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INTRODUCTION: Linear IgA dermatosis (LAD) is a rare subepidermal autoimmune bullous disease (AIBD) defined by predominant or exclusive immune deposits of immunoglobulin A at the basement membrane zone of skin or mucous membranes. This disorder is a rare, clinically and immunologically heterogeneous disease occurring both in children and in adults. The aim of this project is to present the main clinical features of LAD, to propose a diagnostic algorithm and provide management guidelines based primarily on experts' opinion because of the lack of large methodologically sound clinical studies. METHODS: These guidelines were initiated by the European Academy of Dermatology and Venereology (EADV) Task Force Autoimmune Bullous Diseases (AIBD). To achieve a broad consensus for these S2k consensus-based guidelines, a total of 29 experts from different countries, both European and non-European, including dermatologists, paediatric dermatologists and paediatricians were invited. All members of the guidelines committee agreed to develop consensus-based (S2k) guidelines. Prior to a first virtual consensus meeting, each of the invited authors elaborated a section of the present guidelines focusing on a selected topic, based on the relevant literature. All drafts were circulated among members of the writing group, and recommendations were discussed and voted during two hybrid consensus meetings. RESULTS: The guidelines summarizes evidence-based and expert opinion-based recommendations (S2 level) on the diagnosis and treatment of LAD. CONCLUSION: These guidelines will support dermatologists to improve their knowledge on the diagnosis and management of LAD.
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Dermatosis Bullosa IgA Lineal , Humanos , Dermatosis Bullosa IgA Lineal/diagnóstico , Dermatosis Bullosa IgA Lineal/tratamiento farmacológico , Europa (Continente) , Dermatología/normasRESUMEN
BACKGROUND: Biologic agents are rapidly emerging as an effective therapy to treat autoimmune and other chronic diseases. The use of these agents is poorly characterized, resulting in a lack of guidance for dental practitioners. Case reports of oral adverse events have begun to emerge. However, their scope and frequency have not been summarized and analysed to date. The objective of this review was to characterize the literature on oral adverse effects associated with biological therapy when used for autoimmune and inflammatory disorders. METHODS: This review was developed in accordance with scoping review recommendations. Search strategies were developed and employed for six databases. Studies were selected using a systematic search process but with broad inclusion of study types given the paucity of information available. Reports of oral adverse events were analysed descriptively according to agent, mechanism of action, underlying disease, and oral adverse effect observed. RESULTS: Our search returned 2080 articles and 51 met our inclusion criteria, of which most were case reports. The most frequent adverse effects included angioedema, oral lichenoid lesions, osteonecrosis of the jaw, and oral infections. There were also cases of oral malignancies associated with use of biologic agents. Less common effects such as pigmentation were also described. CONCLUSIONS: Oral adverse events have been reported in patients on biologic therapy, albeit in small numbers to date. This limits the generalizability of these results, which should not be used to generate a clinical guideline as they are based primarily on case reports. However, this study presents the first review characterizing the adverse effects observed. Large multi-center studies will be necessary to further define the oral and dental complications caused by biologic agents.
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Enfermedades de la Boca , Osteonecrosis , Humanos , Factores Biológicos , Odontólogos , Rol Profesional , Enfermedades de la Boca/inducido químicamenteRESUMEN
BACKGROUND: Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES: These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS: Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS: These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.
