood vessels, increased transcutaneous penetration of water-soluble chemicals, enhanced immune responsiveness, significant decrease of alkali resistance and a heightened neurosensory stimulation.
Assuntos
Dermatite Alérgica de Contato/fisiopatologia , Dermatite Irritante/fisiopatologia , Pele/fisiopatologia , Adulto , Água Corporal , Dermatite Alérgica de Contato/imunologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Lipídeos/análise , Masculino , Pessoa de Meia-Idade , Absorção Cutânea , Testes CutâneosRESUMO
The term sensitive skin has been used to describe a clinical phenomenon of skin hyperreactivity induced after exposure to different external factors. The diagnosis is mainly based on patient's self-assessment because of the lack of objective clinical signs of the disease. The aim of this study was to investigate psychiatric factors in patients with sensitive skin and to estimate the possible need for psychological intervention to these patients. Thirty-seven patients with sensitive skin and 38 individuals with nonsensitive skin were studied. The psychometric instruments used were the Symptom Checklist-90 (SCL-90) and the Delusions-Symptoms-States Inventory/states of Anxiety and Depression (DSSI/sAD). Statistically significant differences in subjects with sensitive skin compared to those with nonsensitive skin were observed in the SCL-90 subscales of somatization, phobic anxiety, hostility, interpersonal sensitivity and the DSSI/sAD subscale of anxiety. Our findings suggest that somatization, anxiety, phobic anxiety, hostility and interpersonal sensitivity symptoms may be associated with hypersensitivity of human skin. Psychological factors should be taken into consideration in the treatment of patients with sensitive skin.
Assuntos
Dermatite Irritante/psicologia , Escalas de Graduação Psiquiátrica , Adulto , Ansiedade/diagnóstico , Ansiedade/etiologia , Depressão/complicações , Depressão/diagnóstico , Dermatite Irritante/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Testes CutâneosRESUMO
Psoriasis is a chronic debilitating cutaneous disorder that affects both sexes and appears clinically as inflamed, edematous skin lesions covered with a silvery white scale. Strong evidence suggests that immune mechanisms are implicated in its pathogenesis, such as persistent activation of T-lymphocytes, excessive proliferation of keratinocytes and reactivation of proto-oncogenes and other elements. Additionally, several recent studies have demonstrated that cytokines play a significant role in the pathogenesis of the disease, as they can be found in the affected skin of psoriatic patients. In this study we evaluated levels of circulating cytokines in the serum of 45 Greek psoriatic patients before initiation of treatment and compared the results with those in 45 healthy volunteers. According to our findings interleukin (IL)-2, IL-10, IL-12 and tumor necrosis factor-alpha (TNF-alpha) levels were statistically significantly elevated in the serum of psoriatic patients before therapy compared with those of controls. IL-6 serum levels did not differ between psoriatic patients and healthy volunteers. Conversely, interferon-gammaserum levels of psoriatic patients were statistically significantly lower than those of healthy volunteers.
Assuntos
Citocinas/sangue , Psoríase/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Psoríase/etiologiaRESUMO
The aim of this retrospective study was to evaluate melanoma biopsy specimens from the Greek population living in the prefecture of Larissa for the presence of human papillomavirus (HPV) DNA and to determine the possible relationship between HPV and clinical outcome in these patients. Twenty-eight melanoma biopsy specimens, 20 from primary cutaneous melanoma and eight from melanoma metastasis were obtained from 28 patients. The biopsy samples were formalin-fixed and paraffin wax-embedded. The control group consisted of three junctional melanocytic nevi, histologically confirmed, and three punch biopsies from normal skin that were obtained from six healthy individuals. The presence and types of HPV DNA were assessed by the amplification of a fragment of the LI region by consensus primer polymerase chain reaction (PCR) combined with restriction fragment length polymorphism analysis (RFLPA). In each biopsy specimen that was evaluated, HPV 6, HPV 11, HPV 16 and HPV 18 positive controls from genital HPV lesions were included. Five of 28 (17.85%) biopsy melanoma specimens were positive for HPV DNA. Conversely, HPV was not detected in any of the biopsy specimens of the control group (0/6). HPV viral type 16 was found in two samples and HPV 6 DNA in three. Our results regarding the possible relationship between melanoma and HPV DNA were not statistically significant (p > 0.05). These findings suggest that ultraviolet sun exposure remains the main cause of melanoma in our region. The role of cutaneous HPV infection in the pathogenesis of melanoma remains elusive.
Assuntos
DNA Viral/análise , Melanoma/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Neoplasias Cutâneas/virologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Sondas de DNA de HPV , Feminino , Grécia , Humanos , Masculino , Melanoma/patologia , Metástase Neoplásica , Infecções por Papillomavirus/patologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Neoplasias Cutâneas/patologiaRESUMO
Alopecia areata is a chronic, nonscarring hair loss condition with an unpredictable course that may cause emotional stress in affected patients. Regarding its pathogenesis, the most accepted theory is that alopecia areata is a T-cell-mediated autoimmune condition that is most likely to occur in genetically predisposed individuals. Cyclosporin A is an immunosuppressive agent that has provided new approaches in the treatment of autoimmune diseases. Hypertrichosis, one of the common side effects of orally administered cyclosporin A, encouraged a number of investigators to use the drug in the treatment of alopecia areata, but the reports on this subject have been controversial. We present a small series of patients with severe alopecia areata treated systemically with cyclosporin A at a dose of 3-5 mg/kg for 6 months as well as their 3-month follow-up after cessation of the drug.
Assuntos
Alopecia em Áreas/classificação , Alopecia em Áreas/tratamento farmacológico , Ensaios Clínicos como Assunto , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Administração Oral , Adulto , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
The increasing incidence of melanoma in the general population during the last few decades has provoked a great deal of research, aiming to identify the possible relationship between old and new etiological factors involved in the pathogenesis of this tumor. The aim of the study was to evaluate the incidence of melanoma in central Greece, especially in the prefecture of Larissa from January 1988 to December 1998. Data were collected from the General Hospital of Larissa. Seventy-one cases of melanoma were studied (41 females, 30 males). The incidence increased from 1.36/100,000 patients during the first year of the study (1988) to 5.2/100,000 patients in the last year of the study (1998). The patients'skin types were: type 12.8%, type II 52.1%, type III 45.1%. The median age of patients was 61.9 years, 61.4 years in female and 62.5 years in male patients. Concerning their occupation, farmers accounted for 56.3%. Melanomas were most frequently located on head and neck (36.6%), extremities (30.98%) and trunk (11.3%). Superficial spreading melanomas were observed in 44% of the patients and nodular melanomas in 20%. In conclusion. there was a rapid increase in the incidence of melanoma in our region especially during the last 3 years.