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1.
Sleep ; 42(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31099836

RESUMO

STUDY OBJECTIVES: The immune theory of sleep suggests an important role of sleep for a functioning immune system. Insomnia has been associated with heightened risk for infections. The aim of the study was to test whether psychophysiological insomnia (PI) is associated with subsequent respiratory tract infections (RTIs) in the context of an infection-diary-based cohort study. METHODS: We recruited 674 adults from a cross-sectional survey on airway infections into the airway infection susceptibility (AWIS) cohort and invited them to self-report in diaries incident RTIs experienced during 7097 months (mean of 11.9 months of completed infection diaries per individual). The Regensburg Insomnia Scale (RIS) was assessed at baseline to measure PI. As outcome, we considered an infection diary score summing up prospectively reported RTIs. RESULTS: The RIS score correlated significantly with the infection diary score summarizing reported RTIs (correlation coefficient = 0.265, p < 0.001). Adjustments by putative confounders did only marginally affect this relationship. No significant differences in the relationship between RIS score and diary score were found for subgroups including those by gender, body mass index, perceived stress, and comorbidity. People affected by a combination of high PI and obesity were eight times more likely to belong to the group reporting the highest 10% of RTIs compared to the nonobese group with low RIS score (p < 0.001). A high RIS score in men was associated with a higher neutrophil-to-lymphocyte ratio, an indicator of inflammation. CONCLUSIONS: Our data support the relevance of adequate sleep for an immune system ready to fight pathogens and prevent airway infections.

3.
BMC Public Health ; 18(1): 271, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29458350

RESUMO

BACKGROUND: Respiratory tract infections (RTIs) are a major morbidity factor contributing largely to health care costs and individual quality of life. The aim of the study was to test whether obesity (BMI ≥ 30 kg/m2) is one of the risk factors underlying frequent RTIs in the German adult population. METHODS: We recruited 1455 individuals between 18 to 70 years from a cross-sectional survey on airway infections in Germany and invited them to self-report in diaries incident RTIs experienced during three consecutive winter/spring seasons. RTIs reported in these 18 months and summary measures adding-up individual RTIs were the outcomes of interest. RESULTS: Compared to individuals with normal weight, obese individuals reported a consistently higher frequency of upper and lower RTIs and predominantly fell in the upper 10% group of a diary sumscore adding-up 10 different RTI symptoms over time. Obesity was associated both with lower RTIs (adjustedOR = 2.02, 95%CI = 1.36-3.00) and upper RTIs (adjustedOR = 1.55, 95%CI = 1.22-1.96). Adjusting for demographic and lifestyle variables did only marginally affect ORs. Stratified analyses suggested a stronger association for women and effect modifications by sports activity and dietary habits. CONCLUSIONS: We confirm the association of obesity with infection burden and present evidence for putative interaction with sports activity and dietary patterns.


Assuntos
Obesidade/epidemiologia , Infecções Respiratórias/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estações do Ano , Autorrelato , Adulto Jovem
4.
Immunol Cell Biol ; 94(9): 830-837, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27126628

RESUMO

Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)-like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF-κB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF-κB signaling after CD40 stimulation and both B-cell receptor- and Toll-like receptor 9-mediated activation remained unaffected. Reduced canonical NF-κB activation resulted in decreased IκBα and CD40 expression in resting cells. In PPBL patients, expression of Bcl-xL in MZ-like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL-derived B cells that were observed in vitro. The B-cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ-like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF-κB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL.


Assuntos
Linfócitos B/imunologia , Linfocitose/imunologia , Transdução de Sinais/imunologia , Adulto , Antígenos CD40/metabolismo , Pré-Escolar , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária/imunologia , Linfocitose/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo
5.
RMD Open ; 2(1): e000228, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26925253

RESUMO

INTRODUCTION: Prolonged glucocorticoid use may increase the risk of adverse safety outcomes, including cardiovascular events. The European League Against Rheumatism and the Canadian Rheumatology Association advise tapering glucocorticoid dose as rapidly as clinically feasible. There is a paucity of published data on RA that adequately describe concomitant treatment patterns. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) is a non-interventional cohort study of patients from Europe and Canada that investigated the long-term retention of intravenous abatacept in clinical practice. We assessed concomitant glucocorticoids in patients with established RA who had participated in ACTION and received ≥1 biological agent prior to abatacept initiation. RESULTS: The analysis included 1009 patients. Glucocorticoids were prescribed at abatacept initiation in 734 (72.7%) patients at a median 7.5 mg/day dose (n=692). Of the patients who remained on abatacept at 24 months, 40.7% were able to decrease their dose of glucocorticoids, including 26.9% who decreased their dose from >5 mg/day to ≤5 mg/day. CONCLUSION: Reduction and/or cessation of glucocorticoid therapy is possible with intravenous abatacept in clinical practice.

