RESUMEN
LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006-treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re-distribution from target expressing cells resulted in a long terminal half-life and a long-lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well-tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose-limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil-driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.
Asunto(s)
Epóxido Hidrolasas , Plasma , Humanos , Neutrófilos , PielRESUMEN
Coexistence with related species poses evolutionary challenges to which populations may react in diverse ways. When exposed to similar environments, sympatric populations of two species may adopt similar phenotypic trait values. However, selection may also favour trait divergence as a way to reduce competition for resources or mates. The characteristics of external body parts, such as coloration and external morphology, are involved to varying degrees in intraspecific signalling as well as in the adaptation to the environment and consequently may be diversely affected by interspecific interactions in sympatry. Here, we studied the effect of sympatry on various colour and morphological traits in males and females of two related newt species Lissotriton helveticus and L. vulgaris. Importantly, we did not only estimate how raw trait differences between species respond to sympatry, but also the marginal responses after controlling for environmental variation. We found that dorsal and caudal coloration converged in sympatry, likely reflecting their role in adaptation to local environments, especially concealment from predators. In contrast, aspects of male and female ventral coloration, which harbours sexual signals in both species, diverged in sympatry. This divergence may reduce opportunities for interspecific sexual interactions and the associated loss of energy, suggesting reproductive character displacement (RCD). Our study emphasizes the contrasting patterns of traits involved in different functions and calls for the need to consider this diversity in evolutionary studies.
Asunto(s)
Evolución Biológica , Salamandridae , Animales , Femenino , Masculino , Salamandridae/genética , SimpatríaRESUMEN
Recent agricultural intensification threatens global biodiversity with amphibians being one of the most impacted groups. Because of their biphasic life cycle, amphibians are particularly vulnerable to habitat loss and fragmentation that often result in small, isolated populations and loss of genetic diversity. Here, we studied how landscape heterogeneity affects genetic diversity, gene flow and demographic parameters in the marbled newt, Triturus marmoratus, over a hedgerow network landscape in Western France. While the northern part of the study area consists of preserved hedged farmland, the southern part was more profoundly converted for intensive arable crops production after WWII. Based on 67 sampled ponds and 10 microsatellite loci, we characterized regional population genetic structure and evaluated the correlation between landscape variables and (i) local genetic diversity using mixed models and (ii) genetic distance using multiple regression methods and commonality analysis. We identified a single genetic population characterized by a spatially heterogeneous isolation-by-distance pattern. Pond density in the surrounding landscape positively affected local genetic diversity while arable crop land cover negatively affected gene flow and connectivity. We used demographic inferences to quantitatively assess differences in effective population density and dispersal between the contrasted landscapes characterizing the northern and southern parts of the study area. Altogether, results suggest recent land conversion affected T. marmoratus through reduction in both effective population density and dispersal due to habitat loss and reduced connectivity.
Asunto(s)
Flujo Génico , Genética de Población , Animales , Ecosistema , Variación Genética , Repeticiones de Microsatélite , SalamandridaeRESUMEN
Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/terapia , Inmunoterapia/métodos , Inmunoterapia/tendencias , HumanosRESUMEN
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
RESUMEN
Amphibians are particularly sensitive to landscape fragmentation. Potential barriers between breeding sites can negatively influence the dispersal of individuals and increase genetic structure between populations. In this study, we genotyped 10 microsatellites for 334 marbled newts (Triturus marmoratus) at 11 different locations in Western France. Samples were collected in different regions with contrasting agricultural landscapes (low and high proportion of arable land in the north and south, respectively). We found a strong genetic structure between the northern and southern sampling sites. Isolation by distance was recorded after 62 km, but within the northern region, little or no genetic structure was detected over large distances (up to 114 km). Genetic structure at shorter distance (43 km) was found between sites situated in landscapes with larger amounts of arable lands. A significant positive relationship was found between the pairwise genetic distance (Fst) between sites and the amount of arable land together with the distance between sites. Our results suggest that the Loire River might act as a corridor for the marbled newt, while arable land might act as a barrier. Finally, although a large city is located between sampling sites, no effect was detected on population structure.
