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1.
Ann Rheum Dis ; 2021 Feb 10.
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.

2.
RMD Open ; 7(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33479021

RESUMO

INTRODUCTION: Whether patients with inflammatory rheumatic and musculoskeletal diseases (RMD) are at higher risk to develop severe courses of COVID-19 has not been fully elucidated. Aim of this analysis was to describe patients with RMD according to their COVID-19 severity and to identify risk factors for hospitalisation. METHODS: Patients with RMD with PCR confirmed SARS-CoV-2 infection reported to the German COVID-19 registry from 30 March to 1 November 2020 were evaluated. Multivariable logistic regression was used to estimate ORs for hospitalisation due to COVID-19. RESULTS: Data from 468 patients with RMD with SARS-CoV-2 infection were reported. Most frequent diagnosis was rheumatoid arthritis, RA (48%). 29% of the patients were hospitalised, 5.5% needed ventilation. 19 patients died. Multivariable analysis showed that age >65 years (OR 2.24; 95% CI 1.12 to 4.47), but even more>75 years (OR 3.94; 95% CI 1.86 to 8.32), cardiovascular disease (CVD; OR 3.36; 95% CI 1.5 to 7.55), interstitial lung disease/chronic obstructive pulmonary disease (ILD/COPD) (OR 2.79; 95% CI 1.2 to 6.49), chronic kidney disease (OR 2.96; 95% CI 1.16 to 7.5), moderate/high RMD disease activity (OR 1.96; 95% CI 1.02 to 3.76) and treatment with glucocorticoids (GCs) in dosages >5 mg/day (OR 3.67; 95% CI 1.49 to 9.05) were associated with higher odds of hospitalisation. Spondyloarthritis patients showed a smaller risk of hospitalisation compared with RA (OR 0.46; 95% CI 0.23 to 0.91). CONCLUSION: Age was a major risk factor for hospitalisation as well as comorbidities such as CVD, ILD/COPD, chronic kidney disease and current or prior treatment with GCs. Moderate to high RMD disease activity was also an independent risk factor for hospitalisation, underlining the importance of continuing adequate RMD treatment during the pandemic.


Assuntos
/diagnóstico , Glucocorticoides/efeitos adversos , Doenças Musculoesqueléticas/complicações , Doenças Reumáticas/complicações , /genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , /terapia , Estudos de Casos e Controles , Comorbidade , Feminino , Alemanha/epidemiologia , Glucocorticoides/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/tratamento farmacológico , Sistema de Registros , Respiração Artificial/métodos , Estudos Retrospectivos , Doenças Reumáticas/tratamento farmacológico , Fatores de Risco
3.
RMD Open ; 6(2)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32878994

RESUMO

OBJECTIVES: Patients with inflammatory rheumatic diseases (IRD) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be at risk to develop a severe course of COVID-19. The influence of immunomodulating drugs on the course of COVID-19 is unknown. To gather knowledge about SARS-CoV-2 infections in patients with IRD, we established a registry shortly after the beginning of the pandemic in Germany. METHODS: Using an online questionnaire (www.COVID19-rheuma.de), a nationwide database was launched on 30 March 2020, with appropriate ethical and data protection approval to collect data of patients with IRD infected with SARS-CoV-2. In this registry, key clinical and epidemiological parameters-for example, diagnosis of IRD, antirheumatic therapies, comorbidities and course of the infection-are documented. RESULTS: Until 25 April 2020, data from 104 patients with IRD infected with SARS-CoV-2 were reported (40 males; 63 females; 1 diverse). Most of them (45%) were diagnosed with rheumatoid arthritis, 59% had one or more comorbidities and 42% were treated with biological disease-modifying antirheumatic drugs. Hospitalisation was reported in 32% of the patients. Two-thirds of the patients already recovered. Unfortunately, 6 patients had a fatal course. CONCLUSIONS: In a short time, a national registry for SARS-CoV2-infected patients with IRD was established. Within 4 weeks, 104 cases were documented. The registry enables to generate data rapidly in this emerging situation and to gain a better understanding of the course of SARS-CoV2-infection in patients with IRD, with a distinct focus on their immunomodulatory therapies. This knowledge is valuable for timely information of physicians and patients with IRD, and shall also serve for the development of guidance for the management of patients with IRD during this pandemic.


