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1.
J Allergy Clin Immunol ; 137(1): 35-45, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26476479

RESUMO

Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.


Assuntos
Mastocitose Cutânea/classificação , Alergia e Imunologia , Consenso , Humanos , Mastocitose Cutânea/diagnóstico , Mastocitose Cutânea/imunologia , Sociedades Médicas
2.
N Engl J Med ; 363(6): 532-41, 2010 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-20818888

RESUMO

BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Antagonistas de Receptor B2 da Bradicinina , Bradicinina/análogos & derivados , Doença Aguda , Adulto , Bradicinina/administração & dosagem , Bradicinina/efeitos adversos , Bradicinina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Análise de Intenção de Tratamento , Masculino , Estatísticas não Paramétricas , Ácido Tranexâmico/uso terapêutico
4.
J Allergy Clin Immunol ; 128(1): 202-209.e5, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21636116

RESUMO

BACKGROUND: A subgroup of patients with chronic spontaneous urticaria (CU) exhibits IgE antibodies directed against autoantigens, such as thyroperoxidase (TPO). We conducted this study to investigate whether such patients with CU with IgE against TPO benefit from treatment with omalizumab, a humanized anti-IgE mAb licensed for the treatment of severe persistent allergic (IgE-mediated) asthma. OBJECTIVES: We sought to assess the efficacy of omalizumab treatment in patients with CU with IgE autoantibodies against TPO. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy were randomized to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks. The primary end point was the change from baseline in mean weekly urticaria activity score after 24 weeks of treatment, as calculated from patients' diaries. The safety and tolerability of omalizumab were also assessed. RESULTS: Of the 49 randomized patients (omalizumab, n = 27; placebo, n = 22), 42 completed the study. At week 24, patients demonstrated a mean reduction in the weekly urticaria activity score from baseline of 17.8 with omalizumab and 7.9 with placebo (P = .0089). Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse events was similar in both groups. CONCLUSIONS: The results of this study indicate that omalizumab is an effective treatment option for patients with CU with IgE autoantibodies against TPO who are refractory to conventional treatment.


Assuntos
Antialérgicos/uso terapêutico , Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Autoanticorpos/sangue , Autoantígenos/imunologia , Urticária/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Autoanticorpos/imunologia , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Omalizumab , Urticária/sangue , Urticária/imunologia , Adulto Jovem
5.
Contact Dermatitis ; 62(5): 294-302, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20536477

RESUMO

BACKGROUND: As a modification of patch testing, the strip patch test was established to obtain more sensitive and reliable test results. Comparative data on diagnostic accuracy for both tests are missing. OBJECTIVES: To compare the diagnostic accuracy of strip patch tests and patch tests in detecting sensitizations in patients with suspected allergic contact dermatitis by using patient history as the reference standard. PATIENTS/METHODS: In a multicentre, prospective, investigator-blinded study 790 patients were enrolled. The defined reference standard was established prior to patch testing. Patch tests were performed with nickel sulfate, potassium dichromate, and lanolin alcohol. Duplicate tests were simultaneously performed on both sides of the back, of which one randomly chosen side was tape stripped beforehand, according to a standardized procedure. Primary outcome was the difference in sensitivity between strip patch test and patch test. RESULTS: Seven hundred and eighty-seven patients were included in the analysis. Strip patch tests detected considerably more sensitization to nickel sulfate and potassium dichromate than patch tests: differences of sensitivities were 16.4% (95% CI, 8.7-24.1%) for nickel sulfate and 25.0% (95% CI, 8.9-41.0%) for potassium dichromate, both favouring the strip patch test. CONCLUSIONS: The standardized strip patch test proved to be accurate and clinically safe and is promising to improve diagnosis of allergic contact dermatitis beyond the patch test.


Assuntos
Dermatite Alérgica de Contato/diagnóstico , Testes do Emplastro/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alérgenos , Feminino , Humanos , Irritantes , Lanolina , Masculino , Pessoa de Meia-Idade , Níquel , Dicromato de Potássio , Estudos Prospectivos , Sensibilidade e Especificidade , Fita Cirúrgica , Adulto Jovem
6.
Int Immunopharmacol ; 5(4): 735-47, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15710342

