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BACKGROUND: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking. OBJECTIVES: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls. METHODS: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection. RESULTS: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases. CONCLUSIONS: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.
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Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially life-threatening mucocutaneous blistering diseases that clinically can resemble autoimmune bullous diseases. Moreover, it has been shown that autoantibodies against epidermal proteins are present in SJS/TEN. Objectives: To establish the presence of antibodies against desmosomal and hemidesmosomal proteins in confirmed SJS/TEN patients. Methods: Serum of SJS/TEN patients diagnosed based on clinical criteria, e.g., epidermal detachment with erosions and severe mucosal lesions, (suspicion of) a culprit drug, and matching histologic results was evaluated by various techniques, e.g., indirect immunofluorescence on monkey esophagus, salt split skin and rat bladder, immunoblotting (IB) and immunoprecipitation (IP), ELISAs against desmogleins and BP180, keratinocyte footprint assay, and keratinocyte binding assay. Results: A total of 28 patients were included in this study, 15 men and 13 women with a mean age of 56 years. In most patients, none of the serological tests were positive. In two patients, an elevated DSG3 titer was found suspicious for pemphigus vulgaris. Three patients had elevated NC16a titers, suggesting bullous pemphigoid. However, in all these patients, no other tests were positive and in these patients, the biopsy for direct immunofluorescence showed no evidence for an autoimmune bullous disease. Three patients showed reactivity against rat bladder rat bladder; these were, however, completely negative for A2ML1, envoplakin, and periplakin in the IB as well as the IP. Conclusions: Serological analysis for desmosomal and hemidesmosomal antibodies is reliable to rule an autoimmune bullous disease in patients with suspected SJS/TEN. However, one should not rely on one single test method since false positive results can occur. Moreover, this study also makes it less plausible that antibodies against desmosomal and/or hemidesmosomal components are involved in the pathogenesis of SJS/TEN.
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OBJECTIVE: To investigate the proportion of low-density granulocytes (LDGs), circulating plasma neutrophil extracellular traps (NETs), and serum-induced NET formation in patients with incomplete systemic lupus erythematosus (iSLE) and systemic lupus erythematosus (SLE). METHODS: LDGs were measured cross-sectionally in 18 iSLE patients, 11 SLE patients and 14 healthy controls (HCs), whereas circulating NETs and serum-induced NET formation were assessed in 35 iSLE patients, 41 SLE patients and 16 HCs. LDGs (CD14lowCD15+) were measured in PBMCs using flow cytometry and circulating plasma NETs were measured using anti-myeloperoxidase-DNA, anti-citrullinated histone H3 and anti-elastase-DNA complex ELISAs. Serum-induced NET formation was assessed by incubating healthy neutrophils with serum from iSLE patients, SLE patients or HCs and visualizing NETs with fluorescence microscopy. RESULTS: Proportions of LDGs and circulating plasma NETs were similarly elevated in iSLE and SLE patients compared with those in HCs. Furthermore, patients under hydroxychloroquine (HCQ) treatment had lower proportions of LDGs than those without. Serum from iSLE and SLE patients similarly induced NET formation in healthy neutrophils. In iSLE patients, myeloperoxidase-DNA complexes were correlated with proportions of age-associated B-cells, memory B-cells and negatively with naïve B-cells, while we did not find associations between measures of NETs or serum-induced NET formation and interferon score or clinical parameters. CONCLUSION: These results show that neutrophil dysfunction, including higher proportions of LDGs, and increased NET formation, already occur in iSLE, similar to SLE, despite differences in disease manifestations. Thereby, neutrophil dysfunction may contribute to sustained exposure to autoantigens and autoreactivity in early stages of SLE.
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Pemphigus vulgaris (PV) is a rare autoimmune bullous disease characterized by blistering of the skin and mucosa owing to the presence of autoantibodies against the desmosome proteins desmoglein 3 and occasionally in conjunction with desmoglein 1. Fundamental research into the pathogenesis of PV has revolutionized its treatment and outcome with rituximab, a B-cell-depleting therapy. The critical contribution of B cells to the pathogenesis of pemphigus is well accepted. However, the exact pathomechanism, mechanisms of onset, disease course and relapse remain unclear. In this narrative review, we provide an overview of the fundamental research progress that has unfolded over the past few centuries to give rise to current and emerging therapies. Furthermore, we summarize the multifaceted roles of B cells in PV, including their development, maturation and antibody activity. Finally, we explored how these various aspects of B-cell function contribute to disease pathogenesis and pave the way for innovative therapeutic interventions.