6.
Clin Exp Rheumatol ; 34(3): 489-99, 2016 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26966919

RESUMO

OBJECTIVES: To evaluate retention of abatacept over 24 months in patients with rheumatoid arthritis (RA) in routine clinical practice across Europe and Canada. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) was a prospective, observational, multicentre study of adult patients with moderate-to-severe RA who, at their physician's discretion, initiated treatment with intravenous abatacept. Enrolment occurred from May 2008 to December 2010, with up to 30 months of follow-up. The primary endpoint was the abatacept retention rate over 24 months. Crude abatacept retention rate was estimated using the Kaplan-Meier method. Prognostic factors of abatacept retention in patients with ≥1 prior biologic failure were derived from a Cox proportional hazards regression model, accounting for clustered data. RESULTS: A total of 1137 patients were enrolled (1573 patient-years on abatacept); most (89.2%) had experienced prior biologic failure. The overall crude abatacept retention rate at 24 months was 54.4% (95% confidence interval: 51.3, 57.4). Positivity for both rheumatoid factor and anti-cyclic citrullinated antibody, previous exposure to one or no anti-tumour necrosis factor agents, and cardiovascular comorbidity were prognostic of higher abatacept retention. Erythrocyte sedimentation rate ≥51 mm/hour and introduction of corticosteroid use at abatacept initiation were predictors of lower abatacept retention. Abatacept retention varied according to country. Abatacept was well tolerated without any unexpected safety signals. CONCLUSIONS: In a real-world setting, intravenous abatacept treatment retention was more than 50% at 24 months. The identification of prognostic factors of abatacept retention could support individualised biologic treatment strategies in patients with moderate-to-severe RA.


Assuntos
Abatacepte , Artrite Reumatoide , Abatacepte/administração & dosagem , Abatacepte/efeitos adversos , Administração Intravenosa , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Sedimentação Sanguínea/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Prognóstico , Fator Reumatoide/sangue , Fatores de Tempo , Resultado do Tratamento
7.
J Allergy Clin Immunol ; 137(1): 3-17, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26768758

RESUMO

Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity.


Assuntos
Doenças Autoimunes/genética , Síndromes de Imunodeficiência/genética , Animais , Autoimunidade/genética , Predisposição Genética para Doença , Humanos , Herança Multifatorial
8.
BMC Musculoskelet Disord ; 16: 176, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-26228643

RESUMO

BACKGROUND: The emergence of new therapies for the treatment of rheumatoid arthritis (RA), the paucity of head-to-head studies, and the heterogeneous nature of responses to current biologics highlight the need for the identification of prognostic factors for treatment response and retention in clinical practice. Prognostic factors for patient retention have not been explored thoroughly despite data for abatacept and other biologics being available from national registries. Real-world data from the ACTION study may supplement the findings of randomized controlled trials and show how abatacept is used in clinical practice. The aim of this interim analysis was to identify prognostic factors for abatacept retention in patients with RA who received at least one prior biologic agent. METHODS: A large, international, non-interventional cohort of patients with moderate-to-severe RA who initiated intravenous abatacept in Canada and Europe (May 2008-January 2011) enrolled in the ACTION study. Potential prognostic factors for retention in this interim analysis (data cut-off February 2012; including patients from Canada, Germany, Greece, and Italy) were baseline demographics and disease characteristics, medical history, and previous and concomitant medication. Clinically relevant variables with p ≤ 0.20 in univariate analysis and no collinearity were entered into a Cox proportional hazards regression model, adjusted for clustered data. Variables with p ≤ 0.10 were retained in the final model (backward selection). RESULTS: The multivariate model included 834 patients. Anti-cyclic citrullinated peptide (CCP) antibody positivity (hazard ratio [95% confidence interval]: 0.55 [0.40, 0.75], p < 0.001), failure of <2 prior anti-tumor necrosis factors (TNFs) (0.71 [0.56, 0.90], p = 0.005 versus ≥2 prior anti-TNFs), and cardiovascular comorbidity at abatacept initiation (0.48 [0.28, 0.83], p = 0.009) were associated with lower risk of abatacept discontinuation. Patients in Greece and Italy were less likely to discontinue abatacept than patients in Germany and Canada (Greece: 0.30 [0.16, 0.58]; Italy: 0.50 [0.33, 0.76]; Canada: 1.04 [0.78, 1.40], p < 0.001 versus Germany). CONCLUSIONS: Real-world prognostic factors for abatacept retention include anti-CCP positivity and fewer prior anti-TNF failures. Differences in retention rates between countries may reflect differences in healthcare systems. The finding that abatacept has potential advantages in patients with cardiovascular comorbidities needs to be confirmed in further research.


Assuntos
Abatacepte/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/administração & dosagem , Internacionalidade , Adesão à Medicação , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Artrite Reumatoide/epidemiologia , Canadá/epidemiologia , Estudos de Coortes , Feminino , Seguimentos , Alemanha/epidemiologia , Grécia/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
9.
J Allergy Clin Immunol ; 135(4): 988-97.e6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25595268

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. OBJECTIVE: We sought to define the outcomes of HSCT for patients with CVID. METHODS: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. RESULTS: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. CONCLUSION: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.


Assuntos
Imunodeficiência de Variável Comum/terapia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Adolescente , Adulto , Causas de Morte , Criança , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/mortalidade , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto Jovem
10.
Artigo em Inglês | MEDLINE | ID: mdl-25300826

RESUMO

BACKGROUND/OBJECTIVES: The risk to die from an infectious disease in Germany has been continuously decreasing over the last century. Since infections are, however, not only causes of death but risk factors for diseases like cardiovascular diseases, it is essential to monitor and analyze their prevalence and frequency, especially in consideration of the increased life expectancy. To gain more knowledge about infectious diseases as risk factors and their implications on the condition and change of the immune status, the German National Cohort (GNC), a population-based prospective cohort study, will recruit 200,000 subjects between 2014 and 2017. In Pretest 1, a feasibility study for the GNC, we evaluated a self-administered and self-report questionnaire on infectious diseases and on the use of health care facilities (hereinafter called "ID Screen") for feasibility and validity. METHODS: From August-November 2011, 435 participants between the ages of 20-69 completed the ID Screen. All subjects had been recruited via a random sample from the local residents' registration offices by 4 of the 18 participating study centers. The questionnaire encompasses 77 variables in six sections assessing items such as 12-month prevalence of infections, cumulative prevalence of infectious diseases, visit of health care facilities and vaccination. The feasibility was amongst others evaluated by assessing the completeness and comprehensiveness of the questionnaire. To assess the questionnaires ability to measure "immune status" and "susceptibility to infections", multivariate analysis was used. RESULTS: The overall practicability was good and most items were well understood, demonstrated by < 2/33 missing questions per questionnaire and only three variables: vaccination for influenza and pneumococci and infection with chickenpox had a frequency > 5 % of missing values. However, direct comparison of the items 12-month prevalence and lifetime prevalence of nephritis/pyelitis showed poor agreement and thereby poor understanding by 80 % of the participants, illustrating the necessity for a clear, lay person appropriate description of rare diseases to increase comprehensibility. The questionnaire will be used to support the assessment of immune dysfunction and frequency of infection. An analysis of these constructs in an exploratory factor analysis revealed limited applicability due to low interitem correlation (Cronbach's α < 0.5). This is corroborated by the extraction of more than one factor with a Kaiser-Meyer-Olkin measure of 0.6 instead of a unidimensional latent construct for "immune status". CONCLUSION: All in all, the ID Screen is a good and reliable tool to measure infectious diseases as risk factors and outcome in general, but requires a better translation of infection specific terms into lay person terms. For the assessment of the overall immune status, the tool has strong limitations. Vaccinations status should also rather be assessed based on vaccination certificates than on participants' recall.


Assuntos
Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/epidemiologia , Vigilância da População/métodos , Medição de Risco/métodos , Inquéritos e Questionários , Adulto , Idoso , Estudos de Coortes , Doenças Transmissíveis/imunologia , Estudos de Viabilidade , Alemanha/epidemiologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Masculino , Pessoa de Meia-Idade , Prevalência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
11.
Eur J Immunol ; 44(8): 2207-14, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24975475

RESUMO

The use of immunoglobulin (Ig) preparations (intravenous, IVIg, subcutaneous, SCIg) for replacement and immunomodulation therapy worldwide has tripled in the past 20 years and represents an ever-increasing cost factor for healthcare organizations. The limited access to the starting material of this essential medicinal product is currently the driving force for human plasma collection. Increasing awareness and improved diagnosis of human primary immunodeficiencies and a broadening of immunomodulatory indications are responsible for this development, and on a longer run might lead to plasma supply shortages. Consensus recommendations for the optimal use of Ig in clinical practice, including priority rankings for the most urgent indications, are therefore urgently needed. During a recent meeting in Kreuth, Germany, expert nominees from 36 Council of Europe states, together with colleagues from observer countries and regulatory agencies came up with this consensus statement.


Assuntos
Imunização Passiva/métodos , Imunização Passiva/normas , Imunoglobulinas/uso terapêutico , Consenso , Europa (Continente) , Humanos
12.
PLoS One ; 9(6): e100328, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24945754

RESUMO

Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.


Assuntos
Diferenciação Celular , Plasmócitos/citologia , Plasmócitos/metabolismo , Fatores de Transcrição SOXD/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXD/genética
13.
BMC Musculoskelet Disord ; 15: 14, 2014 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-24410774

RESUMO

BACKGROUND: Discontinuation of rheumatoid arthritis (RA) treatment for lack or loss of initial response, tolerability issues, or development of antibodies against the therapeutic agent remains a challenge in clinical practice. Here we present a 6-month interim analysis of a 2-year prospective observational trial in Europe and Canada aiming to assess the real-world effectiveness, safety, and tolerability of intravenous abatacept for the treatment of moderate-to-severe RA. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) is a prospective, observational study assessing effectiveness, safety, and tolerability of abatacept in patients with RA enrolled in Europe and Canada between May 2008 and January 2011. The patient population was divided into two groups: biologic naïve ('first-line') patients and patients who had previously failed treatment with at least one biologic agent ('second-line'). Retention rates were calculated using Kaplan-Meier curve estimates. Effectiveness was measured using European League Against Rheumatism (EULAR) response criteria, the 28-item Disease Activity Score, the Clinical Disease Activity Index (CDAI), and physical function, as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Serious adverse events (SAEs) were reported for all enrolled patients. RESULTS: Of 1138 consecutively enrolled patients, 1114 and 1079 patients were evaluable for retention and effectiveness, respectively. Overall, retention rates were 88.6% (95% confidence interval [CI]: 86.4, 90.4); 67.4% of patients achieved good/moderate EULAR response; 32.8% had a CDAI Low Disease Activity State (LDAS); and 44.7% a HAQ-DI response. Retention rates among first- and second-line patients were 93.0% (95% CI: 85.9, 96.6) and 88.1% (95% CI: 85.7, 90.0), respectively. The percentage of patients achieving CDAI LDAS was 40.0% (95% CI: 26.4, 53.6) for first- and 32.2% (95% CI: 28.4, 36.0) for second-line patients and the proportion achieving a HAQ-DI response was 60.3% (95% CI: 47.8, 72.9) versus 43.1% (95% CI: 39.0, 47.2), respectively. The incidence of SAEs was 4.7%. CONCLUSIONS: Evidence from this 6-month interim analysis suggests that abatacept offers an effective and well-tolerated treatment option for patients with RA, including those who have previously failed anti-tumor necrosis factor treatment. In addition, higher retention rates and effectiveness outcomes were observed when abatacept treatment was initiated earlier in the course of the disease.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/uso terapêutico , Abatacepte , Administração Intravenosa , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Canadá , Avaliação da Deficiência , Substituição de Medicamentos , Europa (Continente) , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
14.
Front Immunol ; 5: 629, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25566244

RESUMO

The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic "per kg" dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki' disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases.

15.
Front Immunol ; 5: 675, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25601868

RESUMO

Immunoglobulin (Ig) replacement therapy is effective in reducing infections in patients with primary antibody deficiency (PAD). Diversity of specific antibodies is achieved by pooling plasma from over 1000 donors usually of a given geographic region. However, there is no agreement with regard to an optimal vaccination schedule for plasma donors. Especially for tick-borne encephalitis (TBE), regional vaccination rates differ widely among populations due to the epidemiology of the disease. We analyzed specific antibody titers against TBE in comparison to total IgG levels in 162 serum samples collected from 110 PAD patients substituted with polyvalent intravenous IgG or subcutaneous IgG. Some patients received different IgG products over time leading to a total number of 122 different patient-IgG product combinations. Positive TBE-specific IgG levels were detected in 35 cases when measured by standard ELISA and could be confirmed by demonstration of neutralizing antibodies in 31 cases. The detection of specific antibody levels correlated with the geographic origin of the IgG preparations. No titers were detectable in patients substituted with IgG products from North-American donors, whereas variable degrees of anti-TBE titers were observed in patients receiving products from different European countries. We suggest considering the patients' personal risk for TBE when selecting an appropriate Ig preparation. These data support regional plasma donation in order to address the diverse local infection profile.

16.
Autoimmunity ; 46(7): 429-38, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23742274

RESUMO

B-lymphocytes play a pivotal role in ANCA-associated vasculitides (AAV). The homeostasis of peripheral human B-lymphocyte subpopulations is tightly regulated, but may be disturbed in autoimmune disease or following immunosuppressive therapies. To elucidate the effect of immunosuppression and the relevance of B-lymphocyte disturbances, the B-lymphocyte compartment was analysed in 61 AAV patients. After immunosuppressive treatment a general B-lymphocytopenia developed in AAV patients. Within the B-lymphocyte subpopulations transitional B cells are the first maturation stage found in the peripheral blood. Transitional B-lymphocytes were significantly lower in AAV patients after immunosuppressive therapy compared to healthy controls. Furthermore, marginal zone B cells--a B-lymphocyte population protecting against encapsulated bacteria--were markedly lowered after immunosuppressive therapy in AAV patients. AAV patients treated with immunosuppressants had lower numbers of naïve and memory B-lymphocytes. Numbers of marginal zone B cells, memory B cells and plasmablasts correlated with concentrations of immunoglobulins. We evaluated plasmablasts for a potential correlation with disease activity. Different from what has been reported for e.g. large vessel vasculitis, absolute numbers of plasmablasts were not increased in patients with AAV and showed no correlation to disease activity. As low transitional B cells after treatment with immunosuppressants indicated an impaired early B-lymphocyte development, seven patients treated with the B cell depleting agent rituximab (RTX) because of relapsing disease activity were analysed for their B cell repopulation kinetics. In the majority of these patients repopulation of the peripheral B cell compartment by newly formed transitional B cells after RTX treatment was constricted and delayed.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Homeostase/imunologia , Imunossupressores/administração & dosagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Subpopulações de Linfócitos B/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Homeostase/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Leflunomida , Contagem de Linfócitos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/análogos & derivados , Rituximab
18.
Arthritis Res Ther ; 14(5): 223, 2012 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-23043756

RESUMO

Common variable immunodeficiency (CVID) describes a heterogeneous subset of hypogammaglobulinemias of unknown etiology. Typically, patients present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A significant proportion of CVID patients develops additional autoimmune, inflammatory or lymphoproliferative complications. CVID is the most frequent symptomatic primary immunodeficiency encountered in adults. Informative monogenetic defects have been found in single patients and families but in most cases the pathogenesis is still elusive. Numerous immunological studies have demonstrated phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells. A hallmark is the impaired memory B-cell formation that has been taken advantage of for classifying CVID patients. Clinical multi-center studies have demonstrated a correlation between immunological markers and clinical presentation. Long-term outcome is significantly influenced by delay of diagnosis and treatment and the presence of chronic inflammatory complications. While immunoglobulin replacement therapy plus antibiotics can control infections in most cases, patients with non-infectious inflammatory complications such as granulomatous inflammation, interstitial lung disease, inflammatory bowel disease, lymphoproliferation and developing malignancies still represent a therapeutic challenge. In this review we provide a systematic overview of the immunological, clinical, diagnostic and therapeutic aspects of CVID and highlight recent developments in these fields.


Assuntos
Imunodeficiência de Variável Comum , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/imunologia , Humanos , Imunoglobulinas/uso terapêutico , Prognóstico
19.
Clin Exp Rheumatol ; 30(5): 772-5, 2012 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22935225

RESUMO

OBJECTIVES: To investigate the role of serum osteopontin concentrations for monitoring idiopathic retroperitoneal fibrosis. METHODS: In 22 patients with idiopathic retroperitoneal fibrosis serum concentrations of osteopontin were measured by an enzyme-linked immunosorbant assay and related to retrospectively gathered clinical data, contrast enhanced magnetic resonance imaging studies, and laboratory parameters. Patients with secondary causes, an inflammatory abdominal aortic aneurysm, and immunoglobulin G4-associated idiopathic retroperitoneal fibrosis were excluded. Twenty-two healthy volunteers served as controls. RESULTS: Serum osteopontin concentrations of patients with idiopathic retroperitoneal fibrosis were elevated compared to healthy controls (p=0.017) and correlated with the transverse diameter of the periaortic cuff as determined by imaging studies (ρ=0.549; p=0.008). Patients presenting with a diameter greater than 10mm had higher osteopontin concentrations than patients with smaller diameters (p=0.004). Increased inflammatory activity as determined by the presence of contrast enhancement in imaging studies (p<0.001) and the presence of typical symptoms (p=0.013) were associated with higher osteopontin concentrations. CONCLUSIONS: Serum osteopontin concentrations were elevated in patients with idiopathic retroperitoneal fibrosis. Increased concentrations correlated with the presence of clinical symptoms and extended disease or activity parameters on magnetic resonance imaging.


Assuntos
Osteopontina/sangue , Fibrose Retroperitoneal/sangue , Aorta/patologia , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Glucocorticoides/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Valor Preditivo dos Testes , Fibrose Retroperitoneal/diagnóstico , Fibrose Retroperitoneal/tratamento farmacológico , Fibrose Retroperitoneal/patologia , Estudos Retrospectivos , Regulação para Cima
20.
J Rheumatol ; 39(7): 1407-12, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22589264

RESUMO

OBJECTIVE: Promising therapeutic approaches have emerged in chronic periaortitis, whereas peripheral blood biomarkers are lacking. CC-chemokine ligand 18 (CCL18) is known as a marker of fibrotic activity and prognosis in pulmonary fibrosis. We investigated whether CCL18 levels are increased in patients with chronic periaortitis and are associated with clinical, laboratory, and imaging findings. METHODS: In this retrospective study, serum concentrations of CCL18 were assessed in 30 patients with chronic periaortitis and related to clinical data, laboratory variables, and imaging studies. Serum levels were compared to 15 apparently healthy volunteers and 15 controls with aortic sclerosis. RESULTS: Serum concentrations of CCL18 were increased in patients with chronic periaortitis (median 197.6 ng/ml, range 73.7-301.0) compared to healthy volunteers (median 34.6 ng/ml, range 22.6-70.4; p < 0.0001) and controls with aortic sclerosis (median 50.4 ng/ml, range 24.5-141.2; p < 0.0001). CCL18 levels correlated with (n = 30; r = 0.461, p = 0.01) and increased with the transversal diameter of the periaortic mantle < 5, 5-10, and ≥ 10 mm (p = 0.008). Contrast enhancement (p = 0.044), treatment naivety (p = 0.042), and the occurrence of systemic symptoms (p = 0.007) were associated with higher CCL18 levels. During followup, changes of CCL18 correlated with changes of the transverse diameter of the periaortic mantle (n = 17; r = 0.512, p = 0.033). CONCLUSION: Serum concentration of CCL18 reflects fibroinflammatory activity and extent of disease in patients with chronic periaortitis.


Assuntos
Quimiocinas CC/sangue , Fibrose Retroperitoneal/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças da Aorta/sangue , Biomarcadores/sangue , Proteína C-Reativa/análise , Creatinina/sangue , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
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