RESUMEN
The physiological mechanisms underlying the 'cost of reproduction' remain under debate, though oxidative stress has emerged as a potential candidate. The 'oxidative cost of reproduction' has received considerable attention with regards to food and antioxidant availability; however, the limitation of water availability has thus far been neglected. In this study, we experimentally examined the combined effect of pregnancy and water deprivation on oxidative status in a viviparous snake (Vipera aspis), a species naturally exposed to periods of water and food deprivation. We predicted a cumulative effect of pregnancy and dehydration on oxidative stress levels. Our results support the occurrence of an oxidative cost of reproduction as we found higher oxidative damage levels in pregnant females than in non-reproductive individuals, despite an up-regulation of antioxidant defences. Surprisingly, water deprivation was associated with an up-regulation of antioxidant defences, and did not increase oxidative damage, either alone or in combination with reproduction.
Asunto(s)
Estrés Oxidativo , Viperidae/fisiología , Viviparidad de Animales no Mamíferos/fisiología , Animales , Antioxidantes/metabolismo , Deshidratación , Eritrocitos/química , Femenino , Reproducción/fisiología , Regulación hacia Arriba , AguaAsunto(s)
Índice de Masa Corporal , Edad Materna , Estrías de Distensión/epidemiología , Aumento de Peso , Adulto , Intervalos de Confianza , Estudios Transversales , Estética , Femenino , Francia , Humanos , Modelos Logísticos , Análisis Multivariante , Oportunidad Relativa , Embarazo , Prevalencia , Factores de Riesgo , Factores Socioeconómicos , Estrías de Distensión/diagnóstico , Adulto JovenAsunto(s)
Síndrome de Hipersensibilidad a Medicamentos/fisiopatología , Infecciones por Herpesviridae/inducido químicamente , Activación Viral/efectos de los fármacos , Adulto , Estudios de Cohortes , Infecciones por Citomegalovirus/inducido químicamente , Síndrome de Hipersensibilidad a Medicamentos/virología , Infecciones por Virus de Epstein-Barr/inducido químicamente , Humanos , Masculino , Estudios Prospectivos , Factores de TiempoRESUMEN
The nature of the antigens recognized by γδ T cells and their potential recognition of major histocompatibility complex (MHC)-like molecules has remained unclear. Members of the CD1 family of lipid-presenting molecules are suggested ligands for Vδ1 TCR-expressing γδ T cells, the major γδ lymphocyte population in epithelial tissues. We crystallized a Vδ1 TCR in complex with CD1d and the self-lipid sulfatide, revealing the unusual recognition of CD1d by germline Vδ1 residues spanning all complementarity-determining region (CDR) loops, as well as sulfatide recognition separately encoded by nongermline CDR3δ residues. Binding and functional analysis showed that CD1d presenting self-lipids, including sulfatide, was widely recognized by gut Vδ1+ γδ T cells. These findings provide structural demonstration of MHC-like recognition of a self-lipid by γδ T cells and reveal the prevalence of lipid recognition by innate-like T cell populations.
Asunto(s)
Antígenos CD1d/química , Lípidos/inmunología , Modelos Moleculares , Receptores de Antígenos de Linfocitos T gamma-delta/química , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/metabolismo , Animales , Presentación de Antígeno , Antígenos CD1d/metabolismo , Cristalografía por Rayos X , Epítopos , Humanos , Células Jurkat , Complejo Mayor de Histocompatibilidad/inmunología , Estructura Cuaternaria de Proteína , Sulfoglicoesfingolípidos/química , Sulfoglicoesfingolípidos/metabolismoRESUMEN
BACKGROUND: Few studies have evaluated pemphigus treatments according to the definitions of the consensus statement. Prognostic factors for complete remission off therapy (CRoffT) remain unknown. OBJECTIVE: We sought to assess the rate of CRoffT in patients with pemphigus treated with different regimens. METHODS: In all, 134 patients with pemphigus were included in a retrospective, multicenter study. Primary end point was the rate of CRoffT. Prognostic factors for CRoffT were determined using univariate and multivariate analyses. RESULTS: Eighty patients with pemphigus vulgaris, 47 with pemphigus foliaceus, and 7 with paraneoplastic pemphigus were included. Mean age was 60 ± 18 years. Patients were treated either with medium (≤0.5 mg/kg/d) (n = 32) or high (≥1 mg/kg/d) (n = 59) doses of prednisone, or without systemic corticosteroids (n = 43). Mean follow-up was 77 ± 64 months. In all, 68 patients (50.7%) achieved CRoffT (95% confidence interval 42.3%-59.2%) after a mean treatment duration of 36 ± 39 months, including 47 of 80 patients with pemphigus vulgaris (58.7%) and 21 of 47 with pemphigus foliaceus (44.7%). Main prognostic factors for CRoffT were initial mucosal involvement (hazard ratio 2.2; 95% confidence interval 1.05-4.58; P = .036) and younger age (<61 years) (hazard ratio 2.5; 95% confidence interval 1.18-5.12; P = .0167). The rate of long-lasting CRoffT was 44%, with a mean follow-up after treatment withdrawal of 59 ± 50 months. LIMITATIONS: This was a retrospective study. CONCLUSION: The rate of CRoffT was 51%. Patients with pemphigus vulgaris were more likely to achieve CRoffT than those with pemphigus foliaceus.
