RESUMEN
To understand the epidemiological and genetic characteristics of B19V, a multiple-province surveillance of patients with febrile rash illnesses (FRIs) were conducted in China during 2009 ~ 2021. The clinical specimens of 3,820 FRI patients were collected and tested for B19V DNA. A total of 99 (2.59%) patients were positive for B19V, and 49 (49.49%) were children under 5 years old. B19V infections occurred throughout the year without obvious seasonal pattern. Ten NS1-VP1u sequences and seven genome sequences were obtained in this study, identified as subgenotype 1a. Combined with the globally representative genome sequences, no temporal and geographic clustering trends of B19V were observed, and there was no significant correlation between B19V sequences and clinical manifestations. The evolutionary rate of the B19V genome was 2.30 × 10-4 substitutions/site/year. The number of negative selection sites was higher than that of positive selection sites. It was the first to comprehensively describe the prevalence patterns and evolutionary characteristics of B19V in FRI patients in China. B19V played the role in FRI patients. Children under 5 years old were the main population of B19V infection. Subgenotype 1a was prevalent in FRI patients in China. B19V showed a high mutation rate, while negative selection acted on the genome.
Asunto(s)
Terapia de Aceptación y Compromiso , Exantema , Parvovirus B19 Humano , Niño , Humanos , Preescolar , Parvovirus B19 Humano/genética , China/epidemiología , Exantema/epidemiología , Exantema/genética , Evolución BiológicaRESUMEN
Monogenic causes are increasingly being recognized in patients with lupus, especially in early-onset disease. We herein report a boy with a novel mutation in the DNase 2 (DNASE2) gene presenting with monogenic lupus. A 6-year-old boy with a global developmental delay with microcephaly presented with chronic febrile illness with anemia, rash, polyarthritis, renal involvement, and hepatosplenomegaly. Laboratory investigations revealed positive antinuclear antibody, high anti-dsDNA antibody titers, hypocomplementemia, hypergammaglobulinemia, nephrotic range proteinuria, and diffuse proliferative glomerulonephritis. Magnetic resonance imaging of brain showed altered signal intensity in subcortical white matter in bilateral fronto-parieto-temporal lobes. Targeted next-generation sequencing revealed a novel pathogenic variant in DNASE2. He was treated with oral prednisolone, mycophenolate mofetil, cyclosporine, and hydroxychloroquine and is doing well on follow up. DNASE2 deficiency has been reported as a rare genetic cause of monogenic lupus. DNASE2 deficiency should be suspected in patients with early-onset lupus with polyarthritis, erythematous rash, and neurological involvement.
Asunto(s)
Artritis , Exantema , Glomerulonefritis , Lupus Eritematoso Sistémico , Masculino , Humanos , Niño , Prednisolona , Ácido Micofenólico , Exantema/etiología , Exantema/genética , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológicoRESUMEN
BACKGROUND: The relationship between the HLA-B*1502 gene and maculopapular exanthema (MPE) induced by antiepileptic drugs (AEDs) has not yet been elucidated. In this study, we investigated the association between AED-induced MPE (AED-MPE) and the HLA-B*1502 gene in patients in Northwest China. METHODS: We enrolled 165 subjects including nine patients with AED-MPE and 156 AED-tolerant patients as controls. HLA-B*1502 gene polymorphism was detected using digital fluorescence molecular hybridization (DFMH). The results of HLA genotyping were expressed as positive or negative for the HLA-B*1502 allele. An analysis of AED-MPE risk factors was performed using binary logistic regression, and differences in genotype frequencies between groups were assessed with the continuity correction chi-square test. RESULTS: We found that the HLA-B*1502 gene was a risk factor for AED-MPE (P = 0.028). The incidence of MPE induced by the two types of AEDs was different, and the incidence of aromatic AEDs use was higher that of non-aromatic AEDs use (P = 0.025). The comparison of the gene frequencies of the HLA-B*1502 allele between the two groups taking aromatic AEDs was also statistically significant (P = 0.045). However, there were no significant differences in terms of age, gender, ethnicity, or region in patients with MPE induced by AEDs. In addition, no association between the HLA-B1502 allele and CBZ- or OXC-induced MPE was found. CONCLUSIONS: In northwestern China, the HLA-B*1502 allele was associated with aromatic AED-MPE. Since MPE can develop into Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the HLA-B*1502 gene should be evaluated before administering AEDs.
