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OBJECTIVES: The study is aimed to evaluate the impact of safety events in the Eurofever registry for Autoinflammatory diseases. METHODS: This was a retrospective and longitudinal observational multicentre study. Data were retrieved from the international registry Eurofever, starting patients' enrolment since 2009. All moderate, severe, or very severe AEs reported by treating physician in Eurofever were analyzed regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities. RESULTS: Complete information on safety were available in 2464 patients enrolled in the registry. In 1499 of them retrospective data encompassing the period from disease onset to enrolment were available, whereas 965 consecutive patients entered in the longitudinal part of the study. A total of 479 AEs have been reported in 275 patients. Eighty-two AEs were reported as serious and 99 were drug-related according to the physicians. Infections or infestations (94; 19.6%), gastrointestinal disorders (66; 13.8%), nervous system disorders (41; 8.6%) and systemic disorders or administration site reactions (35; 7.3%) were the most frequent reported events. The highest absolute number of drug-related AEs were related to biologic DMARDs (40/99 reports, 40,4%) and colchicine (31/99 reports, 31.3%). CONCLUSIONS: Present study shows the importance of a longitudinal and homogeneous registration of the AEs in rare conditions, with a particular focus on the safety profile of the treatments used in these conditions.
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Sistema de Registros , Humanos , Feminino , Masculino , Adulto , Estudos Retrospectivos , Adolescente , Estudos Longitudinais , Adulto Jovem , Pessoa de Meia-Idade , Criança , Pré-Escolar , Idoso , Doenças Hereditárias Autoinflamatórias/epidemiologia , Lactente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Europa (Continente)/epidemiologia , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricosRESUMO
Neutrophil extracellular traps (NET) have been implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Here, we developed a novel, label-free, high-throughput bio-impedance technique to effectively measure serum NET-inducing activity. Using this technique, NET-inducing activity of serum derived from patients with AAV was assessed in a prospective cohort of 62 patients presenting with active AAV with major organ involvement. Thirty-five patients presented with new and 27 patients presented with relapsing AAV, of whom 38 had kidney and/or 31 had lung involvement. NET-inducing activity was assessed at diagnosis of active AAV (time zero), during the first 6 weeks of treatment, and after 6 months of treatment. Forty-seven patients revealed elevated NET-inducing activity at time zero. After initiation of immunosuppressive treatment, NET-inducing activity was reduced at six weeks. A subsequent increase at six months could potentially identify patients with relapsing disease (hazard ratio, 11.45 [interquartile range 1.36-96.74]). NET-inducing activity at time zero correlated with kidney function and proteinuria. Importantly, in kidney tissue, NETs co-localized with lesions typical of ANCA-associated glomerulonephritis and even correlated with systemic serum NET-inducing activity. Thus, our prospective data corroborate the importance of NET formation in AAV and ANCA-associated glomerulonephritis and the potential of longitudinal evaluation, as monitored by our novel bio-impedance assay and detailed histological evaluation.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Armadilhas Extracelulares , Glomerulonefrite , Humanos , Anticorpos Anticitoplasma de Neutrófilos , Impedância Elétrica , Estudos ProspectivosRESUMO
PURPOSE: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID). METHODS: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed. RESULTS: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines. CONCLUSION: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.
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COVID-19 , Imunodeficiência de Variável Comum , Doenças da Imunodeficiência Primária , Humanos , Vacina de mRNA-1273 contra 2019-nCoV , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Estudos Prospectivos , SARS-CoV-2 , Vacinação , Anticorpos Antivirais , Imunoglobulina G , RNA Mensageiro/genética , ImunidadeRESUMO
BACKGROUND: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS. OBJECTIVE: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease. METHODS: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS. RESULTS: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%. CONCLUSION: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation.
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Doenças Hereditárias Autoinflamatórias/genética , Síndromes Mielodisplásicas/genética , Dermatopatias Genéticas/genética , Enzimas Ativadoras de Ubiquitina/genética , Adulto , Idade de Início , Idoso , Doenças Hereditárias Autoinflamatórias/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Países Baixos , Estudos Retrospectivos , Dermatopatias Genéticas/diagnósticoRESUMO
BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.