Asunto(s)
Corticoesteroides/uso terapéutico , Ácido Micofenólico/análogos & derivados , Pénfigo/tratamiento farmacológico , Pénfigo/patología , Prednisona/uso terapéutico , Adulto , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Ácido Micofenólico/uso terapéutico , Pénfigo/mortalidad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Pemphigus is a severe blistering condition of the skin and mucosa caused by autoantibodies directed against desmogleins, which are a type of keratinocyte adhesion protein. B cell depletion by rituximab has short-term efficacy against pemphigus. We aimed to assess the long-term course of pemphigus patients after B cell depletion and to understand the immunological mechanisms that mediate long-lasting remissions. We evaluated the clinical course of 22 pemphigus patients treated with rituximab after a 79-month median follow-up and compared the anti-desmoglein B cell response and B and T lymphocyte subpopulations and repertoire between patients who achieved complete remission (CR) and those who had incomplete remission (IR). Thirteen patients (59%) experienced CR during the study, including 10 patients off treatment and 3 patients with prednisone doses <10 mg/day; 9 patients had IR. A marked increase was observed in the ratio of CD19(+)CD27(-) naïve B cells to CD19(+)CD27(+) memory B cells. Indeed, patients in CR had a fourfold higher number of transitional B cells and interleukin-10-secreting regulatory B cells than those in IR. Furthermore, CR was associated with modification of the initial B cell repertoire and the disappearance of desmoglein-specific circulating immunoglobulin G-positive (IgG(+)) B lymphocytes, whereas a skewed B cell repertoire was observed in patients in IR. Thus, a blockage of B cell maturation, a prolonged repopulation with naïve B cells, and a delayed reappearance of memory B cells, which resulted in the disappearance of circulating desmoglein-specific IgG(+) B lymphocytes, contribute to the long-lasting effectiveness of rituximab for treating pemphigus.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Linfocitos B/inmunología , Desmogleínas/inmunología , Pénfigo/tratamiento farmacológico , Humanos , Inmunofenotipificación , Pénfigo/inmunología , Pénfigo/fisiopatología , RituximabRESUMEN
Octopamine (OA) is an important neuroactive substance that modulates several physiological functions and behaviors of various invertebrate species. This biogenic monoamine, structurally related to noradrenaline, acts as a neurotransmitter, a neuromodulator, or a neurohormone in insects. The tyramine ß-hydroxylase (TBH) catalyzes the last step in OA biosynthesis and thus plays a key role in the regulation of synthesis and secretion of OA in neurons. The aim of this study was to characterize TBH in the cockroach Periplaneta americana and to get a better understanding of its regulation under stress conditions in this insect. First of all, five full-length cDNAs encoding TBH isoforms were cloned from the nerve cord of the physiological model P. americana. PaTBH transcripts were found mainly expressed in nervous tissues and in octopaminergic dorsal unpaired median neurons. In addition, a new ELISA assay was developed so as to allow determination of both OA level and TBH activity in stressed cockroaches. Mechanical stressful stimulation led to a significant increase in TBH activity after 1 and 24 âh, with a higher induction after 1â h than after 24 âh. Thus, TBH could be considered as a promising biomarker of stress in insects rather than OA.