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Síndromes Paraneoplásicos del Sistema Nervioso , Síndromes Paraneoplásicos , Animales , Ratas , Enfermedades Autoinmunes , Neoplasias/complicaciones , Síndromes Paraneoplásicos/diagnóstico , Síndromes Paraneoplásicos/etiología , Síndromes Paraneoplásicos/terapia , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Síndromes Paraneoplásicos del Sistema Nervioso/etiología , Síndromes Paraneoplásicos del Sistema Nervioso/terapia , Sociedades MédicasRESUMEN
PURPOSE: To assess whether a panel of serum pemphigoid autoantibody tests could be used to confirm an immunopathologic diagnosis of mucous membrane pemphigoid (MMP) in direct immunofluorescent negative (DIF-) MMP patients. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Seventy-six patients with multisite MMP with 45 matched control participants. METHODS: Enzyme-linked immunosorbent assays (ELISAs) for BP180 and BP230 (MBL International), immunoglobulin A (IgA) A and immunoglobulin G indirect immunofluorescence (IIF) on human salt-split skin and the keratinocyte footprint assay for anti-laminin 332 antibodies. MAIN OUTCOME MEASURES: Sensitivity and specificity of autoantibody detection and significant differences for individual tests and test combinations for MMP involving different sites. RESULTS: All DIF- patients (24/73 [31.8%]) had either ocular-only disease or ocular involvement in multisite disease. Serum pemphigoid autoantibodies were detected in 29 of 76 MMP patients (38.2%) compared with 3 of 45 control participants (6.7%). Autoantibody reactivity detected by any 1 or more of the tests was present in 6 of 24 DIF- patients (25%) compared with 22 of 49 DIF positive (DIF+) patients (44.9%). Ocular-only MMP serum reactivity was not significantly different for any test or test combination compared with control participants, whereas DIF- multisite ocular MMP differed for 1 ELISA and 3 of 7 test combinations. By contrast, for DIF+ nonocular MMP patients, all the individual tests, apart from IgA IIF, and all test combinations were significantly different compared with those for control participants. For the entire MMP cohort, the sensitivity of all individual tests was low, having a maximum of 21.05% for BP180 reactivity but increasing to 38.16% for an optimal test combination. Disease activity was associated strongly with positive serologic findings. CONCLUSIONS: Pemphigoid serum autoantibody tests did not provide immunopathologic evidence of MMP in ocular-only MMP patients but showed limited value in DIF- multisite ocular MMP patients. The requirement for immunopathologic confirmation of MMP by autoantibody detection is inappropriate for DIF- ocular-only MMP patients, resulting in missed diagnoses, delayed therapy, and poor outcomes. Alternative diagnostic criteria for ocular-only MMP are required to exclude the other causes of scarring conjunctivitis until more sensitive and specific immunopathologic tests become available.
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Autoanticuerpos/sangre , Autoantígenos/inmunología , Enfermedades de la Conjuntiva/diagnóstico , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Penfigoide Ampolloso/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades de la Conjuntiva/inmunología , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Directa , Humanos , Masculino , Persona de Mediana Edad , Penfigoide Benigno de la Membrana Mucosa/inmunología , Estudios Prospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
INTRODUCTION: The United Kingdom and Ireland teachers of Human Disease/Clinical Medical Science for Dentistry (HD/CMSD) group continue to work together and most recently collaborated to review current and future assessments. MATERIALS AND METHODS: The first part of the review of assessments in HD/CMSD took place at a face-to-face meeting with presentations from delegates on assessments in their home institutions. The second and larger part comprised an online survey where all eighteen schools in the UK and Ireland participated. RESULTS: All schools had some element of formative assessment, and the majority had a stand-alone summative assessment at the end of the HD/CMSD teaching block. Most schools had a written paper and practical elements to their assessments, most commonly a combination of a multiple-choice type question combined with an objective structured clinical examination (OSCE). There was a trend towards the use of single best answer (SBA) questions and a willingness amongst participants to share a question bank. All schools incorporated elements of HD/CMSD in their final examinations. DISCUSSION AND CONCLUSION: This collaboration promoted the sharing of developments in assessment for HD/CMSD and demonstrated a willingness to cooperate between institutions. Assessment in HD/CMSD in the UK and Ireland continues to be refined by those responsible for its content and delivery, and assessment methods are progressing following evidence-based best practice.
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Medicina Clínica , Educación de Pregrado en Medicina , Curriculum , Odontología , Educación en Odontología , Humanos , Irlanda , Encuestas y Cuestionarios , Reino UnidoAsunto(s)
Anticuerpos Monoclonales Humanizados , Quimioterapia Combinada , Lupus Eritematoso Sistémico , Rituximab , Humanos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/complicaciones , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Quimioterapia Combinada/métodos , Resultado del Tratamiento , Epidermólisis Ampollosa/tratamiento farmacológico , Epidermólisis Ampollosa/complicaciones , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , AdultoRESUMEN
OBJECTIVE: This systematic review evaluated the efficacy of immunobiologics for the management of oral disease in Sjögren's syndrome (SS). MATERIALS AND METHODS: MEDLINE® , Embase, Scopus, and the Cochrane Library were searched for evidence on the use of immunobiologics for management of glandular disease in SS. Primary outcomes were xerostomia and salivary gland dysfunction, assessed via visual analogue scales, disease-specific scales for SS, measurement of salivary flow, ultrasound data, and quality of life measures. RESULTS: Seventeen studies (11 randomized controlled trials and 6 observational studies) met inclusion criteria. Rituximab showed efficacy in improving salivary gland function but not xerostomia. Abatacept showed promise in improving both xerostomia and salivary flow. Belimumab exhibited long-term improvement of salivary flow and subjective measures. The novel agent CFZ533 improved both disease activity and patient-reported indexes. CONCLUSIONS: There is strong evidence pointing to the efficacy of rituximab in the management of oral disease in SS. Future controlled trials may elucidate the efficacy of belimumab and abatacept. The new drug CFZ533 is a promising alternative for the management of SS and its salivary gland involvement. In considering these agents, the promise of efficacy must be balanced against the harmful effects associated with biologic agents.