RESUMO

NGF and IL-3 play a unique role in supporting human basophil differentiation and mediator secretion. Their importance in allergic disease is underlined further by studies showing elevated levels of these factors in asthmatics. Here, we compared the abilities of IL-3 and NGF to stimulate basophil histamine, IL-4 or IL-13 release, either directly or in conjunction with IgE-dependent stimulation and assessed the intracellular signals responsible. Our results show that the ability of IL-3 and NGF to enhance IgE-dependent histamine release are similar. Both factors also potentiated IgE-dependent IL-13 secretion to a greater degree than the release of histamine or IL-4. At high concentrations (100 ng/ml), IL-3 and NGF alone were capable of releasing cytokines but little histamine. These abilities of IL-3 and NGF to modulate basophil activation were sensitive to blockade by specific inhibitors of PI 3-kinase, p38 MAPK and PLC, but not PKC, suggesting that their effects are mediated considerably by pathways comparable to IgE-dependent signalling.


Assuntos
Basófilos/fisiologia , Imunoglobulina E/fisiologia , Interleucina-3/fisiologia , Fator de Crescimento Neural/fisiologia , Basófilos/metabolismo , Diferenciação Celular/fisiologia , Ativação Enzimática/fisiologia , Liberação de Histamina , Humanos , Técnicas In Vitro , Interleucina-3/imunologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
J Leukoc Biol ; 72(2): 391-400, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12149431

RESUMO

Although human basophils modulate allergic diseases by secreting histamine, leukotriene C(4), interleukin (IL)-4, and IL-13, the intermediary signals controlling the release of these mediators are poorly understood. Here, we show that p38 mitogen-activated protein kinase (MAPK) crucially affects basophil activation following stimulation with various secretagogues. Phosphorylation of p38 MAPK occurred within 5 min following anti-immunoglobulin (Ig)E stimulation, but was more rapidly activated in basophils stimulated with formyl-Met-Leu-Phe or A23187. Additionally, activation of p38 MAPK to the above stimuli was dependent on extracellular influx and intracellular mobilization of calcium. SB 203580, a specific p38 MAPK inhibitor, blocked anti-IgE-induced secretion of all basophil mediators and reduced not only p38 MAPK, but also extracellular signal-regulated kinases 1 and 2 activity, whereas the MAPK antagonist, PD 098059, did not affect p38 MAPK. IgE-dependent activation of p38 MAPK and MKK3/6 was affected by LY 294002 and wortmannin, suggesting that these kinases are targets for phosphatidylinositol 3 kinase (PI 3-K). We conclude that p38 MAPK is a pivotal regulator of basophil function downstream of PI 3-K activation and calcium mobilization.


Assuntos
Albuterol/análogos & derivados , Basófilos/enzimologia , Sinalização do Cálcio , Inibidores Enzimáticos/farmacologia , Liberação de Histamina , Interleucinas/metabolismo , Leucotrieno C4/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Inibidores de Fosfoinositídeo-3 Quinase , Processamento de Proteína Pós-Traducional , Albuterol/farmacologia , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Basófilos/metabolismo , Calcimicina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Cromonas/farmacologia , AMP Cíclico/fisiologia , Ativação Enzimática/efeitos dos fármacos , Flavonoides/farmacologia , Liberação de Histamina/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Imunoglobulina E/imunologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , MAP Quinase Quinase 3 , MAP Quinase Quinase 6 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Morfolinas/farmacologia , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Fosfatidilinositol 3-Quinases/fisiologia , Fosforilação , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Piridinas/farmacologia , Xinafoato de Salmeterol , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Teofilina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno
8.
Arch Dermatol Res ; 296(5): 212-9, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15293061

RESUMO

BACKGROUND: The "strip" patch test (SPT) is a variant of patch testing which is used for substances with a poor percutaneous penetration. Penetration of the substances is enhanced by repeated applications of adhesive tape prior to their application to the skin. However, no guidelines exist for standardized performance of the SPT. OBJECTIVES: The aim of this multicentre study was to obtain a first practical approach towards a standardized SPT procedure. METHODS: Intact noninflamed skin of the upper back of 83 healthy volunteers was tape-stripped. For sequential strips, a 25-mm diameter 3M Blenderm surgical tape was vertically applied and gently pressed downward using the fingertips for about 2 s. The tape was removed in one quick movement at an angle of 45 degrees in the direction of adherence. Each strip was performed with a new piece of tape on exactly the same skin area. RESULTS. In each subject, we first determined the number of strips (A) until the skin surface started to glisten and calculated the median number of strips (A) in the sample (A=26 strips). We then ascertained the median number of strips (a) in the sample that was necessary to achieve a statistically significant and twofold increase in TEWL (a=11 strips), revealing a "critical" stratum corneum strip depth. The unknown number of strips (a) for each subject was finally calculated from the formula a/A=a/A, i.e. the individual number of strips (A) until the skin surface started to glisten was multiplied by a derived tape-specific correction factor (cf=a/A=11/26=0.4). The increase in percutaneous penetration in strip patch testing by performing "a" strips versus conventional patch testing was shown by scoring of clinical and subjective SLS irritant reactions. CONCLUSIONS: The present multicentre study outlines an experimentally derived approach for a uniform SPT procedure, which does not require the use of complex technical equipment. This first approach now requires validation by a study involving the application of allergens to obtain evidence of enhancement in the sensitivity of patch testing.