Assuntos
Antirreumáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Sistema de Registros , Doenças Reumáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Feminino , Alemanha , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Hospitalização , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Polimialgia Reumática/complicações , Polimialgia Reumática/tratamento farmacológico , Prognóstico , Doenças Reumáticas/complicações , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Índice de Gravidade de Doença , Espondilite Anquilosante/complicações , Espondilite Anquilosante/tratamento farmacológico , Adulto Jovem
4.
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
5.
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
6.
Arthritis Care Res (Hoboken) ; 72(12): 1820-1826, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31560454

RESUMO

OBJECTIVE: A project aimed at developing new classification criteria for systemic lupus erythematosus (SLE) is based on weighted criteria that include both laboratory and clinical items. Combinations of certain symptoms may occur commonly in SLE, which provides an argument against independently counting these items. The current study was undertaken to evaluate the interrelationship between candidate criteria items in the International Early SLE cohort and in the Euro-Lupus cohort. METHODS: The International Early SLE cohort included 389 patients, who were diagnosed within 3 years prior to the study. Data on the ACR's 1997 update of the SLE revised criteria, the Systemic Lupus International Collaborating Clinics 2012 criteria, and on 30 additional items were collected. To evaluate the interrelationship of the criteria, a tetrachoric correlation was used to assess the degree of association between different manifestations in the same organ system. The correlations identified in the International Early SLE cohort were validated in the Euro-Lupus cohort. RESULTS: A few relevant correlations were observed among specific clinical cutaneous manifestations (in particular, malar rash correlated with photosensitivity, alopecia, and oral ulcers) and serologic manifestations (anti-Sm and anti-double-stranded DNA and anti-RNA polymerase, anti-Ro and anti-La, and antiphospholipid antibodies), and these results were validated in the Euro-Lupus cohort. The associations within the mucocutaneous domain, hematologic and the specific autoantibodies suggest that within a single domain only the highest ranking item should be counted to avoid overrepresentation. CONCLUSION: Some of the candidate SLE criteria cluster within domains. Given these interrelationships, multiple criteria within a domain should not be independently counted. These results are important to consider for the structure of new SLE classification criteria.

7.
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 , Imunossupressão/métodos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , gama-Globulinas/imunologia
8.
Dtsch Med Wochenschr ; 144(24): 1726-1730, 2019 12.
Artigo em Alemão | MEDLINE | ID: mdl-31791079

RESUMO

IgG4-related disease (IgG4-RD) is an entity first described less than 20 years ago, characterized by tumorous swelling of affected organs. Differentiation from malignant disease, systemic infections and other systemic autoimmune diseases can be challenging. Typical histopathologic findings facilitate a diagnosis in a compatible clinical context. Because nearly every organ system can be affected, management of IgG4-RD is a challenging task requiring multidisciplinary work-up and treatment. Medical treatment usually consists of glucocorticoids, which may be combined with other immunosuppressives. Surgical or interventional treatment may be necessary if complications arise. Since high-quality evidence is lacking for most aspects of the management of IgG4-RD, international collaborative studies are urgently needed.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Glucocorticoides/uso terapêutico , Humanos , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/patologia , Doença Relacionada a Imunoglobulina G4/terapia , Imunossupressores/uso terapêutico
9.
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
10.
Arthritis Rheumatol ; 71(9): 1400-1412, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31385462

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 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 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 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (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 reflects current thinking about SLE and provides an improved foundation for SLE research.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Reumatologia/normas , Adulto , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Anticorpos Antifosfolipídeos/sangue , Anticorpos Antifosfolipídeos/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Coortes , Proteínas do Sistema Complemento/análise , Técnicas de Apoio para a Decisão , Técnica Delfos , Europa (Continente) , Feminino , Humanos , Cooperação Internacional , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Sociedades Médicas , Estados Unidos
11.
Arthritis Rheumatol ; 71(1): 91-98, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30035365