Pemphigus vulgaris (PV) is a rare autoimmune disease, in which the immune system attacks itself and causes blisters on the skin and inside the mouth. This happens because the body mistakenly attacks specific proteins (called desmosomes) that keep the skin together. Globally, this disease affects anywhere from 0.5 to 16.1 people per million, often older than 50â years. PV is life-threatening when left untreated. From carrying out research as far back as the 1700s, we have made significant strides in understanding PV. For example, research has led to a new treatment with the antibody rituximab, which works by eliminating the cells of the immune system that attack desmosomes (called B cells). However, after therapy is completed, the disease often returns because the same troublesome B cells reappear. There are multiple places that are involved when the body attacks desmosomes. The problems range from the bone marrow where the B cells are made and selected to the ways these cells change as they move around the body. It takes a rare combination of these changes to switch from a normal immune system to one that causes PV. Clinicians and researchers are currently developing new treatment options to better target this skin disease. We want to emphasize that research should continue to uncover how the disease works because a better understanding promotes the development of new therapies, and perhaps even a cure. This is vital, because PV can significantly lower the quality of life of people living with this skin disease.
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Linfócitos B , Pênfigo , Rituximab , Pênfigo/imunologia , Pênfigo/tratamento farmacológico , Pênfigo/terapia , Humanos , Linfócitos B/imunologia , Rituximab/uso terapêutico , Autoanticorpos/imunologia , Tolerância Imunológica/imunologiaRESUMO
BACKGROUND: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated. METHODS: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination. RESULTS: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based. CONCLUSIONS: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization.
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Anticorpos Monoclonais Humanizados , Switching de Imunoglobulina , Imunoglobulina G , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Feminino , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , COVID-19/prevenção & controle , COVID-19/imunologia , Adulto , Vacinas de mRNA/imunologia , Idoso , Vacinação , Vacinas contra COVID-19/imunologia , Imunossupressores/uso terapêutico , Imunossupressores/farmacologia , Anticorpos Antivirais/imunologiaRESUMO
Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. Main Outcomes/Measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.
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Síndrome de Hipersensibilidade a Medicamentos , Eosinofilia , Adulto , Humanos , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/terapia , Consenso , Técnica Delphi , Eosinofilia/induzido quimicamente , Eosinofilia/diagnóstico , Eosinofilia/terapia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Several registries for hidradenitis suppurativa (HS) already exist in Europe and the USA. There is currently no global consensus on a core dataset (CDS) for these registries. Creating a global HS registry is challenging, owing to logistical and regulatory constraints, which could limit opportunities for global collaboration as a result of differences in the dataset collected. The solution is to encourage all HS registries to collect the same CDS of information, allowing registries to collaborate. OBJECTIVES: To establish a core set of items to be collected by all HS registries globally. The core set will cover demographic details, comorbidities, clinical examination findings, patient-reported outcome measures and treatments. METHODS: Beginning in September 2022, 20 participants - including both clinicians with expertise in HS and patient advocates - from eight countries across three continents participated in a Delphi process consisting of four rounds of voting, with all participants completing each round. A list of potential items for inclusion in the core set was generated from the relevant published literature, including systematic reviews of comorbidities in HS, clinical and examination findings, and epidemiology. For disease severity and progression items, the Hidradenitis SuppuraTiva Core outcome set International Collaboration (HiSTORIC) core set and other relevant instruments were considered for inclusion. This resulted in 47 initial items. Participants were invited to suggest additional items to include during the first round. Anonymous feedback was provided to inform each subsequent round of voting to encourage consensus. RESULTS: The eDelphi process established a CDS of 48 items recommended for inclusion in all HS registries globally. CONCLUSIONS: The routine adoption of this CDS in current and future HS registries should allow registries in different parts of the world to collaborate, enabling research requiring large numbers of participants.
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Hidradenite Supurativa , Humanos , Consenso , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/epidemiologia , Hidradenite Supurativa/terapia , Resultado do Tratamento , Técnica Delphi , Sistema de RegistrosRESUMO
BACKGROUND: Hidradenitis suppurativa (HS) is a multifactorial inflammatory skin disease that is considered to be an immune-mediated inflammatory disease (IMID). Up till now, the impact of lifestyle on (the development of) HS has not been thoroughly investigated. OBJECTIVES: To investigate the effect of dietary intake and physical activity (PA) on (the development of) HS. MATERIALS AND METHODS: A nested case-control study was performed within the longitudinal Lifelines Cohort Study, that took place in the Northern Netherlands, and identified 1004 adult eligible HS patients and 5000 age-matched controls. Dietary data were collected using a validated food frequency questionnaire, subsequently translated to the Lifelines Diet Score (LLDS), alternate Mediterranean Diet Score (aMED) and Dutch Dietary Guidelines score (DDG), with higher scores reflecting healthier dietary habits. PA was measured by the Short Questionnaire to Assess Health-enhancing PA score. Logistic regression analyses were performed between dietary/PA scores, and the prevalence/development and severity of HS. RESULTS: Compared to controls, HS patients scored lower on the LLDS [OR = 0.98; 95% CI 0.96-0.99], aMED [0.93; 0.89-0.97] and DDG [0.93; 0.88-0.97] with multivariable regression analysis. Overall, this indicates less adherence to dietary recommendations and consumption of a low-quality diet in the HS population. Lower adherence to the LLDS and DDG was also significantly associated with a higher likelihood to HS development in univariable regression analysis [0.96; 0.94-0.99 and 0.91; 0.84-0.99, respectively], and a trend of decreased adherence to the aMED [0.93; 0.85-1.02] was noted. Besides, PA levels were found significantly lower in HS patients (p ≤ 0.001). CONCLUSIONS AND RELEVANCE: Poor diet quality and lower quantities of PA were associated with HS in the general population. Identifying dietary and PA habits of HS patients can contribute to the development of prevention strategies for HS specifically, and for IMIDs in general.
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Exercício Físico , Hidradenite Supurativa , Humanos , Masculino , Adulto , Feminino , Estudos de Casos e Controles , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Dieta , Comportamento de Redução do Risco , Estudos Longitudinais , Dieta Mediterrânea , Índice de Gravidade de DoençaRESUMO
Importance: Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines. Objective: To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied. Evidence Review: Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice. Findings: Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 [85.7%] vs 2 males [11.8%]) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 [71.8%]) and HS Quality of Life score (13 [92.9%]), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 [69.2%]). Conclusions and Relevance: An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting.
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Hidradenite Supurativa , Feminino , Humanos , Masculino , Consenso , Técnica Delphi , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/terapia , Avaliação de Resultados em Cuidados de Saúde , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Adulto , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, devastating, multifactorial skin disease. Patients generally develop HS after puberty and the prevalence of the disease is assumed to decrease with higher age. Data outside the usual age range are limited, especially for elderly patients. OBJECTIVES: To investigate the prevalence, clinical characteristics and associated comorbidities among the elderly HS population. METHODS: Data were collected through a population-wide survey-based study within the Lifelines Cohort Study in the Netherlands. The clinical characteristics of elderly patients with HS (≥ 60â years) were compared with an adult population (< 60â years) with HS. The comorbidities in elderly patients with HS were compared with those of a non-HS sex- and age-matched elderly population in a 1 : 4 ratio. HS in the elderly was defined as active HS in patients aged 60â years and older. Within the HS elderly group, two subgroups were defined, late-onset HS (HS developed after 60â years of age) and persistent HS (HS developed from a younger age but continuing after 60â years of age). RESULTS: Within the Lifelines cohort 209 elderly patients with HS were identified as well as an adult (< 60â years) group with HS (n = 793) and a non-HS sex- and age-matched control elderly group (n = 810). The prevalence of HS among the elderly bootstrap analysis population was 0.8% [95% confidence interval (CI) 0.4-1.2]. A significantly higher age of HS symptom onset was found compared with the adult HS group: respectively, 40 vs. 23â years (odds ratio 1.056, 95% CI 1.05-1.07). Among the elderly HS cohort (in the Discussion, the HS tarda cohort) a female : male ratio of 1.7 : 1.0 and a higher family history for HS were found. Moreover, elderly patients with HS had a significantly higher risk of having HS-associated comorbidities compared with the sex- and age-matched controls. CONCLUSIONS: The prevalence of HS in the elderly is not rare. Among the elderly a shift from female predominance towards a lower female : male ratio in HS is observed. In addition, HS in the elderly showed significant variation in age of onset and involved body areas. Moreover, elderly patients with HS were more susceptible to multimorbidity. Finally, we propose defining HS in the elderly as 'HS tarda' and subdividing it as late-onset and persistent HS tarda.