Asunto(s)
Anticonvulsivantes , Exantema , Anticonvulsivantes/efectos adversos , Pueblo Asiatico/genética , China , Exantema/inducido químicamente , Exantema/genética , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA-B/genética , HumanosAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Inflamación/genética , Policondritis Recurrente/tratamiento farmacológico , Anciano , Exantema/complicaciones , Exantema/genética , Fiebre/complicaciones , Fiebre/genética , Glucocorticoides/uso terapéutico , Humanos , Inflamación/complicaciones , Japón , Masculino , Síndromes Mielodisplásicos/complicaciones , Proyectos Piloto , Policondritis Recurrente/complicaciones , Policondritis Recurrente/genética , Prednisolona/uso terapéutico , Escleritis/complicaciones , Escleritis/genética , Serositis/complicaciones , Serositis/genética , Síndrome , Enzimas Activadoras de Ubiquitina/genética , Vasculitis/complicaciones , Vasculitis/genética , Trombosis de la Vena/complicaciones , Trombosis de la Vena/genéticaRESUMEN
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease and usually involves the skin, musculoskeletal system, and kidneys. More than 30 genes have been to monogenic lupus, so far. Monogenic lupus is often characterized by an early-onset, similar family history, and syndromic appearance. Herein we present a pediatric patient with DNASE1L3 deficiency, suffering from both urticarial skin lesions, recurrent hemoptysis, and renal involvement, eventually diagnosed as this rare monogenic lupus. The patient suffered from recurrent urticarial rash and hemoptysis since the age of 15 months of age. He had microscopic hematuria, mild proteinuria, hypocomplementemia, and positive antinuclear antibody, anti-dsDNA, and antineutrophil cytoplasmic antibodies. Renal biopsy yielded immunocomplex glomerulonephritis. Due to early-onset, similar sibling history and consanguineous parents, we suspected monogenic lupus and performed whole-exome sequencing, which further revealed a homozygous T97Ifs*2 mutation (NM_004944.4: c.290_291delCA/p.Thr97Ilefs*2) in DNASE1L3 gene. In conclusion, DNASE1L3 deficiency should be thought when juvenile SLE occurs with early disease-onset, pulmonary hemorrhage, glomerulonephritis, and recurrent urticarial rash along with ANCA positivity.
Asunto(s)
Endodesoxirribonucleasas/genética , Exantema/genética , Glomerulonefritis/genética , Hemorragia/genética , Síndromes de Inmunodeficiencia/genética , Enfermedades Pulmonares/genética , Niño , Endodesoxirribonucleasas/deficiencia , Exantema/patología , Glomerulonefritis/patología , Hemorragia/patología , Humanos , Síndromes de Inmunodeficiencia/patología , Enfermedades Pulmonares/patología , MasculinoRESUMEN
Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Erupciones por Medicamentos/etiología , Exantema/inducido químicamente , Piel/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Relación CD4-CD8 , Erupciones por Medicamentos/genética , Erupciones por Medicamentos/inmunología , Erupciones por Medicamentos/patología , Exantema/genética , Exantema/inmunología , Exantema/patología , Femenino , Genes Codificadores de los Receptores de Linfocitos T , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Piel/inmunología , Piel/patología , Linfocitos T/inmunologíaRESUMEN
Mutations in GJB2 encoding Connexin 26 (CX26) are associated with hearing loss and hyperproliferative skin disorders of differing severity including keratitis-ichthyosis-deafness (KID) and Vohwinkel syndrome. A 6-year-old Caucasian girl who presented with recurrent skin rashes and sensorineural hearing loss harboured a heterozygous point mutation in GJB2 (c.424T > C; p.F142L). To characterize the impact of CX26F142L on cellular events. Plasmids CX26WT, CX26F142L, CX26G12R (KID) or CX26D66H (Vohwinkel) were transfected into HeLa cells expressing Cx26 or Cx43 or into HaCaT cells, a model keratinocyte cell line. Confocal microscopy determined protein localization. MTT assays assessed cell viability in the presence or absence of carbenoxolone, a connexin-channel blocker. Co-immunoprecipitation/Western blot analysis determined Cx43:Cx26 interactions. Quantitative real-time polymerase chain reaction assessed changes in gene expression of ER stress markers. Dye uptake assays determined Connexin-channel functionality. F142L and G12R were restricted to perinuclear areas. Collapse