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Antirreumáticos/uso terapéutico , Factores Biológicos/uso terapéutico , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Rituximab/uso terapéutico , Enfermedades de las Glándulas Salivales/terapia , Glándulas Salivales/fisiopatología , Síndrome de Sjögren/tratamiento farmacológico , Xerostomía/fisiopatología , Congresos como Asunto , Humanos , Calidad de Vida , Saliva/química , Saliva/metabolismo , Enfermedades de las Glándulas Salivales/patología , Síndrome de Sjögren/fisiopatología , Escala Visual AnalógicaRESUMEN
OBJECTIVE: To assess the evidence for treatment of oral involvement of pemphigus and pemphigoid with biologics. STUDY DESIGN: This systematic review used a comprehensive search strategy to identify literature describing oral involvement of pemphigus or pemphigoid treated with a biologic agent. The primary outcome measures were efficacy and safety of biologic therapy. RESULTS: Inclusion criteria were met by 154 studies including over 1200 patients. Treatment of pemphigus with a total of 11 unique biologic agents and 3 unique combinations of agents is reported. Five randomized controlled trials (RCT) were included in the final analysis that investigated infliximab, IVIg, rituximab, and autologous platelet-rich plasma therapy for pemphigus vulgaris. Three non-RCT studies reported on successful rituximab or IVIg therapy for mucous membrane pemphigoid. Studies demonstrated considerable heterogeneity in agent, methods, and quality. CONCLUSIONS: Evidence clearly describing oral tissue response to biologic therapy is sparse. Two RCTs support use of rituximab, one supports use of IVIg, and one pilot study suggests intralesional injection of autologous platelet-rich plasma aids healing of oral PV lesions. As oral lesions of pemphigus and pemphigoid can be refractory to systemic therapy, drug trials including biologic therapies should document details regarding response of the oral lesions to therapy.
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Factores Biológicos/uso terapéutico , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso/terapia , Pénfigo/terapia , Rituximab/uso terapéutico , Congresos como Asunto , Humanos , Penfigoide Ampolloso/patología , Pénfigo/patología , Proyectos Piloto , Resultado del TratamientoRESUMEN
PURPOSE: This study explored the validity of the First International Consensus on Mucous Membrane Pemphigoid (MMP) guidance, which recommends that clinically indistinguishable patients, who have direct immunofluorescence (DIF)-negative biopsies, be excluded from a diagnosis of MMP. Misdiagnosis, or delayed diagnosis, of MMP with ocular involvement leads to the inappropriate use of topical therapy, the standard of care for causes of cicatrising conjunctivitis other than MMP, rather than systemic immunomodulatory therapy, resulting in irreversible clinical deterioration in patients with MMP. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients meeting the clinical criteria of ocular MMP, including those with positive and negative DIF findings. METHODS: A case report form was used to collect the demographic details, the clinical history, and the results of a detailed clinical assessment by ophthalmologists, otolaryngologists, dermatologists, and oral medicine specialists. All anatomic sites potentially affected by MMP were examined apart from the esophagus (and larynx in a subset). The DIF results were recorded. MAIN OUTCOME MEASURES: Differences between DIF-positive and -negative patients in demography, sites of involvement, and disease severity as determined by the degree of conjunctival scarring (using Tauber staging), central corneal disease (vascularization, scarring, ulceration, and conjunctivalization), history of conjunctival or lid surgery, and requirement for systemic immunotherapy at the time of screening. RESULTS: A total of 73 patients with ocular MMP were recruited, of whom 20 of 73 (27.4%) had ocular-only disease. There was no significant demographic or clinical difference between patients with positive and negative DIF results. This finding included differences in disease severity for which the only significant difference was that of more severe central corneal disease in DIF-negative patients. Asymptomatic disease at different sites was frequent. CONCLUSIONS: These findings do not support the classification of DIF-negative patients, meeting the clinical criteria for ocular MMP, as having a different disease. This category of patients should be accepted as having DIF-negative MMP, for clinical management purposes, with patients having inflamed eyes being treated with systemic immunomodulatory therapy. The frequent finding of asymptomatic ocular, oral, and nasopharyngeal MMP is clinically significant and implies that these sites should be routinely screened in asymptomatic patients.