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Hidradenite Supurativa , Adulto , Humanos , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/epidemiologia , Estudos de Coortes , Comorbidade , Prevalência , Projetos de PesquisaRESUMO
BACKGROUND: Axial spondyloarthritis (axSpA) is known to be associated with several extra-skeletal manifestations (ESM), including the inflammatory skin disease psoriasis. It is important to recognize and diagnose psoriasis timely in axSpA in order to provide optimal treatment and outcome for both axSpA and psoriasis. METHODS: In this observational study, all patients from the Dutch Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort included before June 2016 were sent a questionnaire with self-screening psoriasis questions including prototypical color pictures. RESULTS: Of the 592 questionnaires sent, 448 (75.7%) were eligible for analysis. Of these 448 respondents, 58 (13%) had a positive self-screening for psoriasis symptoms, currently or in the past. In 28 (48%) of 58 patients, psoriasis diagnosis could be verified by medical records, resulting in a psoriasis prevalence rate of 6.3%. In comparison with patients with a confirmed psoriasis diagnosis, patients reporting psoriasis symptoms without a verified diagnosis mentioned more mild than moderate-severe psoriasis symptoms (25% vs. 3%, p = 0.02), and their psoriasis lesions were less often located on the torso area (3% vs. 18%, p = 0.04), the intergluteal cleft (0% vs. 25%, p = 0.02), and legs (7% vs. 43%, p < 0.01). Of the 31 axSpA patients who reported currently active psoriasis, 74% had only mild psoriasis symptoms. CONCLUSIONS: Especially mild psoriasis seems often underdiagnosed in patients with axSpA using a patient questionnaire with prototypical pictures of psoriasis lesions. This questionnaire could be beneficial in tracing patients with undiagnosed psoriasis in daily clinical practice. As a next step, further validation of this questionnaire is needed.
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Espondiloartrite Axial , Psoríase , Espondilartrite , Espondilite Anquilosante , Humanos , Espondilartrite/complicações , Espondilartrite/diagnóstico , Espondilartrite/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Inquéritos e Questionários , Psoríase/complicações , Psoríase/diagnóstico , Psoríase/epidemiologiaRESUMO
Hidradenitis suppurativa (HS) is a heterogeneous chronic relapsing skin disease. Several assessment tools are used to assess disease severity and to classify disease phenotype; however, no consensus exists. This review evaluates the various assessment tools and phenotypes, assessing their validity and reliability. Numerous assessment tools and phenotype classifications have been proposed for identifying various subtypes within the hidradenitis suppurativa disease spectrum. Each has a different purpose, such as use in daily practice or in clinical trial settings. Several assessment tools and phenotype classifications have been validated but not always with satisfactory results and often with studies showing divergent intra-rater reliability results. A consensus is needed for a validated, easy-to-use, and timesaving assessment tool for routine daily practice. For clinical trials, a validated and extensive assessment tool that also measures response to treatment is also needed.
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Hidradenite Supurativa , Humanos , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/tratamento farmacológico , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Gravidade do Paciente , FenótipoRESUMO
BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. METHODS: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. RESULTS: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). CONCLUSION: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. TRIAL REGISTRATION: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.