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Vacina de mRNA-1273 contra 2019-nCoV , Anticorpos Neutralizantes , COVID-19 , Doenças Genéticas Inatas , Síndromes de Imunodeficiência , Vacina de mRNA-1273 contra 2019-nCoV/sangue , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Vacina de mRNA-1273 contra 2019-nCoV/uso terapêutico , Adulto , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Estudos Prospectivos , SARS-CoV-2 , Glicoproteína da Espícula de CoronavírusRESUMO
OBJECTIVE: SSc is a complex CTD affecting mental and physical health. Fatigue, hand function loss, and RP are the most prevalent disease-specific symptoms of systemic sclerosis. This study aimed to develop consensus and evidence-based recommendations for non-pharmacological treatment of these symptoms. METHODS: A multidisciplinary task force was installed comprising 20 Dutch experts. After agreeing on the method for formulating the recommendations, clinically relevant questions about patient education and treatments were inventoried. During a face-to-face task force meeting, draft recommendations were generated through a systematically structured discussion, following the nominal group technique. To support the recommendations, an extensive literature search was conducted in MEDLINE and six other databases until September 2020, and 20 key systematic reviews, randomized controlled trials, and published recommendations were selected. Moreover, 13 Dutch medical specialists were consulted on non-pharmacological advice regarding RP and digital ulcers. For each recommendation, the level of evidence and the level of agreement was determined. RESULTS: Forty-one evidence and consensus-based recommendations were developed, and 34, concerning treatments and patient education of fatigue, hand function loss, and RP/digital ulcers-related problems, were approved by the task force. CONCLUSIONS: These 34 recommendations provide guidance on non-pharmacological treatment of three of the most frequently described symptoms in patients with systemic sclerosis. The proposed recommendations can guide referrals to health professionals, inform the content of non-pharmacological interventions, and can be used in the development of national and international postgraduate educational offerings.
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Doença de Raynaud , Escleroderma Sistêmico , Úlcera Cutânea , Consenso , Fadiga/etiologia , Fadiga/terapia , Humanos , Doença de Raynaud/diagnóstico , Doença de Raynaud/etiologia , Doença de Raynaud/terapia , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/terapia , Úlcera Cutânea/tratamento farmacológico , Úlcera Cutânea/terapia , ÚlceraRESUMO
Systemic sclerosis is a rare autoimmune disease associated with rapidly evolving interstitial lung disease, responsible for the disease severity and mortality. Specific biomarkers enabling the early diagnosis and prognosis associated with the disease progression are highly needed. Volatile organic compounds in exhaled breath are widely available and non-invasive and have the potential to reflect metabolic processes occurring within the body. Comprehensive two-dimensional gas chromatography coupled to high-resolution mass spectrometry was used to investigate the potential of exhaled breath to diagnose systemic sclerosis. The exhaled breath of 32 patients and 30 healthy subjects was analyzed. The high resolving power of this approach enabled the detection of 356 compounds in the breath of systemic sclerosis patients, which was characterized by an increase of mainly terpenoids and hydrocarbons. In addition, the use of 4 complementary statistical approaches (two-tailed equal variance t-test, fold change, partial least squares discriminant analysis, and random forest) resulted in the identification of 16 compounds that can be used to discriminate systemic sclerosis patients from healthy subjects. Receiver operating curves were generated that provided an accuracy of 90%, a sensitivity of 92%, and a specificity of 89%. The chemical identification of eight compounds predictive of systemic sclerosis was validated using commercially available standards. The analytical variations together with the volatile composition of room air were carefully monitored during the timeframe of the study to ensure the robustness of the technique. This study represents the first reported evaluation of exhaled breath analysis for systemic sclerosis diagnosis and provides surrogate markers for such disease.