Assuntos
Testes do Emplastro/métodos , Testes do Emplastro/normas , Pele/metabolismo , Adesivos , Idoso , Sistemas de Liberação de Medicamentos , Epiderme/metabolismo , Feminino , Humanos , Irritantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Permeabilidade , Padrões de Referência , Dodecilsulfato de Sódio/administração & dosagem , Perda Insensível de Água
9.
Wien Klin Wochenschr ; 116(19-20): 647-51, 2004 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-15941072

RESUMO

The European Competence Network on Mastocytosis (ECNM) is a Europe-wide, multinational cooperative approach attempting to improve recognition, diagnosis, and therapy of mastocytosis. The network is composed of local centers, physicians, and scientists who have dedicated their work to patients with mastocytosis. However, because of the rarity and complexity of the disease, each single component in the network alone would fail to meet important demands and to reach solid conclusions in this field of applied medicine. The ECNM represents an attempt to overcome this restriction as a cooperative multicenter platform that should serve as an important basis for the development of new therapeutic strategies and diagnostic concepts, and for the standardization of techniques used to determine diagnostic and prognostic parameters. Moreover, using future central databases and registries, a suitable infrastructure for the development of co-operative multicenter clinical trials will be established. In addition, the ECNM is dedicated to provide the best available information about the disease to patients and physicians.


Assuntos
Competência Clínica/normas , Serviços de Informação/organização & administração , Cooperação Internacional , Mastócitos , Mastocitose/diagnóstico , Mastocitose/terapia , Pesquisa , Conferências de Consenso como Assunto , Europa (Continente) , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrões de Referência , Encaminhamento e Consulta/normas
11.
Dtsch Arztebl Int ; 105(25): 458-65; quiz 465-6, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19626183

RESUMO

INTRODUCTION: The term "urticaria" refers to any of a group of distinct skin conditions that are characterized by itchy, wheal-and-flare skin reactions (hives). In spontaneous urticaria, the most common type, the hives seem to arise without provocation. METHODS: Selective review of the literature, including current guidelines. RESULTS: Spontaneous urticaria is divided into acute (lasting less than six weeks) and chronic types. The pathognomonic itching, hives, and angioedema arise by the same mechanism--cutaneous mast cell activation and release of histamine and other mediators of inflammation--in both acute and chronic urticaria, but these two disorders have different etiological profiles. The underlying cause of acute urticaria cannot be identified in about half of all cases. Chronic urticaria, which is much rarer, is usually caused by autoreactivity, chronic infection, or intolerance to food additives. If the condition persists after the underlying cause has been treated or eliminated, non-sedating antihistamines are the agents of first choice for symptomatic treatment. DISCUSSION: Unlike acute urticaria, which is self-limited and should be treated symptomatically, chronic urticaria should be treated by the identification and elimination of underlying causes, which is usually curative.

12.
Int Arch Allergy Immunol ; 136(4): 329-39, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15741731

RESUMO

BACKGROUND: Exposure of human basophils to allergens results in a rapid secretion of histamine, LTC(4), IL-4 and IL-13, which dominate both the symptomology of allergic diseases and support the underlying Th2/IgE predominance associated with these reactions. The IgE-dependent release of these mediators in basophils crucially involves PI 3-kinase and the subsequent activation of p38 MAPK and ERK1&2. Here, we investigated the role of the third major member of the mitogen activated kinase family, namely the c-Jun amino terminal kinase (JNK), which is rapidly activated following IgE receptor cross-linking in murine mast cells. METHODS: Human basophils were highly purified by magnetic cell sorting. The activities of various intracellular signaling components, in basophils that had been stimulated under various conditions, were assessed by Western blotting. Mediator secretions were also determined using either spectrofluorometric analysis (histamine) or ELISA (LTC(4), IL-4 and IL-13). RESULTS: Our results show that while JNK is moderately expressed in human basophils, it is not consistently phosphorylated upon anti-IgE stimulation. Phosphorylation of the transcription factor c-Jun, a downstream target of JNK, was also undetected in contrast to p38 MAPK and ERK1&2, which were clearly activated following anti-IgE stimulation of the cells. Additionally, inhibitors of the JNK pathway failed to prevent basophil mediator release and had no effect on the phosphorylation of p38 MAPK or ERK1&2 at concentrations which were specific for JNK blockade. CONCLUSIONS: These data suggest major differences in utilizing various members of the mitogen-activated kinase family in the signal transduction cascade of IgE-receptor-bearing cells.