of the microtubule network, rescued by co-treatment with paclitaxel, occurred. ER stress was not involved. Cell viability was reduced in cells expressing F142L and G12R but not D66H. Unlike G12R that forms "leaky" hemichannels, F142L had restricted permeability. Cell viability of F142L and G12R transfected cells was greater in HeLa cells expressing Cx43 than in native Cx-free HeLa cells. Co-immunoprecipitation suggested a possible interaction between Cx43 and the three mutations. Expression of CX26F142L and G12R results in microtubule collapse, rescued by interaction with Cx43. The GJB2 mutations interacted with Cx43 suggesting that unique Cx43:Cx26 channels are central to the diverse phenotype of CX26 skin-related channelopathies.
Asunto(s)
Transporte Biológico/genética , Conexina 26/genética , Conexina 26/metabolismo , Exantema/genética , Pérdida Auditiva Sensorineural/genética , Microtúbulos/ultraestructura , Carbenoxolona/farmacología , Supervivencia Celular/genética , Niño , Conexina 43/metabolismo , Estrés del Retículo Endoplásmico/genética , Femenino , Expresión Génica , Células HaCaT , Células HeLa , Heterocigoto , Humanos , Microtúbulos/efectos de los fármacos , Mutación , Paclitaxel/farmacología , Transfección , Moduladores de Tubulina/farmacologíaRESUMEN
Aim: To examine gene expression in different clinical phenotypes of allopurinol-induced severe cutaneous adverse reactions (SCARs). Materials & methods: Gene expression profiling was performed using microarray on 11 RNA samples (four controls, three hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms, four Stevens-Johnson syndrome/toxic epidermal necrolysis) followed by quantitative real-time PCR in a total of 11 SCARs patients and 11 controls. Results: The biological pathways which were significantly enriched in differentially expressed genes in Stevens-Johnson syndrome/toxic epidermal necrolysis compared with hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms patients included; cell surface interactions at the vascular wall, immunoregulatory interactions at the immunological synapse and MyD88 signaling pathways. Overexpression of miR146a occurred in allopurinol-tolerant HLA-B*58:01 carriers. Conclusion: Biological pathways are identified which appear to be implicated in determining clinical phenotypes in allopurinol-induced SCARs. Overexpression of miR146a is potentially important for allopurinol tolerance in HLA-B*58:01 carriers.
Asunto(s)
Alopurinol/efectos adversos , Pueblo Asiatico/genética , Erupciones por Medicamentos/genética , Expresión Génica/genética , Piel/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/efectos adversos , Exantema/inducido químicamente , Exantema/genética , Femenino , Perfilación de la Expresión Génica/métodos , Supresores de la Gota/efectos adversos , Antígenos HLA-B/genética , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal/genética , Síndrome de Stevens-Johnson/genéticaRESUMEN
No disponible
Asunto(s)
Humanos , Femenino , Adulto , Exantema/patología , Leiomioma/patología , Neoplasias Cutáneas/patología , Biopsia , Piel/patología , Exantema/genética , Leiomioma/genética , Neoplasias Cutáneas/genéticaAsunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/complicaciones , Exantema/virología , Neumonía Viral/complicaciones , Enfermedades Cutáneas Infecciosas/virología , Piel/virología , Enzima Convertidora de Angiotensina 2 , Betacoronavirus/genética , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Proteínas de la Nucleocápside de Coronavirus , Exantema/diagnóstico , Exantema/genética , Humanos , Proteínas de la Nucleocápside/genética , Pandemias , Peptidil-Dipeptidasa A/genética , Fosfoproteínas , Neumonía Viral/diagnóstico , Neumonía Viral/genética , Neumonía Viral/virología , RNA-Seq , SARS-CoV-2 , Análisis de la Célula Individual , Enfermedades Cutáneas Infecciosas/diagnóstico , Enfermedades Cutáneas Infecciosas/genéticaRESUMEN
OBJECTIVE: To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations. METHODS: Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations. RESULTS: 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset (p = 0.42), between low- and high-penetrance mutations (p = 0.62), and according to different dosages (p = 0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response. CONCLUSIONS: Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.