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Cromatografia Gasosa-Espectrometria de Massas/métodos , Escleroderma Sistêmico/diagnóstico , Compostos Orgânicos Voláteis/análise , Biomarcadores/análise , Testes Respiratórios/métodos , Humanos , Hidrocarbonetos/análise , Terpenos/análiseRESUMO
OBJECTIVES: To gain insight into SSc patients' perspective on quality of care and to survey their preferred quality indicators. METHODS: An online questionnaire about healthcare setting, perceived quality of care (CQ index) and quality indicators, was sent to 2093 patients from 13 Dutch hospitals. RESULTS: Six hundred and fifty patients (mean age 59 years, 75% women, 32% limited cutaneous SSc, 20% diffuse cutaneous SSc) completed the questionnaire. Mean time to diagnosis was 4.3 years (s.d. 6.9) and was longer in women compared with men (4.8 (s.d. 7.3) vs 2.5 (s.d. 5.0) years). Treatment took place in a SSc expert centre for 58%, regional centre for 29% or in both for 39% of patients. Thirteen percent of patients was not aware of whether their hospital was specialized in SSc. The perceived quality of care was rated with a mean score of 3.2 (s.d. 0.5) (range 1.0-4.0). There were no relevant differences between expert and regional centres. The three prioritized process indicators were: good patient-physician interaction (80%), structural multidisciplinary collaboration (46%) and receiving treatment according to SSc guidelines (44%). Absence of disease progression (66%), organ involvement (33%) and digital ulcers (27%) were the three highest rated outcome indicators. CONCLUSION: The perceived quality of care evaluated in our study was fair to good. No differences between expert and regional centres were observed. Our prioritized process and outcome indicators can be added to indicators suggested by SSc experts in earlier studies and can be used to evaluate the quality of care in SSc.
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Satisfação do Paciente , Relações Médico-Paciente , Qualidade da Assistência à Saúde , Escleroderma Sistêmico/terapia , Adulto , Feminino , Pessoal de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Indicadores de Qualidade em Assistência à Saúde , Escleroderma Sistêmico/diagnóstico , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Background Severe hypertension can induce thrombotic microangiopathy (TMA) in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. Complement defects may be the culprit of disease in patients who present with severe renal disease and often progress to ESRD, despite BP control.Methods We studied a well defined cohort of 17 patients with hypertension-associated TMA to define the prevalence of complement defects by a specific ex vivo serum-based microvascular endothelial cell assay.Results Compared with normal human serum and samples from patients with hypertensive arterionephrosclerosis, 14 of 16 (87.5%) serum samples collected at presentation from 16 patients with hypertension-associated TMA induced abnormal C5b9 formation on microvascular endothelial cells. We detected rare variants in complement genes in eight of 17 (47%) patients. ESRD occurred in 14 of 17 (82%) patients, and recurrent TMA after transplant occurred in seven of 11 (64%) donor kidneys. Eculizumab improved the renal function in three patients and prevented TMA recurrence in an allograft recipient.Conclusions These observations point to complement defects as the key causative factor of ESRD and recurrent TMA after transplant in patients presenting with severe hypertension. Complement defects can be identified by measurements of complement activation on microvascular endothelial cells, which should substantially influence treatment and prognosis.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Hipertensão/epidemiologia , Nefropatias/epidemiologia , Microangiopatias Trombóticas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Células Cultivadas , Comorbidade , Complexo de Ataque à Membrana do Sistema Complemento/efeitos dos fármacos , Proteínas do Sistema Complemento/efeitos dos fármacos , Progressão da Doença , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Nefropatias/diagnóstico , Nefropatias/tratamento farmacológico , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/tratamento farmacológicoRESUMO
The shoulder is one of the most commonly dislocated joints in the human body. Complications usually represent local damage. However, it is unclear whether joint dislocations can have systemic sequellae as wSell. Here we present the case of an 86-year-old female who developed necrotizing cryoglobulinaemic vasculitis in immediate response to a shoulder dislocation. We hypothesize there might be a link between trauma and systemic disease.