Asunto(s)
Cucarachas/fisiología , Oxigenasas de Función Mixta/metabolismo , Estrés Fisiológico , Regulación hacia Arriba , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Biocatálisis , Clonación Molecular , Cartilla de ADN , ADN Complementario , Ensayo de Inmunoadsorción Enzimática , Oxigenasas de Función Mixta/genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de AminoácidoRESUMEN
The syndrome termed 'Drug Reaction with Eosinophilia and Systemic Symptoms' (DRESS) is an unpredictable, life-threatening condition associated with adverse reactions to therapy. Although the etiology of DRESS is poorly understood, genetic susceptibility markers have been identified within the HLA complex and there are several prevailing models of pathogenesis. Modification of host antigens by haptens (drugs or their metabolites), or non-covalent drug binding to endogenous proteins (the p-i concept), may drive pro-inflammatory immune responses in patients. Alternatively, a viral trigger for DRESS has been proposed based on the concomitant detection of herpesviruses and the recent demonstration of Epstein-Barr virus-specific immune responses in DRESS patients. In the present review, we discuss the latest findings concerning the pathogenesis of drug reactions and known risk factors for DRESS.
Asunto(s)
Hipersensibilidad a las Drogas/etiología , Eosinofilia/etiología , Animales , Erupciones por Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/complicaciones , Herpesvirus Humano 4/fisiología , Humanos , Factores de Riesgo , Linfocitos T/inmunología , Activación Viral/efectos de los fármacosRESUMEN
OBJECTIVE: To identify the prognostic factors of overall survival in a series of patients with paraneoplastic pemphigus (PNP). DESIGN: Multicenter retrospective cohort study. SETTING: Twenty-seven dermatology departments in France. PATIENTS: A total of 53 patients (31 men and 22 women; median age, 59 years; age range, 30-88 years) were diagnosed as having PNP between 1992 and 2010. MAIN OUTCOME MEASURES: Overall Kaplan-Meier survival rates were estimated, and features associated with survival were assessed using univariate (log-rank test) and multivariate (Cox regression) analyses. RESULTS: The study included 53 patients with PNP. Thirty-six patients (68%) died during the study. The 1-, 3-, and 5-year overall survival rates were 49%, 41%, and 38%, respectively. The main causes of death were infections (n=21) and evolution of neoplasia (n=6). In univariate analysis, the main detrimental prognostic factors identified were erythema multiformelike skin lesions (P=.05) and histologic keratinocyte necrosis (P=.03). None of the 5 patients with Castleman disease died during the study. After adjustment for age and sex in multivariate analysis, erythema multiformelike skin lesions remained predictive of fatal outcome, with a 2-fold increase in death rate (hazard ratio [HR], 2.3; 95% CI, 1.05-5.03; P=.04). The prognosis of patients with PNP was even poorer when erythema multiformelike skin lesions were associated with severe skin or mucosal involvement at presentation (HR of death, 3.0; 95% CI, 1.01-8.92; P=.049). CONCLUSION: Patients with PNP with erythema multiformelike skin lesions and histologic keratinocyte necrosis, especially when associated with extensive lesions at presentation, are likely to have a more severe and rapid fatal outcome and should be managed very carefully.
Asunto(s)
Eritema Multiforme/patología , Neoplasias/complicaciones , Síndromes Paraneoplásicos/patología , Pénfigo/patología , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Autoanticuerpos/sangre , Proteínas Portadoras/inmunología , Proteínas del Citoesqueleto/inmunología , Desmoplaquinas/inmunología , Distonina , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Masculino , Proteínas de la Membrana/inmunología , Persona de Mediana Edad , Membrana Mucosa/patología , Análisis Multivariante , Proteínas del Tejido Nervioso/inmunología , Síndromes Paraneoplásicos/tratamiento farmacológico , Síndromes Paraneoplásicos/inmunología , Pénfigo/tratamiento farmacológico , Pénfigo/inmunología , Plaquinas/inmunología , Pronóstico , Modelos de Riesgos Proporcionales , Precursores de Proteínas/inmunología , Estudios Retrospectivos , Rituximab , Índice de Severidad de la EnfermedadRESUMEN
αß T-cell lines specific for sulfatide, an abundant myelin glycosphingolipid presented by various CD1 molecules, have been previously derived from PBMCs of patients with demyelinating diseases such as multiple sclerosis (MS) but also from healthy subjects. Using an unbiased tetramer-based MACS enrichment method to enrich for rare antigen-specific cells, we confirmed the presence of CD1d-sulfatide-specific T cells in all healthy individuals examined. Surprisingly, the great majority of fresh sulfatide-specific T cells belonged to the γδ lineage. Furthermore, these cells used the Vδ1 TCR variable segment, which is uncommon in the blood but predominates in tissues such as the gut and specifically accumulates in MS lesions. Recombinant Vδ1 TCRs from different individuals were shown to bind recombinant CD1d-sulfatide complexes in a sulfatide-specific manner. These results provide the first direct demonstration of MHC-like-restricted, antigen-specific recognition by γδ TCRs. Together with previous reports, they support the notion that human Vδ1 T cells are enriched in CD1-specific T cells and suggest that the Vδ1 T-cell population that accumulates in MS lesions might be enriched in CD1-sulfatide-specific cells.
