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In: Parasitology Research, Springer Science and Business Media LLC, Vol. 74, No. 2 ( 1987), p. 112-115

Type of Medium: Online Resource

ISSN: 0044-3255 , 1432-1955

URL: Article

DOI: 10.1007/BF00536021

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 1987

detail.hit.zdb_id: 1462976-8

detail.hit.zdb_id: 2573958-X

In: npj Genomic Medicine, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2022-10-05)

Abstract: Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A , C4B , and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4 -independent signals.

Type of Medium: Online Resource

ISSN: 2056-7944

URL: Article

DOI: 10.1038/s41525-022-00327-8

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2813848-X

In: Lupus, SAGE Publications, Vol. 18, No. 3 ( 2009-03), p. 257-263

Abstract: Systemic lupus erythematosus (SLE) is a complex, multisystem autoimmune disorder, which often involves referral to multiple medical specialists. Lupus nephritis (LN) occurs in ~35% of adults with SLE and predicts poor survival. There is currently no consensus on how to manage patients with SLE or LN across specialties and across different European countries. The Lupus Nephritis Terminology Advisory Group was formed to address this issue as it impacts upon LN treatment. It has developed consensus statements based on opinions from expert panel meetings with nephrologists, nephropathologists, rheumatologists, clinical immunologists and internal medicine specialists from many European countries, after reviewing current guidelines from the European League Against Rheumatism, the American College of Rheumatology and the participants’ experience. In this article, we report consensus statements that were developed in six important areas: classification of patients with LN, how classification affects the selection of treatment options and definitions of induction, response, flare and maintenance. We have also proposed a consensus for the terminology involved in the management of LN that is consistent with clinical opinion gathered from multidisciplinary expert meetings and with existing guidelines. We believe this consensus approach provides agreed expert opinion to clinicians and will form the basis for optimising LN treatment.

Type of Medium: Online Resource

ISSN: 0961-2033 , 1477-0962

URL: Article

DOI: 10.1177/0961203308100481

Language: English

Publisher: SAGE Publications

Publication Date: 2009

detail.hit.zdb_id: 2008035-9

In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 1493.3-1493

Abstract: Depletion of long-lived plasma cells (PC) resembles a novel concept for the treatment of antibody-mediated autoimmune diseases, such as systemic lupus erythematosus (SLE). Therapeutic approaches such as autologuos stem-stem cell transplantation and proteasome inhibition are limited by significant treatment-related toxicity. A novel target for PC depletion is CD38, a surface protein that is highly expressed on plasma cells (PCs) but also activated T-cells and most myeloid cells. Daratumumab is a monoclonal antibody targeting CD38 that is licensed for the treatment of multiple myeloma. Objectives: Here, we aimed to ascertain clinical safety and efficacy of Daratumumab for the treatment of refractory SLE, as well as to gain insights into effects of Daratumumab on the immune system. Methods: We treated two SLE patients with life- and organ-threatening SLE with four weekly dosis of 16 mg/kg Daratumumab. We performed integrative analyses of clinical, serological and immunological effects over a follow-up period of 6 months. Using flow cytometry and single-cell RNA and T-cell receptor sequencing we followed CD38 expression and composition of peripheral blood leukocytes with a special focus on memory T cells. Results: Patient 1, a 50-year old woman, suffered from active biopsy-proven class III lupus nephritis (LN) with nephrotic syndrome, pericarditis, arthritis and skin rash. Upon Daratumumab treatment, her glomerular filtration rate normalized within 3 months and proteinuria gradually declined from 6.4 to 1.9g/g Creatinine during the 180-day follow-up period. Pericarditis, arthritis and skin rash completely resolved. Patient 2, a 32-year-old woman, presented with autoimmune hemolytic anemia requiring blood transfusions, immune thrombocytopenia and cutaneous vasculitis. Her direct antiglobulin test normalized within 3 months and remained negative throughout follow-up with consecutive recovery of the hemolytic anemia. Immune thrombocytopenia stabilized and vasculitic skin lesions completely resolved. Infusions were well tolerated without severe adverse drug reactions. NK cells and Dendritic Cells were transiently depleted, while numbers of T cells, B cells and Monocytes in the peripheral blood remained stable. CD38+ memory T cells that were expanded prior to treatment were virtually undetectable early after treatment. Their single cell transcriptomics demonstrated an upregulation of genes associated with activation, cytotoxicity and type 1 interferon response. CD38+ CD8+ memory T-cells showed marked oligoclonality. These prominent clones persisted upon treatment but their transcription profile gradually normalized. Conclusion: Daratumumab appears to be a safe and effective treatment for refractory SLE. Further investigations are warranted to establish the efficacy in a clinical trial and to gain further insights into the pathophysiologic mechanism of action. Disclosure of Interests: Lennard Ostendorf: None declared, Udo Schneider: None declared, Marie Urbicht: None declared, Philipp Enghard: None declared, Frederik Heinrich: None declared, Pawel Durek: None declared, Gitta Heinz: None declared, Henrik Mei: None declared, Mir-Farzin Mashreghi: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Andreas Radbruch: None declared, Falk Hiepe: None declared, Tobias Alexander: None declared