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Crioglobulinemia/diagnóstico , Crioglobulinemia/etiologia , Luxação do Ombro/complicações , Vasculite/etiologia , Idoso de 80 Anos ou mais , Crioglobulinemia/terapia , Feminino , Humanos , Metilprednisolona/uso terapêutico , Troca Plasmática , Luxação do Ombro/fisiopatologia , Vasculite/terapiaAssuntos
Betacoronavirus/patogenicidade , Coagulação Sanguínea , Ativação do Complemento , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/virologia , Neutrófilos/virologia , Pneumonia Viral/virologia , Trombofilia/virologia , Trombose/virologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/imunologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , SARS-CoV-2 , Trombofilia/sangue , Trombofilia/imunologia , Trombose/sangue , Trombose/imunologiaRESUMO
Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSAs/MAAs) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD (n = 558). Our PH cohort (n = 121) showed a significantly higher prevalence of overall weak positive MSAs/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group (p < 0.001). Notably, MSAs/MAAs were found in PH patients both with and without ILD, though more prevalent in those with ILD. Anti-synthetase and anti-overlap syndrome antibodies were the most common. Our study is the first to systematically show a high MSA/MAA prevalence in PH without IIM presentation. This highlights the need to consider PH when diagnosing MSA/MAA-associated conditions. We recommend MSA/MAA screening for newly diagnosed PH, especially in those with ILD, for early detection and potential immunomodulatory treatment. Further research should explore the link between MSAs/MAAs and PH, and the value of monitoring patients with weak MSA/MAA positivity over time.
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ABSTRACT: The risk of a venous thrombotic event (VTE) is increased in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, a detailed understanding of the underlying mechanisms of hypercoagulability is limited. We assessed prospectively different coagulation parameters in 71 patients with active AAV at baseline and after 6 months of follow-up. D-dimers and fibrinogen were increased in most patients at presentation and remained elevated in half of the patients. Particularly, thrombin-antithrombin (T:AT) complex and activated coagulation factors in complex with their natural inhibitors of the intrinsic coagulation pathway (ie, activated FXII:C1 esterase inhibitor [FXIIa:C1Inh], FXIa:AT, and FXIa:alpha1-antitrypsin [FXIa:α1AT]) were profoundly elevated in patients at baseline. Thrombin formation was dominantly correlated with coagulation factors of the intrinsic pathway (ie, FXIIa:AT, FXIa:AT, FXIa:α1AT, and FXIa:C1Inh) compared to the extrinsic pathway (ie, FVIIa:AT). Hypercoagulability correlated with higher disease activity, ANCA levels, C-reactive protein, serum creatinine, and proteinuria. VTEs were observed in 5 out of 71 (7%) patients within 1 month (interquartile range, 1-5) after inclusion. Baseline T:AT levels were significantly higher in patients with VTE than in those without VTE (P = .044), but other clinical or laboratory markers were comparable between both groups. Hypercoagulability is dominantly characterized by activation of the intrinsic coagulation pathway and elevated D-dimers in active AAV. The driving factors of hypercoagulability are yet to be studied but are most likely related to an interplay of increased disease activity, vascular inflammation, and endothelial damage. Future targets for intervention could include inhibitors of the intrinsic coagulation pathway and compounds specifically reducing the hyperinflammatory state.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Trombofilia , Humanos , Anticorpos Anticitoplasma de Neutrófilos , Trombina , Coagulação Sanguínea , Trombofilia/etiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicaçõesRESUMO
Purpose: Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign. Methods: This study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections. Results: After booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer. Conclusion: Our study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.
