Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial

Humrich, Jens Y; Spee-Mayer, Caroline von; Siegert, Elise; Bertolo, Martina; Rose, Angelika; Abdirama, Dimas; Enghard, Philipp; Stuhlmüller, Bruno; Sawitzki, Birgit; Huscher, Dörte; Hiepe, Falk; Alexander, Tobias; Feist, Eugen; Radbruch, Andreas; Burmester, Gerd‐Rüdiger; Riemekasten, Gabriela

doi:10.1016/s2665-9913(19)30018-9

Cited by 63 publications

(76 citation statements)

References 24 publications

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“…Hierzu gehören neue B-Zell-depletierende Anti-CD20-Antikörper, Antikörper, die die B-T-Zell-Kostimulation inhibieren, und die Immunmodulation durch regulatorische T-Zellen. Regulatorische T-Zellen können durch Injektion von niedrig-dosiertem IL2, das beim SLE vermindert ist, stimuliert werden, was bei chronisch-aktiven Patienten zu einer klinischen Verbesserung geführt hat [21]. Alle diese therapeutischen Konzepte haben keinen Einfluss auf die existierenden langlebigen Plasmazellen im Knochenmark.…”

Section: B-zell-hyperaktivitätunclassified

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

Hiepe

2020

Aktuelle Rheumatologie

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ZusammenfassungAutoantikörper sind essentiell in der Pathogenese des SLE. Sie sind das Ergebnis einer Störung des erworbenen (adaptiven) Immunsystems mit fehlender Toleranz gegen Selbst. Eine Typ-I Interferon-Signatur, die im angeborenen (innaten) Immunsystem ihren Ursprung hat, ist ein wesentlicher Treiber dieser Störung. Autoantikörper können sowohl von kurzlebigen, proliferierenden Plasmablasten, die B-Zell-Hyperaktivität widerspiegeln, als auch von langlebigen, nicht-proliferierenden Gedächtnis-Plasmazellen sezerniert werden. Gedächtnis-Plasmazellen, die in Nischen im Knochenmark und im entzündeten Gewebe lokalisiert sind, lassen sich nicht durch konventionelle Immunsuppressiva und Therapien mit B-Zellen als Target eliminieren. Konzepte, die auf die Depletion von Gedächtnis-Plasmazellen abzielen, können im Zusammenspiel mit Targets, die eine Aktivierung von autoreaktiven B-Zellen verhindern, ein kuratives Potenzial haben.

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Section: B-zell-hyperaktivitätunclassified

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

Hiepe

2020

Aktuelle Rheumatologie

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“…Disturbances in regulatory T cell (Treg) homeostasis from the acquired deficiency of interleukin-2 (IL-2) contribute to SLE pathogenesis [66,67]. Low-dose IL-2 therapy is now being evaluated in clinical trials as it has been shown to restore Treg homeostasis in SLE [68][69][70][71]. Interestingly, there was no difference in the serum levels of IL-2 autoantibodies between responders and non-responders to low dose recombinant IL-2 therapy in one study [56], although the development of treatment induced neutralizing antibodies to IL-2 has been previously reported [72].…”

Section: Therapy With Cytokines and Cytokine Immunization In Slementioning

confidence: 99%

Anti-Cytokine Autoantibodies in Systemic Lupus Erythematosus

Howe

Leung

2019

Cells

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Cytokine dysregulation is characteristic of systemic lupus erythematosus (SLE), a systemic autoimmune disease of considerable heterogeneity. Insights gained about the cytokine dysregulation in SLE have the potential for identifying patient subsets before the onset of clinical disease and during established disease. Clustering patients by cytokine and disease activity subsets is more informative than isolated cytokine studies, as both pro inflammatory and immunoregulatory cytokines contribute to the cytokine dysregulated state in SLE. Endogenous anti-cytokine autoantibodies (ACAAs) may be involved in the regulation of cytokine biology by reducing excessive production or by prolonging their half-life in the circulation through the formation of cytokine-antibody immune complexes. Although endogenous ACAAs may have deleterious effects such as contributing to immunodeficiency states, their role in the pathophysiology of autoimmune conditions such as SLE has yet to be clearly elucidated. The aim of the present article is to provide a focused review of the current knowledge of ACAAs in SLE.

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“…Richard Furie, 2 Matthew D Cascino, 2 Jay P Garg, 3 Gustavo Aroca, 4 Analía Alvarez, 5 Hilda Fragoso-Loyo, 6 Elizabeth Zuta Santillán, 7 Ana Malvar, 2 Paul G Brunetta, 8 Thomas Schindler, 2 Cary Michael Donna Looney, 9 Imran Hassan, 10 Brad H Rovin.…”

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confidence: 99%

“…Northwell Health Great Neck, New York; 2 Genentech, Inc., South San Francisco, USA; 3 Simon Bolivar University y Clinica de la Costa, Barranquilla, Colombia; 4 CEMIC, Buenos Aires, Argentina; 5 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; 6 Instituto de Ginecología y Reproducción, Lima, Peru; 7 Organización Maedica de Investigación, Buenos Aries, Argentina; 8 F. Hoffmann-La Roche AG, Basel, Switzerland; 9 Hoffmann-La Roche Ltd, Mississauga, Canada; 10 Ohio State University, Columbus, USA 10.1136/lupus-2020-eurolupus.46…”

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O35 B-cell depletion and response in a randomized, controlled trial of obinutuzumab for proliferative lupus nephritis

Furie

Cascino²,

Garg³

et al. 2020

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Methods The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN and LN-negative patients. SNPs with a p-value <0.001 in the LN vs LN-negative analysis in the discovery cohort (n SNPs =139) were analyzed in replication cohort 1. Ten SNPs associated to LN (p<0.0002) in the discovery cohort were genotyped in replication cohort 2. A Bonferroni-corrected p-value of <1.0×10-6 correcting for 48,000 independent SNPs was considered significant. Results In the discovery cohort, strong association to LN was found with several highly linked SNPs in BANK1, with the top signal in the intronic SNP rs4699261 (p=9.9×10-5 , OR 0.66). The association was also present in replication cohort 1 (p=9.5×10-4). In a meta-analysis of the discovery and replication cohort 1, a total of 20 SNPs in BANK1 were associated to LN with the highest signal in rs4699261 (p=3.3×10-7). There was a tendency towards association in replication cohort 2 (p=0.05) and in a meta-analysis of all cohorts, the association with BANK1 was strengthened (p=1.7×10-7). Conclusion BANK1 variations are associated with LN in patients with SLE. Upregulated BANK1 expression in renal biopsies from LN patients has previously been shown, however the exact role of BANK1 in LN pathogenesis remains to be elucidated.

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Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial

Cited by 63 publications

References 24 publications

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

Anti-Cytokine Autoantibodies in Systemic Lupus Erythematosus

O35 B-cell depletion and response in a randomized, controlled trial of obinutuzumab for proliferative lupus nephritis

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