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. METHODS: Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of <1 year. Clinical and serologic manifestations were compared between patients diagnosed as having SLE and those diagnosed as having SLE-mimicking conditions. Diagnostic performance of the 1997 American College of Rheumatology (ACR) SLE classification criteria and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria was tested. RESULTS: Data were collected on 389 patients with early SLE and 227 patients with SLE-mimicking conditions. Unexplained fever was more common in early SLE than in SLE-mimicking conditions (34.5% versus 13.7%, respectively; P < 0.001). Features less common in early SLE included Raynaud's phenomenon (22.1% versus 48.5%; P < 0.001), sicca symptoms (4.4% versus 34.4%; P < 0.001), dysphagia (0.3% versus 6.2%; P < 0.001), and fatigue (28.3% versus 37.0%; P = 0.024). Anti-double-stranded DNA, anti-ß2 -glycoprotein I antibodies, positive Coombs' test results, autoimmune hemolytic anemia, hypocomplementemia, and leukopenia were more common in early SLE than in SLE-mimicking conditions. Symptoms detailed in the ACR and SLICC classification criteria were significantly more frequent among those with early SLE. Fewer patients with early SLE were not identified as having early SLE with use of the SLICC criteria compared to the ACR criteria (16.5% versus 33.9%), but the ACR criteria demonstrated higher specificity than the SLICC criteria (91.6% versus 82.4%). CONCLUSION: In this multicenter cohort, clinical manifestations that could help to distinguish early SLE from SLE-mimicking conditions were identified. These findings may aid in earlier SLE diagnosis and provide information for ongoing initiatives to revise SLE classification criteria.


Assuntos
Doenças Autoimunes/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Síndrome de Sjogren/diagnóstico , Adulto , Anemia Hemolítica Autoimune/etiologia , Anticorpos Antinucleares , Síndrome Antifosfolipídica/diagnóstico , Artrite Reumatoide/diagnóstico , Autoanticorpos/imunologia , Estudos de Coortes , Proteínas do Sistema Complemento/imunologia , Teste de Coombs , DNA/imunologia , Transtornos de Deglutição/etiologia , Diagnóstico Diferencial , Feminino , Febre de Causa Desconhecida/etiologia , Hepatite Autoimune/diagnóstico , Humanos , Leucopenia/etiologia , Doenças Pulmonares Intersticiais/diagnóstico , Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/diagnóstico , Doença de Raynaud/etiologia , Escleroderma Sistêmico/diagnóstico , Síndrome de Sjogren/etiologia , Tireoidite Autoimune/diagnóstico , Doenças do Tecido Conjuntivo Indiferenciado/diagnóstico , Adulto Jovem , beta 2-Glicoproteína I/imunologia
12.
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
13.
Arthritis Care Res (Hoboken) ; 70(10): 1488-1494, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29287313

RESUMO

OBJECTIVE: The American College of Rheumatology and the European League Against Rheumatism embarked on a project to reevaluate classification criteria for systemic lupus erythematosus (SLE). The first phase of the classification project involved generation of a broad set of items potentially useful for classification of SLE and their selection for use in a subsequent forced-choice decision analysis. METHODS: A large international group of expert lupus clinicians was invited to participate in a 2-step process to generate, rate, and select items based on their importance in diagnosing early and established SLE, via a web-based survey. RESULTS: A total of 135 and 147 experts were invited to participate in the item-generation and item-reduction process, respectively. Of 145 items generated, item reduction resulted in 40 candidate items moving forward to the next phase. Key features for classifying both early and established SLE included characteristic autoantibodies, specific renal features, and skin manifestations. A small majority (51%) stated that 1 organ system would be sufficient for classifying SLE, but that additional typical laboratory features (antinuclear antibody, anti-double-stranded DNA) would be required. Notably, 85% of the expert group would positively classify SLE if renal pathology alone showed lupus nephritis. CONCLUSION: The Delphi exercise resulted in a set of 40 candidate criteria for the classification of SLE for subsequent assessment. This study comprised the largest panel ever involved in the development of SLE classification criteria, providing a broadly representative view of the current approach to classification of SLE.


Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Anticorpos Antinucleares/análise , Técnica Delfos , Humanos , Rim/patologia , Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/patologia
14.
Arthritis Rheumatol ; 69(10): 2018-2028, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28622453

RESUMO

OBJECTIVE: To analyze the composition of known plasmacytosis in systemic lupus erythematosus (SLE) to obtain further insight into the nature of underlying mechanisms. METHODS: Plasmablasts from patients with active SLE, patients with inactive/treated SLE, and healthy controls were characterized by flow cytometry, enzyme-linked immunospot assay, and Transwell migration assays and compared to vaccination-induced plasmablasts. Serum cytokine levels were analyzed by Luminex assay, and histologic analysis of kidney biopsy specimens was performed. RESULTS: Circulating plasmablasts in SLE expressed markers of mucosal immune reactions. IgA, CCR10, and ß7 integrin were expressed by 48%, 40%, and 38% of plasmablasts, respectively, with varying coexpression patterns. Consistent with mucosal homing, some SLE plasmablasts migrated toward the mucosal chemokine CCL28 and secreted polymeric IgA. SLE plasmablasts shared phenotypic characteristics with antigen-specific plasmablasts induced by oral, but not parenteral, vaccinations. Autoreactive antibody-secreting cells of the IgG and IgA isotypes were detectable, but only the emergence of phenotypically mucosal plasmablasts was positively associated with serum interleukin-2 and platelet-derived growth factor BB levels. CONCLUSION: Our data suggest that distinct plasmablast differentiation pathways jointly contribute to peripheral plasmacytosis in SLE, i.e., a cytokine-amplified mucosal "steady-state" plasmablast response, and an autoreactive plasmablast response, representing conventional autoimmunity. Our results indicate an overly activated mucosal immune system in patients with SLE, with both immunologic and clinical implications.


Assuntos
Autoanticorpos/imunologia , Citocinas/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Membrana Mucosa/imunologia , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Becaplermina , Estudos de Casos e Controles , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Quimiocinas CC/imunologia , Ensaio de Imunoadsorção Enzimática , ELISPOT , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Técnicas In Vitro , Cadeias beta de Integrinas/imunologia , Interleucina-2/imunologia , Rim/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas c-sis/imunologia , Receptores CCR10/imunologia , Adulto Jovem
15.
Immunol Lett ; 189: 10-12, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28455167

RESUMO

The immune system can be divided into two major parts: innate and adaptive immunity. Adaptive immunity is characterized by its major cellular players: the B and T cells. B cells will, in the context of an immune reaction, differentiate into plasma cells. These plasma cells produce antibodies, which are secreted. Antibodies are characterized by their specificity against a selected antigen and by their isotype. The isotype changes with the duration or phase of the immune reaction. Early immune reactions are usually characterized by the predominant production of IgM antibodies. With the persistence of the immune reaction immunoglobulin class switch occurs and plasma cells will produce IgG, IgE or IgA-antibodies (Radbruch et al., 2006) [1].


Assuntos
Anticorpos/metabolismo , Linfócitos B/imunologia , Memória Imunológica , Infecções/imunologia , Plasmócitos/imunologia , Animais , Autoimunidade , Humanos , Imunidade Humoral , Switching de Imunoglobulina
16.
PLoS One ; 10(8): e0135081, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26252021