Asunto(s)
Colchicina/uso terapéutico , Exantema/tratamiento farmacológico , Fiebre/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/metabolismo , Adolescente , Adulto , Edad de Inicio , Amiloidosis , Niño , Preescolar , Exantema/genética , Oftalmopatías/tratamiento farmacológico , Femenino , Fiebre/genética , Humanos , Artropatías/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación , Mialgia/tratamiento farmacológico , Fenotipo , Estudios Retrospectivos , Riesgo , Síndrome , Adulto JovenRESUMEN
AIMS: Nakajo-Nishimura syndrome (NNS) is an autosomal recessive disease caused by biallelic mutations in the PSMB8 gene that encodes the immunoproteasome subunit ß5i. There have been only a limited number of reports on the clinicopathological features of the disease in genetically confirmed cases. METHODS: We studied clinical and pathological features of three NNS patients who all carry the homozygous p.G201V mutations in PSMB8. Patients' muscle specimens were analysed with histology and immunohistochemistry. RESULTS: All patients had episodes of typical periodic fever and skin rash, and later developed progressive muscle weakness and atrophy, similar to previous reports. Oral corticosteroid was used for treatment but showed no obvious efficacy. On muscle pathology, lymphocytes were present in the endomysium surrounding non-necrotic fibres, as well as in the perimysium perivascular area. Nearly all fibres strongly expressed MHC-I in the sarcolemma. In the eldest patient, there were abnormal protein aggregates in the sarcoplasm, immunoreactive to p62, TDP-43 and ubiquitin antibodies. CONCLUSIONS: These results suggest that inflammation, inclusion pathology and aggregation of abnormal proteins underlie the progressive clinical course of the NNS pathomechanism.
Asunto(s)
Eritema Nudoso/genética , Eritema Nudoso/patología , Dedos/anomalías , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/patología , Miositis/genética , Miositis/patología , Retículo Sarcoplasmático/patología , Adulto , Edad de Inicio , Preescolar , Exantema/genética , Exantema/patología , Femenino , Fiebre/genética , Fiebre/patología , Dedos/patología , Genes MHC Clase I/genética , Humanos , Lactante , Linfocitos/patología , Masculino , Debilidad Muscular/genética , Debilidad Muscular/patología , Mutación/genética , Fibras Nerviosas/patología , Complejo de la Endopetidasa Proteasomal/genética , Sarcolema/patología , Adulto JovenRESUMEN
BACKGROUND: Acute exanthemas (AEs) are frequently seen; they can be caused by drugs or viruses but often the cause is unknown. OBJECTIVES: To describe the clinical, virological and histological aspects of AEs and explore their cytokinic and metagenomic profiles. METHODS: This prospective study examined 98 patients with AE, from February to July 2014. Clinical data were recorded in a standardized chart. Virological investigation and skin biopsies were performed. In addition, blood and skin samples were analysed for cytokines and then by a shotgun metagenomic approach. We identified five groups of patients: those with maculopapular exanthemas (MPEs) that were virally induced (group 1); those with drug-induced MPEs (group 2), those with MPEs that were both viral and drug induced (group 3), those with idiopathic MPEs (group 4) and those with pityriasis rosea (group 5). RESULTS: A virus was identified in 29 cases (human herpesvirus 6, 72%). Cytokinic analysis of the skin (n = 23 MPEs) showed higher levels of interferon-γ and interleukin-1 receptor-α in viral MPEs, higher interleukin-33 levels