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Autoanticuerpos/análisis , Conjuntivitis/diagnóstico , Técnica del Anticuerpo Fluorescente Directa , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Conjuntivitis/inmunología , Estudios Transversales , Femenino , Técnica del Anticuerpo Fluorescente Directa/métodos , Humanos , Inmunoglobulina A/análisis , Inmunoglobulina G/análisis , Masculino , Persona de Mediana Edad , Penfigoide Benigno de la Membrana Mucosa/inmunología , Fenotipo , Estudios Prospectivos , Adulto JovenAsunto(s)
Investigación Biomédica , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso , Pénfigo , Humanos , Penfigoide Ampolloso/tratamiento farmacológico , Pénfigo/tratamiento farmacológico , Penfigoide Benigno de la Membrana Mucosa/tratamiento farmacológico , Investigación , Reino Unido , Membrana Mucosa , Prioridades en SaludRESUMEN
Mucous membrane pemphigoid (MMP) is a rare, chronic and often aggressive subepidermal autoimmune blistering disease potentially affecting several mucous membranes with blisters and secondary erosions and scars. The pathogenesis of MMP is poorly understood, and the contribution of genetic predispositions, other than HLA class II allele variants to MMP, is unknown. The objective of this study is to identify susceptibility genes for MMP in a British cohort of MMP patients. A GWAS was conducted in a British cohort of 106 MMP patients. Publicly available genotypes of 2900 blood donors of the UK Blood Service and of 6740 individuals of the 1958 British Birth Cohort served as control. Subsequently, putative susceptibility genes were independently replicated in a German cohort of 42 MMP patients. The GWAS found 38 SNPs in 28 haploblocks with an odds ratio >2 reaching genomewide significance (P < 5.7 × 10-7 ). Replication confirmed an association of MMP with SNPs in rs17203398 (OR: 3.9), located intronically in the ß-galactocerebrosidase gene (GALC) on chromosome 14 and with recessive polymorphisms in rs9936045 (OR: 3.1) in the intergenic region between CASC16 and CHD9 on chromosome 16. The risk of developing MMP is partially genetically determined. SNPs in GALC enhance the risk for MMP, indicating that ß-galactocerebrosidase may be involved in the pathogenesis of MMP. Likewise, impacts of polymorphisms in the intergenic region between CASC16 and CHD9 on the activity of neighbouring genes may facilitate the emergence of MMP. The putative role of both polymorphisms requires functional studies in the future.
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Galactosilceramidasa/genética , Penfigoide Benigno de la Membrana Mucosa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 16 , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Anagen effluvium with reversible scalp alopecia is a known side effect of chemotherapy. However, there are an increasing number of reports in the literature documenting permanent alopecia in patients treated with taxanes. OBJECTIVE: We sought to describe the clinicopathologic features in breast cancer patients who underwent treatment with taxanes and adjuvant hormonal chemotherapy. METHODS: We reviewed the clinical and histopathologic information of a cohort of 10 patients treated with taxanes and adjuvant hormonal chemotherapy. RESULTS: We have observed 3 types of clinical patterns of alopecia (types A, B, and C), and have validated the histopathologic features showing alopecia areata-like and female pattern hair loss. LIMITATIONS: The study was based on a small sample size and retrospective retrieval of clinical information and histopathologic review of posttreatment slides. CONCLUSIONS: We hypothesize a clinicopathologic model of hair follicle cycle disruption in response to the chemoinflammatory and hormonal insults to the hair follicles resulting in permanent alopecia. Clinicopathologic correlation is paramount to the understanding of the morphobiologic pathways in chemotherapy-induced alopecia caused by taxanes and adjuvant hormonal treatment.