RESUMO

METHODS: NZB/W F1 mice were treated with: 1) anti-CD20, 2) anti-CD20 plus bortezomib, 3) anti-CD20 plus anti-LFA-1/anti-VLA-4 blocking antibodies, 4) anti-CD20 plus bortezomib and anti-LFA-1/anti-VLA4 blocking antibodies. Short- and long-lived plasma cells including autoreactive cells in the bone marrow and spleen were enumerated by flow cytometry and ELISPOT seven days after treatment. Based on these data in another experiment, mice received one cycle of anti-CD20 plus bortezomib followed by four cycles of anti-CD20 therapy every 10 days and were monitored for its effect on plasma cells and disease. RESULTS: Short-lived plasma cells in bone marrow and spleen were efficiently depleted by all regimens targeting plasma cells. Conversely, LLPCs and anti-dsDNA-secreting plasma cells in bone marrow and spleen showed resistance to depletion and were strongly reduced by bortezomib plus anti-CD20. The effective depletion of plasma cells by bortezomib complemented by the continuous depletion of their precursor B cells using anti-CD20 promoted the persistent reduction of IgG anti-dsDNA antibodies, delayed nephritis and prolonged survival in NZB/W F1 mice. CONCLUSIONS: These findings suggest that the effective depletion of LLPCs using bortezomib in combination with a therapy that continuously targeting B cells as their precursors may prevent the regeneration of autoreactive LLPCs and, thus, might represent a promising treatment strategy for SLE and other (auto)antibody-mediated diseases.


Assuntos
Linfócitos B/citologia , Bortezomib/uso terapêutico , Nefrite Lúpica/sangue , Nefrite Lúpica/tratamento farmacológico , Baço/imunologia , Animais , Antígenos CD20/metabolismo , Antineoplásicos/uso terapêutico , Autoanticorpos/imunologia , Medula Óssea/patologia , Separação Celular , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Integrina alfa4beta1/metabolismo , Nefrite Lúpica/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Plasmócitos/citologia , Regeneração , Baço/efeitos dos fármacos , Baço/patologia
17.
Arthritis Res Ther ; 17: 39, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25889236

RESUMO

INTRODUCTION: Autoantibodies contribute significantly to the pathogenesis of systemic lupus erythematosus (SLE). Unfortunately, the long-lived plasma cells (LLPCs) secreting such autoantibodies are refractory to conventional immunosuppressive treatments. Although generated long before the disease becomes clinically apparent, it remains rather unclear whether LLPC generation continues in the established disease. Here, we analyzed the generation of LLPCs, including autoreactive LLPCs, in SLE-prone New Zealand Black/New Zealand White F1 (NZB/W F1) mice over their lifetime, and their regeneration after depletion. METHODS: Bromodeoxyuridine pulse-chase experiments in mice of different ages were performed in order to analyze the generation of LLPCs during the development of SLE. LLPCs were enumerated by flow cytometry and autoreactive anti-double-stranded DNA (anti-dsDNA) plasma cells by enzyme-linked immunospot (ELISPOT). For analyzing the regeneration of LLPCs after depletion, mice were treated with bortezomib alone or in combination with cyclophosphamide and plasma cells were enumerated 12 hours, 3, 7, 11 and 15 days after the end of the bortezomib cycle. RESULTS: Autoreactive LLPCs are established in the spleen and bone marrow of SLE-prone mice very early in ontogeny, before week 4 and before the onset of symptoms. The generation of LLPCs then continues throughout life. LLPC counts in the spleen plateau by week 10, but continue to increase in the bone marrow and inflamed kidney. When LLPCs are depleted by the proteasome inhibitor bortezomib, their numbers regenerate within two weeks. Persistent depletion of LLPCs was achieved only by combining a cycle of bortezomib with maintenance therapy, for example cyclophosphamide, depleting the precursors of LLPCs or preventing their differentiation into LLPCs. CONCLUSIONS: In SLE-prone NZB/W F1 mice, autoreactive LLPCs are generated throughout life. Their sustained therapeutic elimination requires both the depletion of LLPCs and the inhibition of their regeneration.


Assuntos
Autoanticorpos/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Animais , Diferenciação Celular/fisiologia , Senescência Celular/fisiologia , Progressão da Doença , Feminino , Lúpus Eritematoso Sistêmico/terapia , Camundongos , Camundongos Endogâmicos NZB
18.
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
20.
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
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