Asunto(s)
Antígenos CD1d/inmunología , Epítopos de Linfocito T/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Sulfoglicoesfingolípidos/inmunología , Linfocitos T/inmunología , Antígenos/inmunología , Genes MHC Clase I/inmunología , Humanos , Esclerosis Múltiple/inmunologíaAsunto(s)
Erupciones por Medicamentos/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Inmunoglobulinas Intravenosas/efectos adversos , Activación Viral , Corticoesteroides/uso terapéutico , Adulto , Anciano , Citomegalovirus/fisiología , Progresión de la Enfermedad , Erupciones por Medicamentos/inmunología , Erupciones por Medicamentos/virología , Eosinofilia/inmunología , Eosinofilia/virología , Femenino , Fiebre/etiología , Herpesvirus Humano 4/fisiología , Herpesvirus Humano 6/fisiología , Herpesvirus Humano 7/fisiología , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Interferón gamma/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Medición de Riesgo , Factores de Necrosis Tumoral/sangreRESUMEN
Rare CD1d-α-galactosylceramide-specific T cells that do not express the invariant Vα24 chain of human NKT cells were recently identified after expansion in vitro with the lipid Ag, but their phenotype and frequency in vivo and lineage relationship with NKT cells could not be elucidated. By using a CD1d tetramer-based method to enrich these cells from fresh peripheral blood, we demonstrated their naive-like CD62L(high)CD45RO(-)CD4(+) phenotype and relatively high frequency of â¼10(-5) in several healthy individuals. Notably, these cells expressed the NKT lineage-specific transcription promyelocytic leukemia zinc finger (PLZF), indicating a developmental relationship with NKT cells and ruling out the possibility that they were conventional MHC-restricted T cells cross-reacting against CD1d-α-galactosylceramide. Although PLZF is known to direct the effector program of NKT cells, we show in this study that the naive-like cells expressed it at a significantly lower amount than NKT cells. Further, we present mouse studies demonstrating a sharp PLZF expression threshold requirement for induction of the effector phenotype. These findings directly demonstrate in vivo the existence of naive-like CD1d-restricted human T cells marked by intermediate levels of PLZF.
Asunto(s)
Antígenos CD1d/fisiología , Factores de Transcripción de Tipo Kruppel/biosíntesis , Fase de Descanso del Ciclo Celular/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto , Animales , Antígenos CD1d/sangre , Línea Celular Transformada , Células Clonales , Regulación de la Expresión Génica/inmunología , Humanos , Factores de Transcripción de Tipo Kruppel/sangre , Leucemia Promielocítica Aguda/inmunología , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Subgrupos de Linfocitos T/patología , Timo/citología , Timo/inmunología , Timo/metabolismo , Adulto Joven , Dedos de ZincRESUMEN
BACKGROUND: Skin manifestations of relapsing polychondritis (RP) are usually nonspecific. OBJECTIVE: We report a series of patients with RP who presented with annular skin lesions. METHODS: The clinical and histologic features and follow-up data of patients with RP and an annular urticarial eruption were retrospectively reviewed. RESULTS: Ten patients (9 male, 1 female) (mean age 63.7 years) were included. All patients had tense, fixed, urticarial papules with an annular configuration predominantly located on the upper part of the trunk. Skin lesions occurred before the chondritis in 7 of 10 cases with a mean delay of 23 ± 13 months. Histologic examination consistently showed a lymphocytic vasculitis with no leukocytoclastic vasculitis, even when biopsies were repeated during the evolution (n = 7). Hematologic abnormalities were found in all cases. A myelodysplastic syndrome was found in 4 patients. Oral corticosteroids were effective in all cases, although skin lesions recurred during the decrease of corticosteroid doses in 4 cases. Five patients died during the evolution. LIMITATION: Retrospective case series design is a limitation. CONCLUSION: Annular and papular fixed urticarial eruption may represent a characteristic skin manifestation of RP. It is frequently associated with hematologic abnormalities and may auger a poor prognosis.