in idiopathic MPEs, and higher macrophage inflammatory protein 1α levels in drug-induced MPEs. By metagenomics analysis (n = 10 MPEs), viruses identified with routine practice methods were not found in group 1 (n = 4 MPEs). However, Enterovirus A was detected in two cases, especially in a group 1 patient for whom metagenomic analysis rectified the diagnosis of the culprit agent. CONCLUSIONS: Human herpesvirus 6 was the virus most frequently identified, and histology did not discriminate MPEs. In addition, the level of interleukin-33 seen in idiopathic MPEs suggests that an environmental factor may be the trigger for these. The results bring into question the utility of routine polymerase chain reaction analysis and viral serology for determining cause in AE. What's already known about this topic? Acute exanthemas, especially maculopapular exanthemas, are a frequent reason for patients consulting emergency and dermatology departments. It is difficult to evaluate the aetiology of acute exanthema based on the clinical aspects. Few data are available on the investigations needed in routine practice, and no prospective series have been published. What does this study add? Our study provides a global and prospective description of acute exanthemas. Cytokine analysis could help to investigate the pathophysiology of idiopathic eruptions. Metagenomic analysis provides new insights about the value of routine practice virological investigations. We show for the first time the feasibility of metagenomics analysis in the skin, which results question the interest of routine PCR and viral sérologies for the exploration of such acute exanthemas.
Asunto(s)
Exantema , Metagenómica , Pitiriasis Rosada , Adulto , Exantema/inducido químicamente , Exantema/genética , Humanos , Estudios Prospectivos , PielRESUMEN
Epithelial ovarian cancer (OvCa) is the most lethal female reproductive tract malignancy. A major clinical hurdle in patient management and treatment is that when using current surveillance technologies 80% of patients will be clinically diagnosed as having had a complete clinical response to primary therapy. In fact, the majority of women nonetheless develop disease recurrence within 18 mo. Thus, without more accurate surveillance protocols, the diagnostic question regarding OvCa recurrence remains framed as "when" rather than "if." With this background, we describe the case of a 61-yr-old female who presented with a 3-mo history of unexplained whole-body rash, which unexpectedly led to a diagnosis of and her treatment for OvCa. The rash resolved immediately following debulking surgery. Nearly 1 yr later, however, the rash reappeared, prompting the prospect of tumor recurrence and requirement for additional chemotherapy. To investigate this possibility, we undertook a genomics-based tumor surveillance approach using a targeted 56-gene NGS panel and biobanked tumor samples to develop personalized ctDNA biomarkers. Although tumor-specific TP53 and PTEN mutations were detectable in all originally collected tumor samples, pelvic washes, and blood samples, they were not detectable in any biosample collected beyond the first month of treatment. No additional chemotherapy was given. The rash spontaneously resolved. Now, 2 yr beyond the patient's original surgery, and in the face of continued negative ctDNA findings, the patient remains with no evidence of disease. As this single case report suggests, we believe for the first time that ctDNA can provide an additional layer of information to avoid overtreatment.