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2020-eular.5052

Language: English

Publisher: BMJ

Publication Date: 2020

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 362.1-362

Abstract: EULAR/ACR 2019 SLE Classification Criteria were validated in an international cohort. Objectives: To evaluate performance characteristics of SLE classification systems in sex, race/ethnicity, and disease duration subsets. Methods: Sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated in the validation cohort. 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; and patients with an SLE duration of 1-3 years (n=196), 3-5 years (n=157), and ≥5 years (n=879). Among patients with 1-3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% (95%CI 92-99%) vs 81% (95%CI 72-88%). The new criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). The new criteria had better sensitivity than the ACR criteria in White (95% vs 83%), Hispanic (100% vs 86%) and Asian patients (97% vs 77%). Conclusion: The EULAR/ACR 2019 criteria perform well in patients with early disease, and across sexes and ethnicities. Disclosure of Interests: Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Ralph Brinks: None declared, Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca, David Daikh: None declared, Marta Mosca: None declared, Rosalind Ramsey-Goldman: None declared, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer, Roche – grant/research support, Consultant of: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – consultant, Speakers bureau: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – speaker, David Wofsy: None declared, Dimitrios Boumpas Grant/research support from: Unrestricted grant support from various pharmaceutical companies, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Ricard Cervera: None declared, Nathalie Costedoat-Chalumeau Grant/research support from: UCB to my institution, Betty Diamond: None declared, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Bevra H. Hahn Grant/research support from: Janssen Research & Development, LLC, Falk Hiepe: None declared, Soren Jacobsen: None declared, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB, Kirsten Lerstrom: None declared, Elena Massarotti: None declared, William Joseph McCune: None declared, Guillermo Ruiz-Irastorza: None declared, Jorge Sanchez-Guerrero: None declared, Matthias Schneider: None declared, Murray B Urowitz: None declared, George Bertsias Grant/research support from: GSK, Consultant of: Novartis, Bimba F. Hoyer: None declared, Nicolai Leuchten: None declared, Chiara Tani: None declared, Sara Tedeschi: None declared, Zahi Touma: None declared, Gabriela Schmajuk Grant/research support from: Pfizer, Branimir Anic: None declared, Florence Assan: None declared, Tak Chan: None declared, Ann E Clarke: None declared, Mary K. Crow: None declared, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Winfried Graninger: None declared, Bernadett Halda-Kiss: None declared, Sarfaraz Hasni: None declared, Peter Izmirly: None declared, Michelle Jung: None declared, Gabor Kumanovics Consultant of: Boehringer, Teva, Speakers bureau: Roche, Lilly, Novartis, Xavier Mariette: None declared, Ivan Padjen: None declared, Jose M Pego-Reigosa: None declared, Juanita Romero-Diaz Consultant of: Biogen, Iñigo Rua-Figueroa: None declared, Raphaèle Seror Consultant of: BMS, Medimmune, Novartis, Pfizer, GSK, Lilly, Georg Stummvoll: None declared, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Maria Tektonidou Grant/research support from: AbbVie, MSD, Novartis and Pfizer, Consultant of: AbbVie, MSD, Novartis and Pfizer, Carlos Vasconcelos: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK, Daniel J Wallace: None declared, Sule Yavuz: None declared, Pier Luigi Meroni: None declared, Marvin Fritzler: None declared, Raymond Naden: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen, Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2020-eular.2324

Language: English

Publisher: BMJ

Publication Date: 2020

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 69, No. Suppl 2 ( 2010-03-01), p. A11-A11