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Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunização Secundária , Imunogenicidade da Vacina , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , Masculino , Feminino , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Adulto , Pessoa de Meia-Idade , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Seguimentos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Estudos Prospectivos , Linfócitos T/imunologia , Adulto Jovem , Vacinação , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Síndromes de Imunodeficiência/imunologia , AdolescenteRESUMO
BACKGROUND: VEXAS-syndrome is an X-linked acquired multisystemic autoinflammatory disease caused by a somatic mutation in UBA1. CASE DESCRIPTION: In this manuscript we describe a 79-year-old male suffering from skin lesions, macrocytic anemia and lab results showing inflammation in which, based on finding a mutation in UBA1, VEXAS was diagnosed. He was treated with a combination of high dose corticosteroids and anti-IL-6 with good response. CONCLUSION: In middle aged males presenting with multisystemic inflammation without evidence of infection a diagnosis of VEXAS should be considered, especially if there is evidence of a macrocytic anemia. Early testing for UBA1 mutations helps in making the diagnosis. Despite treatment with intensive immunosuppression mortality remains high.
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Anemia Macrocítica , Anemia , Masculino , Pessoa de Meia-Idade , Humanos , Idoso , Anemia/diagnóstico , Anemia/etiologia , Inflamação , MutaçãoRESUMO
BACKGROUND: Systemic sclerosis (SSc) patients face an elevated risk of cardiovascular disease (CVD), even when classic cardiovascular risk factors are considered. Plasma dephosphorylated-uncarboxylated Matrix Gla-protein (dp-ucMGP), an inactive form of MGP, is associated with increased CVD risk. Smooth muscle cells, implicated in SSc's development, are the primary dp-ucMGP producers. This study assessed dp-ucMGP levels and initial CVD events in early-diagnosed SSc patients, investigating its potential as a CVD and all-cause mortality predictor over time. METHODS: In a cohort of 87 SSc patients (excluding those with pre-existing CVD or on dialysis), baseline dp-ucMGP levels were measured, along with cardiovascular risk factors. Validation involved assessing dp-ucMGP in a subset of treatment-naive SSc patients. RESULTS: A significantly elevated median dp-ucMGP level of 634 pmol/L (IQR 301) compared with healthy controls (dp-ucMGP < 393 pmol/L; p < 0.001) was observed. Validation in a treatment-naive SSc patient subset yielded similar results (median 589 pmol/L; IQR 370). During a median 10.5-year follow-up among 78 SSc patients, 33.3% experienced their first CVD event, independent of traditional risk factors. Elevated dp-ucMGP levels (>634 pmol/L) correlated with a higher risk of CVD and/or death (log-rank test: p < 0.01). CONCLUSIONS: In summary, dp-ucMGP emerges as a novel biomarker in SSc patients, with elevated levels indicating an increased risk of CVD and/or mortality in this population.
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A patient presented with late onset disseminated nontuberculous mycobacterium (NTM) infection due to a novel interleukin-12/interleukin-23 receptor ß1 (IL-12/IL-23Rß1) mutation, r.1561C>G, leading to the amino acid substitution R521G. This is the second patient reported with a partial IL-12/IL-23Rß1 defect.
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Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/imunologia , Micobactérias não Tuberculosas/imunologia , Receptores de Interleucina/deficiência , Adulto , Sequência de Bases , Citocinas/biossíntese , Citocinas/imunologia , Genótipo , Humanos , Imunofenotipagem , Subunidade beta 1 de Receptor de Interleucina-12/genética , Subunidade beta 1 de Receptor de Interleucina-12/metabolismo , Masculino , Mutação , Fosforilação , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Fator de Transcrição STAT4/metabolismoRESUMO
The ACR/EULAR classification criteria for systemic sclerosis (SSc) entail three autoantibodies: anti-centromere antibodies (ACA), anti-topoisomerase I antibodies (ATA), and anti-RNA-polymerase III antibodies (ARA). The importance of ACA and ATA in the classification criteria is evidence based, but the diagnostic value is overestimated by clinicians. Fortunately, these autoantibodies are characterized by good agreement between different immuno-assays. Inclusion of ARA, however, is based on limited evidence and is related to limited agreement between different immuno-assays. Harmonization of immuno-assays in terms of interpretation based on likelihood ratio's may improve future classification criteria for SSc and this needs to be achieved by close collaboration between clinicians, laboratory specialists and the diagnostic industry.
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Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell-mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease.