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1.
Allergy ; 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39049686

RESUMO

BACKGROUND: Recently, it has been questioned whether vaccination of patients with inflammatory (auto)immune diseases under anti-tumor necrosis factor (TNF) treatment leads to impaired vaccine-induced immune responses and protection against breakthrough infections. However, the effects of TNF blockade on short- and long-term immune responses after repeated vaccination remain unclear. Vaccination studies have shown that initial short-term IgG antibodies (Abs) carry highly galactosylated and sialylated Fc glycans, whilst long-term IgG Abs have low levels of galactosylation and sialylation and are most likely generated by long-lived plasma cells (PCs) derived primarily from the germinal center (GC) response. Thus, IgG Fc glycosylation patterns may be applicable to distinguish short- and long-term vaccine responses after repeated vaccination under the influence of anti-TNF treatment. METHODS: We used COVID-19 vaccination as a model to investigate vaccine-induced IgG subclass levels and Fc glycosylation patterns, B cell subsets, and effector functions of short- and long-term Ab responses after up to three vaccinations in patients on anti-TNF or other immunosuppressive treatments and in healthy individuals. Using TriNetX, a global healthcare database, we determined the risk of SARS-CoV-2 breakthrough infections in vaccinated patients treated with anti-TNF or other immunosuppressive drugs. RESULTS: Anti-TNF treatment reduced the long-term abundance of all anti-S IgG subclasses with low levels of galactosylation and sialylation. Re-activation of potential memory B cells initially generated highly galactosylated and sialylated IgG antibodies, which were progressively reduced after each booster dose in anti-TNF-treated patients, especially in the elderly. The reduced short- and long-term IgG (1) levels in anti-TNF-treated patients correlated with diminished functional activity and an increased risk for the development of COVID-19. CONCLUSIONS: The data suggest that anti-TNF treatment reduces both GC-dependent long-lived PCs and GC-dependent memory B cell-derived short-lived PCs, hence both the long- and short-term IgG subclass responses, respectively, after repeated vaccination. We propose that anti-TNF therapy, especially in the elderly, reduces the benefit of booster vaccination.

2.
Z Rheumatol ; 83(3): 200-209, 2024 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-36600054

RESUMO

BACKGROUND: Immune-mediated inflammatory diseases (IMID) can lead to a substantial disease burden for those affected, in particular by the concomitant occurrence of other IMIDs or in the presence of comorbidities. The care of patients with IMIDs is complex and involves various medical disciplines. OBJECTIVE: To describe the burden of disease and the current routine drug treatment of patients with IMID. MATERIAL AND METHODS: The retrospective cross-sectional analysis was based on statutory health insurance claims data from the InGef database. Prevalent patients with psoriasis (Pso), psoriatic arthritis (PsA), spondylarthritis (SpA), rheumatoid arthritis (RA), Crohn's disease (MC), ulcerative colitis (CU), or connective tissue disease were identified among 3,988,695 insured patients in 2018. The concomitant occurrence of different IMIDs and the extent to which patients with IMID are affected by other comorbidities compared to a reference population were investigated. The current routine drug treatment was described based on the use of predefined forms of treatment. RESULTS: In the database 188,440 patients with IMID (4.7%) were identified. Compared to the reference population the prevalence of comorbidities, such as depressive episodes and cardiovascular risk factors was higher in patients with IMID. For MC, CU, RA, and PsA disease-modifying antirheumatic drugs (DMARD) and classical systemic forms of treatment were used most commonly. In Pso, SpA, and connective tissue disease nonsteroidal anti-inflammatory drugs (NSAID) were the most frequently used treatment often in combination with other drugs. CONCLUSION: A considerable number of patients with IMIDs (16.9-27.5%) suffer from different diseases of the IMID group. They are frequently affected by accompanying illnesses and require interdisciplinary medical treatment.


Assuntos
Artrite Psoriásica , Artrite Reumatoide , Psoríase , Espondilartrite , Humanos , Estudos Transversais , Estudos Retrospectivos , Espondilartrite/terapia , Agentes de Imunomodulação
3.
Z Rheumatol ; 81(8): 660-666, 2022 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-35380249

RESUMO

Various research groups at the German Rheumatism Research Center in Berlin, in close cooperation with the Department of Rheumatology and Clinical Immunology of the Medical Clinic at the Charité, have made important contributions to the significance of B cells and plasma cells in rheumatic diseases, which are relevant not only for rheumatology but for all clinical specialties in which antibody-mediated diseases play a role. In particular, the research addresses impaired B cell homeostasis, the importance of the IgM Fc receptor in the regulation of autoimmunity, the role of long-lived memory plasma cells in maintaining autoimmunity and ensuring its survival in specific niches organized by stromal cells in bone marrow and inflamed tissues. The research results have contributed to a better understanding of the immunological and molecular mechanisms in rheumatic diseases and their treatment. The identification of the long-lived memory plasma cell has led to promising treatment approaches with curative potential in autoimmune diseases.


Assuntos
Doenças Autoimunes , Doenças Reumáticas , Autoimunidade , Linfócitos B , Humanos , Memória Imunológica , Plasmócitos , Doenças Reumáticas/terapia
4.
Eur J Immunol ; 50(2): 284-291, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31714996

RESUMO

Antibody-mediated diseases affect more than 10% of the human population. For most, no cure is available, particularly when the pathogenic antibodies are secreted by long-lived plasma cells resistant to conventional immunosuppressive therapies. Current therapeutic approaches target not only the plasma cells that secrete pathogenic antibodies, but also those providing protective antibodies. Here, in a murine model bearing long-lived plasma cells secreting anti-OVA and -chicken gamma globulin (CGG) antibodies, we describe the first-time use of an antigen-antibody (OVA/anti-CD138 antibody) conjugate for in vivo labeling and selective ablation of plasma cells that secrete antibodies specific for the antigen OVA. The selective depletion also led to a stable reduction of the corresponding serum anti-OVA antibody levels. In contrast, CGG-specific plasma cells and circulating anti-CGG antibody levels remained unchanged. The method described here should enable the development of unique causative treatment strategies for established antibody-mediated diseases sparing humoral immunity.


Assuntos
Anticorpos/imunologia , Formação de Anticorpos/imunologia , Plasmócitos/imunologia , Animais , Antígenos/imunologia , Feminino , Imunidade Humoral/imunologia , Terapia de Imunossupressão/métodos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , gama-Globulinas/imunologia
5.
Ann Rheum Dis ; 80(10): 1306-1311, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33762264

RESUMO

INTRODUCTION: In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID. OBJECTIVE: Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls. METHODS: 42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations. RESULTS: Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare. CONCLUSION: We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Hospedeiro Imunocomprometido/imunologia , Imunogenicidade da Vacina/imunologia , Inflamação/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Estudos de Coortes , Feminino , Humanos , Imunossupressores/uso terapêutico , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/imunologia , SARS-CoV-2 , Vacinas Sintéticas/imunologia , Vacinas de mRNA
6.
Ann Rheum Dis ; 80(6): 775-781, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33568386

RESUMO

BACKGROUND/OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. METHODS: We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. RESULTS: Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement. CONCLUSIONS: Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.


Assuntos
Lúpus Eritematoso Sistêmico , Doenças Reumáticas , Reumatologia , Anticorpos Antinucleares , Estudos de Coortes , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Doenças Reumáticas/diagnóstico , Reumatologia/métodos , Sensibilidade e Especificidade , Estados Unidos
7.
Clin Exp Rheumatol ; 39(3): 639-647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33822706

RESUMO

OBJECTIVES: Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the most common inflammatory rheumatic diseases (IRD). The aim of this study was to elucidate differences in the outcome of SARS-CoV-2 infection in RA- and SpA-patients. METHODS: Data from the German COVID-19 registry for IRD patients from 30th March to 16th November 2020 were analysed. 208 RA and SpA patients were included in the study, matched for gender and age. RESULTS: 104 SpA patients (40% patients with ankylosing spondylitis, 54% with psoriatic arthritis and 6% with enteropathic arthritis) were compared to 104 RA patients. For both groups, median age was 56 years. TNF-i treatment was reported in 45% of the SpA and in 19% of RA patients (p=0.001). Glucocorticoids were used in 13% of the SpA and in 40% of the RA patients (p=0.001). In both groups, the majority of the patients (97% SpA, 95% RA) recovered from COVID-19. Hospitalisation was needed in 16% of the SpA and in 30% of the RA patients (p=0.05), and oxygen treatment in 10% and 18% respectively (p=ns). Three versus six (p=ns) fatal courses were reported in the SpA versus the RA group. CONCLUSIONS: The study revealed that the hospitalisation rate during COVID-19 infection, but not the mortality, was significantly higher in RA as compared to SpA patients. This could be explained either by different treatment strategies or by different susceptibilities of the two diseases.


Assuntos
Artrite Psoriásica , Artrite Reumatoide , COVID-19 , Espondilartrite , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Humanos , Pessoa de Meia-Idade , SARS-CoV-2 , Espondilartrite/tratamento farmacológico , Espondilartrite/epidemiologia
8.
Ann Rheum Dis ; 79(10): 1333-1339, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32816709

RESUMO

OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to <3 years (n=196) and ≥5 years (n=879). Among patients with 1 to <3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 81%). The EULAR/ACR criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). Among women, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 83%) and better specificity than the SLICC criteria (94% vs 82%). Among white patients, the EULAR/ACR criteria had better sensitivity than the ACR criteria (95% vs 83%) and better specificity than the SLICC criteria (94% vs 83%). The EULAR/ACR criteria performed well among black patients (sensitivity of 98%, specificity 100%), and had better sensitivity than the ACR criteria among Hispanic patients (100% vs 86%) and Asian patients (97% vs 77%). CONCLUSIONS: The EULAR/ACR 2019 criteria perform well among patients with early disease, men, women, white, black, Hispanic and Asian patients. These criteria have superior sensitivity than the ACR criteria and/or superior specificity than the SLICC criteria across many subgroups.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Índice de Gravidade de Doença , Feminino , Humanos , Masculino , Seleção de Pacientes , Sensibilidade e Especificidade
9.
Z Rheumatol ; 79(4): 342-350, 2020 May.
Artigo em Alemão | MEDLINE | ID: mdl-32303822

RESUMO

Improved understanding of the immunopathogenesis of systemic lupus erythematosus (SLE) has paved the way for new selective treatment strategies for these inflammatory systemic diseases, similarly to diseases such as rheumatoid arthritis and the spondylarthritides. New specific biologics were developed or are being developed and open up new treatment options for patients. Belimumab is particularly important in this respect. The monoclonal antibody that blocks the cytokine BAFF/BLyS is the first medicament approved for the treatment of serologically active SLE in the last decade and also the first biologic approved for this disease. A number of other biologics for the treatment of SLE are in clinical development. This article addresses the promising new drugs currently under development for the treatment of SLE.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide , Produtos Biológicos , Lúpus Eritematoso Sistêmico , Anticorpos Monoclonais/uso terapêutico , Produtos Biológicos/uso terapêutico , Citocinas , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico
10.
Eur J Immunol ; 48(9): 1573-1579, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29979809

RESUMO

Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m2 intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19- phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.


Assuntos
Autoanticorpos/sangue , Bortezomib/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Plasmócitos/efeitos dos fármacos , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos T/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Humanos , Imunoglobulinas/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Contagem de Linfócitos , Plasmócitos/citologia , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos T/citologia
11.
Ann Rheum Dis ; 78(9): 1151-1159, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31383717

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Doenças Reumáticas , Reumatologia , Sociedades Médicas , Humanos
14.
Ann Rheum Dis ; 74(7): 1474-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25710470

RESUMO

OBJECTIVES: To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory systemic lupus erythematosus (SLE). METHODS: Twelve patients received a median of two (range 1-4) 21-day cycles of intravenous bortezomib (1.3 mg/m(2)) with the coadministration of dexamethasone (20 mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity. RESULTS: Upon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (∼60%) than vaccine-induced protective antibody titres (∼30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (∼50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined. CONCLUSIONS: These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials.


Assuntos
Ácidos Borônicos/farmacologia , Ácidos Borônicos/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Plasmócitos/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Administração Intravenosa , Adulto , Anticorpos/sangue , Ácidos Borônicos/administração & dosagem , Bortezomib , DNA/imunologia , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Quimioterapia Combinada , Feminino , Alemanha , Humanos , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Plasmócitos/patologia , Inibidores de Proteassoma/administração & dosagem , Pirazinas/administração & dosagem , Índice de Gravidade de Doença , Resultado do Tratamento
15.
Immunol Rev ; 237(1): 117-39, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20727033

RESUMO

Vaccination provides a powerful means to control infections. It exploits and exemplifies the ability of the immune system to preserve the information that a specific pathogen has been encountered in the past. The cells and molecular mechanisms of immunological memory are still being discussed controversially. Here, we review the current concepts of memory B cells, the signals involved in their maintenance, and their role in enhanced secondary reactions. Memory plasma cells, secreting protective antibodies over lifetime, have been recognized only recently. Their characterization as cells resting in terms of proliferation and migration, and surviving in dedicated stromal niches, in the absence of antigen, has generated new concepts of how memory cells in general are organized by stroma cells, the 'resting memory'. In autoimmunity and chronic inflammation, memory B cells and memory plasma cells can be essential players, and they require special attention, as they do not respond to most conventional therapies. Their selective targeting will depend on a molecular understanding of their lifestyle.


Assuntos
Linfócitos B/classificação , Linfócitos B/imunologia , Memória Imunológica , Plasmócitos/imunologia , Animais , Humanos , Camundongos , Transdução de Sinais
16.
Front Med (Lausanne) ; 11: 1332716, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38510457

RESUMO

Objectives: To investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared. Methods: 4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total. Results: Regarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19. Conclusion: Inflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.

17.
Ann Rheum Dis ; 72(12): 2011-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24114925

RESUMO

OBJECTIVES: We have previously shown that both short- and long-lived plasma cells (PCs) significantly contribute to autoantibody production in NZB/W mice as a model of lupus nephritis. The aim of this study was to determine the role of autoreactive long-lived (memory) PCs refractory to immunosuppression and B cell depletion in the pathogenesis of systemic lupus erythematosus. METHODS: Splenic CD138+ antibody-secreting cells (ASCs) from >6-month-old NZB/W mice with high titres of anti-dsDNA autoantibodies or from Balb/c mice 5 days after secondary immunisation with ovalbumin (OVA) were adoptively transferred to immunodeficient Rag1(-/-) mice, in which the development of nephritis was investigated by measuring proteinuria. Total IgG and IgM as well as anti-dsDNA and anti-OVA antibody levels were followed up by ELISA. After 21 weeks the recipient mice were sacrificed so that PCs in spleen and bone marrow could be analysed using ELISPOT and flow cytometry and renal immunohistology performed. RESULTS: The adoptive transfer of NZB/W and anti-OVA ASCs resulted in the continuous generation of anti-dsDNA antibodies and anti-OVA antibodies, respectively, exclusively by long-lived PCs that had homed to the spleen and bone marrow of recipient Rag1(-/-) mice. Rag1(-/-) mice generating autoantibodies including anti-dsDNA had reduced survival, proteinuria and immune complex nephritis with C1q, C3, IgG and IgM deposits 21 weeks after transfer. CONCLUSIONS: These findings demonstrate that autoantibodies exclusively secreted by long-lived (memory) PCs contribute to autoimmune pathology and should be considered as candidate targets for future therapeutic strategies.


Assuntos
Autoanticorpos/imunologia , Nefrite Lúpica/imunologia , Plasmócitos/imunologia , Transferência Adotiva , Animais , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Células da Medula Óssea/imunologia , Proliferação de Células , DNA/imunologia , Feminino , Proteínas de Homeodomínio/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Memória Imunológica/imunologia , Rim/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NZB , Camundongos Knockout , Baço/imunologia
18.
Ann Rheum Dis ; 71(1): 75-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21953334

RESUMO

UNLABELLED: Introduction Takayasu arteritis (TA) is a large vessel vasculitis involving the aorta and its major branches. T cell-mediated autoimmunity is thought to play a major role in its pathogenesis, while the role of B cells is still unclear. METHODS: B cell subsets in the peripheral blood of 17 patients with TA were analysed and compared with nine patients with active systemic lupus erythematosus (SLE) and nine healthy controls by flow cytometry. Based on these findings, three patients with active refractory TA were treated with B cell depletion therapy (BCDT) using monoclonal anti-CD20 antibodies (rituximab). RESULTS: The absolute number and frequency of peripheral blood CD19(+)/CD20(-)/CD27(high) antibody-secreting cells in patients with active TA was significantly higher than in healthy donors. As in active SLE, the majority of these cells are newly generated plasmablasts which significantly correlated with TA activity. Three patients with active refractory TA and expansion of plasmablasts were successfully treated with BCDT, which resulted in remission. CONCLUSION: Disturbances of B cell homeostasis may be critical in TA. Circulating plasmablasts could be a useful biomarker of disease activity and a tool for selecting appropriate candidates for BCDT. B cells and plasmablasts/plasma cells may therefore represent novel targets for effective therapies for TA.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Imunossupressores/uso terapêutico , Depleção Linfocítica/métodos , Arterite de Takayasu/tratamento farmacológico , Adolescente , Adulto , Idoso , Avaliação de Medicamentos , Feminino , Homeostase/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Rituximab , Índice de Gravidade de Doença , Arterite de Takayasu/imunologia , Resultado do Tratamento , Adulto Jovem
19.
J Autoimmun ; 39(3): 180-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22727274

RESUMO

Antibodies contribute to the pathogenesis of many chronic inflammatory diseases, including autoimmune disorders and allergies. They are secreted by proliferating plasmablasts, short-lived plasma cells and non-proliferating, long-lived memory plasma cells. Memory plasma cells refractory to immunosuppression are critical for the maintenance of both protective and pathogenic antibody titers. Here, we studied the response of plasma cells in spleen, bone marrow and inflamed kidneys of lupus-prone NZB/W mice to high-dose dexamethasone and/or cyclophosphamide. BrdU+, dividing plasmablasts and short-lived plasma cells in the spleen were depleted while BrdU- memory plasma cells survived. In contrast, all bone marrow plasma cells including anti-DNA secreting cells were refractory to both drugs. Unlike bone marrow and spleen, which showed a predominance of IgM-secreting plasma cells, inflamed kidneys mainly accommodated IgG-secreting plasma cells, including anti-DNA secreting cells, some of which survived the treatments. These results indicate that the bone marrow is the major site of memory plasma cells resistant to treatment with glucocorticoids and anti-proliferative drugs, and that inflamed tissues and secondary lymphoid organs can contribute to the autoreactive plasma cell memory. Therefore, new strategies targeting autoreactive plasma cell memory should be considered. This could be the key to finding a curative approach to the treatment of chronic inflammatory autoantibody-mediated diseases.


Assuntos
Medula Óssea/imunologia , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Plasmócitos/imunologia , Animais , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Autoimunidade/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Bromodesoxiuridina/administração & dosagem , Ciclofosfamida/farmacologia , DNA/imunologia , Dexametasona/farmacologia , Modelos Animais de Doenças , Feminino , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Imunoglobulina M/biossíntese , Imunoglobulina M/imunologia , Memória Imunológica/efeitos dos fármacos , Imunossupressores/farmacologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos NZB , Especificidade de Órgãos , Plasmócitos/efeitos dos fármacos , Plasmócitos/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia
20.
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