Asunto(s)
Carcinoma Epitelial de Ovario/genética , Exantema/genética , Biomarcadores de Tumor/genética , Carcinoma Epitelial de Ovario/diagnóstico , ADN Tumoral Circulante/genética , Exantema/etiología , Femenino , Humanos , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/genética , Neoplasias Ováricas/genética , Ovario/patología , Fosfohidrolasa PTEN , Medicina de Precisión/métodosRESUMEN
BACKGROUND: Drug-induced skin reactions present with a range of clinical symptoms, from mild maculopapular skin rashes to potentially fatal blistering skin rashes - such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) - which may result in death. Milder reactions may be troublesome and lead to low drug compliance. The pathogenesis of these drug reactions is not yet fully understood; however, there is evidence that pretreatment genetic testing may help to predict and prevent these reactions in some cases. OBJECTIVES: To assess the effects of prospective pharmacogenetic screening to reduce drug-associated skin reactions in a patient population. SEARCH METHODS: We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers, and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs of participants who had prospective pharmacogenetic screening to determine genetic variants associated with hypersensitivity reactions, compared with those who did not have prospective pharmacogenetic screening. We included participants in any setting, who were of any age, gender, and ethnicity, who had been prescribed drugs known to cause delayed type hypersensitivity reactions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. To assess studies for inclusion, two review authors independently screened all of the titles and abstracts of publications identified by the searches. Because there was only one included study, many of the planned data analyses were not applicable to the review. We used GRADE to assess the quality of the included study.The review's primary outcomes were the incidence of severe skin rashes with systemic symptoms (such as fever and multiple organ involvement), and long-term effects (such as scarring of eyelids or lung tissue). Secondary outcomes were hospitalisation for drug-induced skin reactions, blistering skin reactions (such as SJS, hypersensitivity (HSS) syndrome), and death. MAIN RESULTS: One study, which was a randomised, double-blind, controlled, multicentre trial, fulfilled our inclusion criteria. The trial included 1956 adult participants (74% men, with a mean age of 42 years) across 265 centres (medical centres, hospitals, outpatient clinics) in 19 countries around the world who were infected with HIV-type 1 and who had not received abacavir previously. The participants, who had a clinical need for treatment with an antiretroviral-drug regimen containing abacavir, were randomly assigned to undergo prospective human leukocyte antigen (HLA) Class I, locus B, allele 57:01 (HLA-B*57:01) screening (prospective-screening group) before this treatment, or to undergo a standard-care approach of abacavir use without prospective HLA-B*57:01 screening (control group). Participants who tested positive for HLA-B*57:01 were not given abacavir; instead, they received antiretroviral therapy that did not include abacavir. The control group did have retrospective HLA-B*57:01 pharmacogenetic testing. The trial duration was six months. Each participant was observed for six weeks. Assessments were performed at the time of study entry, at baseline (day one of abacavir treatment), and at weeks one, two and six. This study was funded by the manufacturer of abacavir, GlaxoSmithKline.The study did not assess any of our primary outcomes, and it measured none of our secondary outcomes in isolation. However, it did assess an outcome of (characteristically severe) hypersensitivity reaction which included (but was not limited to) our secondary outcomes of HSS and SJS/TEN.The study demonstrated that prospective HLA-B*57:01 screening probably reduces the incidence of hypersensitivity reaction to abacavir. The incidence of clinically diagnosed HSS reaction to abacavir was lower in the screening arm (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.28 to 0.67; 1650 participants; moderate-quality evidence), as was immunologically confirmed HSS reaction (RR 0.02, 95% 0.00 to 0.37; 1644 participants; moderate-quality evidence). A positive result from an epicutaneous patch test performed six to ten weeks after clinical diagnosis provided immunological confirmation.Overall, the study demonstrates a low risk of bias across five out of seven domains. There was a high risk of detection bias because hypersensitivity reactions were diagnosed by the principal investigator at the recruitment site without the use of predefined clinical criteria. Although there was also high risk of attrition bias due to excluding participants with incomplete follow-up from analyses, the authors did undertake a series of sensitivity analyses based on the intention-to-treat population, which demonstrated consistent results with the primary analysis. We rated the study quality as moderate-quality using GRADE criteria. AUTHORS' CONCLUSIONS: Prospective screening for HLA-B*57:01 probably reduces severe hypersensitivity skin reactions to abacavir in patients positive for HIV-type 1. However, these results are only based on one study, which was at high risk of attrition and detection bias.Our primary outcomes (incidence of severe skin rashes with systemic symptoms, and long-term effects) were not assessed by the trial, and only one of the review's secondary outcomes was measured (hypersensitivity reaction); thus, we found no evidence relating to hospitalisation, death, or long-term conditions resulting from drug injury.We found no eligible evidence on genetic testing for severe drug-induced skin rash in relation to different drugs and classes of drugs. Further clinical trials based on other drugs, and in different patient populations, would be useful for advising policy changes for improving the prevention of adverse skin reactions to drug treatments.