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COVID-19 , Humanos , SARS-CoV-2 , Imunidade Humoral , Estudos Prospectivos , Inibidores do Fator de Necrose Tumoral , Imunossupressores/uso terapêutico , Fator de Necrose Tumoral alfa , Vacinação , Anticorpos AntiviraisRESUMO
Photosensitizing properties of hydrochlorothiazide may increase skin cancer risk. To date, study findings on the association between hydrochlorothiazide use and skin cancer risk are inconsistent, notably regarding confounding and dose-response. The aim of this study was to investigate the association between hydrochlorothiazide use and incidence of skin cancer in a cohort of unselected Caucasian adults, taking dosing into account. As part of the PharmLines Initiative, which links data from the Lifelines Cohort Study and prescription database IADB.nl, patients aged ≥ 40 years were included from Lifelines, a prospective population-based cohort study in the north of the Netherlands. Skin cancer incidence was compared between subjects starting hydrochlorothiazide treatment (n = 608), subjects starting treatment with other antihypertensives (n = 508), and non-antihypertensive long-term medication users (n = 1,710). Cox regression analyses were performed to obtain hazard ratios, adjusted for potential confounders. The risk of any skin cancer, keratinocyte carcinoma, basal cell carcinoma and squamous cell carcinoma was not significantly increased in general hydrochlorothiazide users. A clear association was observed between high cumulative hydrochlorothiazide use (≥ 5,000 defined daily dose; ≥ 125,000 mg) and the risk of any skin cancer (adjusted hazard ratio 5.32, 95% confidence interval (95% CI) 2.40-11.81), keratinocyte carcinoma (adjusted hazard ratio 7.31, 95% CI 3.12-17.13), basal cell carcinoma (adjusted hazard ratio 7.72, 95% CI 3.11-19.16) and squamous cell carcinoma (adjusted hazard ratio 19.63, 95% CI 3.12-123.56). These findings should lead to awareness with high use of hydrochlorothiazide in Caucasian adults.
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Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Adulto , Hidroclorotiazida/efeitos adversos , Estudos de Coortes , Estudos Prospectivos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma Basocelular/induzido quimicamente , Carcinoma Basocelular/epidemiologia , Carcinoma Basocelular/tratamento farmacológico , Carcinoma de Células Escamosas/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Epidermolysis bullosa (EB) is a rare, genetically and clinically heterogeneous group of skin fragility disorders. No cure is currently available, but many novel and repurposed treatments are upcoming. For adequate evaluation and comparison of clinical studies in EB, well-defined and consistent consensus-endorsed outcomes and outcome measurement instruments are necessary. OBJECTIVES: To identify previously reported outcomes in EB clinical research, group these outcomes by outcome domains and areas and summarize respective outcome measurement instruments. METHODS: A systematic literature search was performed in the databases MEDLINE, Embase, Scopus, Cochrane CENTRAL, CINAHL, PsycINFO and trial registries covering the period between January 1991 and September 2021. Studies were included if they evaluated a treatment in a minimum of three patients with EB. Two reviewers independently performed the study selection and data extraction. All identified outcomes and their respective instruments were mapped onto overarching outcome domains. The outcome domains were stratified according to subgroups of EB type, age group, intervention, decade and phase of clinical trial. RESULTS: The included studies (n = 207) covered a range of study designs and geographical settings. A total of 1280 outcomes were extracted verbatim and inductively mapped onto 80 outcome domains and 14 outcome areas. We found a steady increase in the number of published clinical trials and outcomes reported over the past 30â years. The included studies mainly focused on recessive dystrophic EB (43%). Wound healing was reported most frequently across all studies and referred to as a primary outcome in 31% of trials. Great heterogeneity of reported outcomes was observed within all stratified subgroups. Moreover, a diverse range of outcome measurement instruments (n = 200) was identified. CONCLUSIONS: We show substantial heterogeneity in reported outcomes and outcome measurement instruments in EB clinical research over the past 30â years. This review is the first step towards harmonization of outcomes in EB, which is necessary to expedite the clinical translation of novel treatments for patients with EB.