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Alopecia/inducido químicamente , Alopecia/patología , Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/efectos adversos , Taxoides/efectos adversos , Anciano , Antineoplásicos Hormonales/efectos adversos , Quimioterapia Adyuvante/efectos adversos , Femenino , Folículo Piloso/efectos de los fármacos , Humanos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Syphilis is on the increase globally. While recognized more frequently in patients with, HIV/AIDS, it is not unusual among immune competent individuals sometimes presenting with unusual manifestations and/or behaviour. This paper reviews the history and clinical features of syphilis and draws attention to the oral manifestations. CPD/Clinical Relevance: Syphilis should be in the differential diagnosis of oral ulcers or unusual oral lesions.
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Sífilis , Humanos , Enfermedades de la Boca/microbiología , Sífilis/complicaciones , Sífilis/diagnóstico , Sífilis/terapiaRESUMEN
OBJECTIVE: This study aimed to explore the lived experience of patients with oral lichen planus (OLP) and investigate what treatment-related outcomes are the most important to them and should be included in a core outcome set (COS) for OLP. STUDY DESIGN: A qualitative study involving focus group work with 10 participants was conducted. Interviews with each focus group were held twice: session 1 explored the lived experience of patients with OLP, and session 2 allowed patients to review a summary of the outcome domains used in the OLP literature to date. The discussions were recorded, transcribed verbatim, and analyzed using framework analysis. RESULTS: In session 1, 4 themes and 8 sub-themes emerged from the data analysis. An additional outcome, 'knowledge of family and friends,' was suggested in session 2. CONCLUSIONS: We have gained valuable insight into the lived experience of patients with OLP via this qualitative study. To our knowledge, this study is the first to explore the patient perspective on what should be measured in clinical trials on OLP, highlighting an important additional suggested outcome. This additional outcome will be voted upon in a consensus process to determine a minimum COS for OLP.
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Liquen Plano Oral , Humanos , Liquen Plano Oral/tratamiento farmacológico , Evaluación de Resultado en la Atención de SaludRESUMEN
OBJECTIVE: A core outcome set (COS) is the minimum agreed-on data set required to be measured in interventional trials. To date, there is no COS for oral lichen planus (OLP). This study describes the final consensus project that brought together the results of the previous stages of the project to develop the COS for OLP. STUDY DESIGN: The consensus process followed the Core Outcome Measures in Effectiveness Trials guidelines and involved the agreement of relevant stakeholders, including patients with OLP. Delphi-style clicker sessions were conducted at the World Workshop on Oral Medicine VIII and the 2022 American Academy of Oral Medicine Annual Conference. Attendees were asked to rate the importance of 15 outcome domains previously identified from a systematic review of interventional studies of OLP and a qualitative study of OLP patients. In a subsequent step, a group of OLP patients rated the domains. A further round of interactive consensus led to the final COS. RESULTS: The consensus processes led to a COS of 11 outcome domains to be measured in future trials on OLP. CONCLUSION: The COS developed by consensus will help reduce the heterogeneity of outcomes measured in interventional trials. This will allow future pooling of outcomes and data for meta-analyses. This project showed the effectiveness of a methodology that could be used for future COS development.
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Liquen Plano Oral , Humanos , Liquen Plano Oral/tratamiento farmacológico , Técnica Delphi , Evaluación de Resultado en la Atención de Salud/métodos , Proyectos de Investigación , Consenso , Resultado del TratamientoRESUMEN
OBJECTIVE: There is a lack of consensus regarding clinician- and patient-reported oral lichen planus (OLP) outcomes. The World Workshop on Oral Medicine Outcomes Initiative for the Direction of Research (WONDER) Project aims to develop a core outcome set (COS) for OLP, which would inform the design of clinical trials and, importantly, facilitate meta-analysis, leading to the establishment of more robust evidence for the management of this condition and hence improved patient care. STUDY DESIGN: Ovid MEDLINE, Embase, CINAHL, CENTRAL, and Clinicaltrials.gov were searched for interventional studies (randomized controlled trials, controlled clinical trials, and case series including ≥5 participants) on OLP and oral lichenoid reactions published between January 2001 and March 2022 without language restriction. All reported primary and secondary outcomes were extracted. RESULTS: The searches yielded 9,135 records, and 291 studies were included after applying the inclusion criteria. A total of 422 outcomes were identified. These were then grouped based on semantic similarity, condensing the list to 69 outcomes. The most frequently measured outcomes were pain (51.9%), clinical grading of the lesions (29.6%), lesion size/extension/area (27.5%), and adverse events (17.5%). CONCLUSION: As a first step in developing a COS for OLP, we summarized the outcomes that have been used in interventional studies over the past 2 decades, which are numerous and heterogeneous.