Type of Medium: Online Resource

ISSN: 0003-4967

URL: Article

DOI: 10.1136/ard.2010.129585a

Language: English

Publisher: BMJ

Publication Date: 2010

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 1369.2-1370

Abstract: Plasma Cells (PCs) are implicated in the pathogenesis of Systemic Lupus erythematosus (SLE) and their targeting proved a promising treatment modality. As there is a monoclonal therapeutic antibody targeting CD38 licensed for clinical use in multiple myeloma, plasma cell depletion via CD38 seems to represent a promising path in SLE treatment. While CD38 Is highly expressed on plasmacells, it is present on the surface of subsets of T and B lymphocytes as well as myeloid cells. Objectives: Here we aim to identify the differential expression of CD38 on peripheral blood leukocytes in SLE compared to healthy controls (HC) investigate the function of CD38+ T lymphocytes Methods: We performed flow cytometry to investigate the expression of CD38 on peripheral blood mononuclear cells of SLE patients (n=36) and HCs (n=20). We additionally analyzed the expression of T lymphocytes within the urine of patients with lupus nephritis as well as the skin of SLE patients. We investigated the inflammatory potential of CD38 positive memory T lymphocytes after stimulation and performed single-cell RNA sequencing analyses. Results: CD38 Expression is increased on certain immune cell subsets: Plasmablasts and unswitched Memory B cells, as well as plasmacytoid dendritic cells and CD16+ non-classical monocytes. We observed a drastic increase CD38 in both memory CD4 and CD8 T lymphocytes in SLE patients. These cells were mostly effector T cells (and not regulatory T cells) and expressed other markers of T cell activation and proliferation. We found an enrichment of CD38+ memory T cells in the urine of patients with lupus nephritis. After polyclonal stimulation of T cells, CD38+ produced less inflammatory cytokines. Preliminary single-cell sequencing results indicate that CD38+ CD8+ T-lymphocytes have decreased clonal diversity and that these cells express genes associated with exhaustion and type 1 interferon response. Conclusion: Increased CD38 expression on various lymphocyte subsets provides an additional rationale for investigating CD38-directed therapies in SLE. Targeting CD38 could not only deplete plasma cells but also has the potential to target interferon alpha producing plasmacytoid dendritic cells and modulate inflammatory T cell functions. Disclosure of Interests: Lennard Ostendorf: None declared, Philipp Enghard: None declared, Pawel Durek: None declared, Frederik Heinrich: None declared, Mir-Farzin Mashreghi: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Andreas Radbruch: None declared, Falk Hiepe: None declared, Tobias Alexander: None declared

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2020-eular.6531

Language: English

Publisher: BMJ

Publication Date: 2020

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 80, No. Suppl 1 ( 2021-06), p. 207.1-207

Abstract: We recently reported the beneficial clinical responses of the anti-CD38 monoclonal antibody daratumumab in two patients with systemic lupus erythematosus (SLE) [1]. While the primary rationale for its use was the depletion of autoantibody-producing long-lived plasma cells, daratumumab may promote additional therapeutic effects on CD38-expressing T cells, but their origin, lifestyle and role in lupus pathophysiology remains elusive. Objectives: To investigate the phenotype, transcriptional program, functional properties and clinical associations of CD4+ and CD8+CD38+ memory T cells in SLE compared to healthy controls (HC). Methods: CD38-expression on memory T cell subsets was measured by flow cytometry in 65 patients with SLE and 28 healthy controls. We investigated the functional capacity of CD38+ T cells using CFSE staining and intracellular cytokine staining after polyclonal stimulation. Additionally, we performed single-cell transcriptome and T-cell-receptor sequencing of 7 SLE patients and 7 matched healthy controls, including surface protein expression analysis using CITE-seq (RNA-barcoded) antibodies. Results: Compared to healthy controls, the frequency of CD38-expressing memory T cells in SLE was significantly increased in both CD4+ and CD8+ T cells. SLE patients with a previous or current lupus nephritis had significantly increased levels of CD8+CD38+ memory T cells compared to those without history of renal involvement. CD38+ memory T cells expressed increased levels of Ki-67 and displayed higher proliferative capacity upon polyclonal stimulation than their CD38- counterparts, both in SLE patients and HC, while they showed decreased ability to secrete IFN-γ, IL-2, GM-CSF and TNF-α. Single-cell transcriptome sequencing revealed that CD8+CD38+ memory T cells were enriched within terminally differentiated, cytotoxic CD8 T cells, and had reduced TCR repertoire diversity compared to their CD38- counterparts. CD8+CD38+ memory T cells from SLE patients had significantly higher expression of type I interferon associated genes, both compared to CD38- memory T cells from SLE patients and CD38+ cells from HCs. Conclusion: CD38+ memory T cells with increased proliferative capacity but altered effector functions are significantly expanded in peripheral blood of SLE and correlate with the lupus nephritis. Although the factors mediating their generation and their precise role in the disease pathophysiology remain to be investigated, CD38-expressing T cells may be useful as a future biomarker for lupus nephritis. References: [1]Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, et al. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149–55. [2]Katsuyama E, Suarez-Fueyo A, Bradley SJ, Mizui M, Marin AV, Mulki L, et al. The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections. Cell Reports. 2020 Jan;30(1):112-123.e4. Acknowledgements: We thank our patients and healthy controls for making our research possible. Disclosure of Interests: None declared.

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2021-eular.3104

Language: English

Publisher: BMJ

Publication Date: 2021

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 53, No. 12 ( 1994-12-01), p. 798-800

Type of Medium: Online Resource

ISSN: 0003-4967

URL: Article

DOI: 10.1136/ard.53.12.798

Language: English

Publisher: BMJ

Publication Date: 1994

detail.hit.zdb_id: 1481557-6

In: Clinical Rheumatology, Springer Science and Business Media LLC, Vol. 16, No. 6 ( 1997-11), p. 562-569

Type of Medium: Online Resource

ISSN: 0770-3198 , 1434-9949

URL: Article

DOI: 10.1007/BF02247796

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 1997

detail.hit.zdb_id: 1480901-1