Asunto(s)
Exantema/genética , Exantema/prevención & control , Pruebas Genéticas , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/prevención & controlAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/sangre , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/genética , Factor H de Complemento/análisis , Factor H de Complemento/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Exantema/sangre , Exantema/diagnóstico , Exantema/tratamiento farmacológico , Exantema/genética , Hernia Umbilical/sangre , Hernia Umbilical/diagnóstico , Hernia Umbilical/tratamiento farmacológico , Hernia Umbilical/genética , Humanos , Hipospadias/sangre , Hipospadias/diagnóstico , Hipospadias/tratamiento farmacológico , Hipospadias/genética , Recién Nacido , Masculino , Insuficiencia Renal/sangre , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/tratamiento farmacológico , Insuficiencia Renal/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/sangre , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Resultado del TratamientoRESUMEN
Adverse drug reactions (ADRs) are a common cause of hospital admissions (up to 19%), with the majority of cases due to off-target predictable drug effects (type A reactions). However, idiosyncratic drug-induced immune activated (type B) reactions contribute to a range of hypersensitivity reactions, with T-cell-mediated type IV hypersensitivity reactions mainly manifesting as cutaneous ADRs (cADRs). Aromatic antiepileptic drugs (AEDs), used in the treatment of epilepsy as well as bipolar disorder or neuropathic pain, have been implicated as culprit drugs in a spectrum of pathologies ranging from mild maculopapular exanthema (MPE) to severe and life-threatening conditions including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These AED-induced cADRs are unpredictable based on pharmacological and clinical factors alone, thereby prompting investigations into genomic contributors mediating risk of pathology. The most strongly associated risk genes identified are from the human leukocyte antigen (HLA) class I alleles, which play a critical role in adaptive immunity by flagging either infected or aberrant cells for recognition by surveying T-cells. In the setting of drug hypersensitivity, the immunogenicity of HLA molecules and their peptide cargo can be modulated by interactions with small drug molecules that drive inappropriate T-cell responses. This review discusses the current understanding of HLA class I molecules in modifying risk of AED-induced cADRs.
Asunto(s)
Anticonvulsivantes/efectos adversos , Hipersensibilidad a las Drogas/genética , Antígenos HLA/genética , Piel/efectos de los fármacos , Alelos , Hipersensibilidad a las Drogas/inmunología , Epilepsia , Exantema/genética , Exantema/inmunología , Frecuencia de los Genes , Estudios de Asociación Genética , Ligamiento Genético , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Humanos , Admisión del Paciente , Polimorfismo Genético , Factores de Riesgo , Piel/inmunología , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/inmunología , Linfocitos T/inmunologíaAsunto(s)
Endopeptidasas/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Consanguinidad , Endopeptidasas/deficiencia , Exantema/genética , Resultado Fatal , Femenino , Homocigoto , Humanos , Lactante , Recién Nacido , Inflamación/genética , Irán , Mutación , Edema Pulmonar/genéticaRESUMEN
Cetuximab, an inhibitor of the epidermal growth factor receptor that is used widely to treat human cancers including oral squamous cell carcinoma (OSCC), has characteristic side effects of skin rash and hypomagnesemia. However, the mechanisms of and therapeutic agents for skin rashes and hypomagnesemia are still poorly understood. Our gene expression profiling analyses showed that cetuximab activates the p38 MAPK pathways in human skin cells (human keratinocyte cell line [HaCaT]) and inhibits c-Fos-related signals in human embryonic kidney cells (HEK293). We found that while the p38 inhibitor SB203580 inhibited the expression of p38 MAPK targets in HaCaT cells, flavagline reactivated c-Fos-related factors in HEK293 cells. It is noteworthy that, in addition to not interfering with the effect of cetuximab by both compounds, flavagline has additive effect for OSCC growth inhibition in vivo. Collectively, our results indicate that combination of cetuximab and these potential therapeutic agents for cetuximab-related toxicities could be a promising therapeutic strategy for patients with OSCC.