Assuntos
Basófilos/enzimologia , Basófilos/imunologia , Imunoglobulina E/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transdução de Sinais/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
13.
Exp Dermatol ; 13(9): 535-42, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15335353

RESUMO

In order to better understand the mechanisms governing display of mast cell characteristics in human myeloid cells, we have studied the mast cell phenotype in human promyelocytic (HL-60) and myelocytic (U-937, TPH-1) vs. basophilic (KU-812) and mast cell (HMC-1) lines, in part also in skin mast cells and blood monocytes, at mRNA and protein level before and after stimulation with mast cell growth factors. In unstimulated cells, mRNA for the stem cell factor (SCF) receptor c-kit and the gamma chain of the high-affinity IgE receptor (FcepsilonRI) was noted in all cells studied. Like mast and basophilic cells, THP-1 cells expressed the FcepsilonRIalpha and beta chains and weakly histidine decarboxylase (HDC), but they lacked mRNA for mast cell-specific proteases [tryptase, chymase, carboxypeptidase A (CPA)]. In contrast, HL-60 and U-937 cells lacked FcepsilonRIalpha, but expressed tryptase and chymase, HL-60 cells also CPA. KU-812 cells failed to express the basophil-specific marker 2D7. After a 10-day culture with SCF or fibroblast supernatants, baseline mRNA expression of most mast cell characteristics was upregulated, whereas c-kit mRNA expression decreased in all but THP-1 cells. Differential mRNA expression of FcepsilonRI vs. protease (tryptase) was confirmed at protein level by immunocytochemistry and enzymatic activity. KU-812 cells are thus closest to skin mast cells in that they express all molecules studied, except for chymase, followed by THP-1 cells that lack all mast cell proteases. In contrast, HL-60 and U-937 cells fail to express the FcepsilonRIalpha and beta chains but express most mast cell proteases. The selective and differential expression of mast cell characteristics in human myeloid cell lines suggests that induction of the mast cell phenotype is regulated by several independent genes and that mast cells and basophils branch off at early and distinct points of myeloid development.


Assuntos
Mastócitos/citologia , Mastócitos/fisiologia , Células Mieloides/citologia , Células Mieloides/fisiologia , Diferenciação Celular , Quimases , Expressão Gênica , Células HL-60 , Histidina Descarboxilase/genética , Humanos , Fenótipo , Receptores de IgE/genética , Serina Endopeptidases/metabolismo , Triptases , Células U937 , Regulação para Cima
14.
Contact Dermatitis ; 46(5): 258-61, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12084077

RESUMO

Thiuram mix is tested in the standard series at a test concentration of 1% pet. The single thiurams (DPTD, TMTD, TMTM, TETD), however, are usually tested at 0.25% pet. in Germany. In other countries, the individual components of thiuram mix are tested at 1% pet. The German Contact Dermatitis Research Group (DKG) compared both patch test concentrations in 530 patients in order to find out if (i) a significant number of positive patch tests are missed by testing at the lower concentration, (ii) problems with irritant test reactions occur by increasing the test concentration to 1%, and (iii) the sensitivity of the thiuram mix rises when the breakdown test is done with the higher concentration. Slightly more positive reactions were seen with the higher concentration, but this increase did not reach statistical significance. The reaction index, as a measure for the relation of positive to irritant and/or questionable reactions, remained unchanged for the individual thiurams. The sensitivity of the mix also did not change when the breakdown test was performed with 1% pet. instead of 0.25% pet. Thus, we conclude that both concentrations are of equal diagnostic value in patch testing.


Assuntos
Dermatite Alérgica de Contato/diagnóstico , Testes do Emplastro , Tiram , Humanos , Vaselina , Sensibilidade e Especificidade , Tiram/efeitos adversos
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