Effect of in vivo Hydroxychloroquine and ex vivo Anti-BDCA2 mAb Treatment on pDC IFNα Production From Patients Affected With Cutaneous Lupus Erythematosus

Objective: Plasmacytoid dendritic cells (pDCs) are a major source of Type-I Interferon (IFN-I), a key driver in cutaneous lupus erythematosus (CLE). Currently evaluated in Phase II clinical trial, 24F4A (BIIB059) is an antibody targeting BDCA2, an inhibitory receptor expressed on pDCs. Given that Hydroxychloroquine (HCQ), a widely-used CLE therapy, and 24F4A are both able to inhibit pDC-derived IFN-I production; this study aimed to determine whether 24F4A would show an additional inhibitory effect on pDC response after ex vivo or in vivo treatment with HCQ. Methods: The effect of 24F4A on pDC-derived IFNα was measured from peripheral blood mononuclear cells (PBMC) either from healthy donors in presence or absence of HCQ or from CLE patients clinically exposed to various levels of HCQ. TLR7, TLR7/8, and TLR9 agonists (ssRNA, R848, and CpG-A) were used for pDC stimulation. Results: PDCs were the only producers of IFNα in response to CpG-A, R848, and ssRNA stimulation in PBMC cultures. CLE patients with higher levels of blood HCQ showed lower ex vivo pDC responses to CpG-A, but not R848 or ssRNA. In contrast, 24F4A reduced the amount of IFNα produced by pDCs from CLE patients in response to all TLR agonists, irrespective of the blood HCQ level. Conclusion: Our findings reveal that clinically-relevant HCQ concentrations partially inhibit the pDC response to TLR9 and weakly affect the response to TLR7/8 stimulation. 24F4A robustly inhibits pDC responses even in the presence of HCQ, highlighting its unique potential to disrupt pDC disease relevant biology, which could provide additional therapeutic benefit for CLE patients.

[1]  P. Auluck,et al.  Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus , 2019, The Journal of clinical investigation.

[2]  L. Rönnblom,et al.  Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor , 2018, Arthritis Research & Therapy.

[3]  R. Landewé,et al.  Are gender-specific approaches needed in diagnosing early axial spondyloarthritis? Data from the SPondyloArthritis Caught Early cohort , 2018, Arthritis Research & Therapy.

[4]  V. Werth,et al.  Quinacrine Suppresses Tumor Necrosis Factor-α and IFN-α in Dermatomyositis and Cutaneous Lupus Erythematosus. , 2017, The journal of investigative dermatology. Symposium proceedings.

[5]  C. Huard,et al.  Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis , 2017, The British journal of dermatology.

[6]  C. Ponticelli,et al.  Hydroxychloroquine in systemic lupus erythematosus (SLE) , 2017, Expert opinion on drug safety.

[7]  K. Kalunian,et al.  Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus , 2017, Arthritis & rheumatology.

[8]  S. de Ridder,et al.  Type I interferon response gene expression in established rheumatoid arthritis is not associated with clinical parameters , 2016, Arthritis Research & Therapy.

[9]  L. Langman,et al.  Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis , 2016, Arthritis care & research.

[10]  T. Gambichler,et al.  Cutaneous characteristics and association with antinuclear antibodies in 402 patients with different subtypes of lupus erythematosus , 2016, Journal of the European Academy of Dermatology and Venereology : JEADV.

[11]  D. Olive,et al.  Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells , 2016, PloS one.

[12]  M. Petri,et al.  OP0187 Hydroxychloroquine Blood Levels in Sle: Clarifying Dosing Controversies and Improving Adherence , 2015 .

[13]  A. Ranger,et al.  Anti-BDCA2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc-dependent and Fc-independent mechanisms , 2015, EMBO molecular medicine.

[14]  M. Marmor,et al.  The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. , 2014, JAMA ophthalmology.

[15]  N. Costedoat-Chalumeau,et al.  Hydroxychloroquine: a multifaceted treatment in lupus. , 2014, Presse medicale.

[16]  N. Seidah,et al.  Processing of human toll-like receptor 7 by furin-like proprotein convertases is required for its accumulation and activity in endosomes. , 2013, Immunity.

[17]  C. Coch,et al.  A Human In Vitro Whole Blood Assay to Predict the Systemic Cytokine Response to Therapeutic Oligonucleotides Including siRNA , 2013, PloS one.

[18]  W. White,et al.  Pharmacogenomics and Translational Simulations to Bridge Indications for an Anti‐Interferon‐α Receptor Antibody , 2013, Clinical pharmacology and therapeutics.

[19]  V. Werth,et al.  Cutaneous lupus erythematosus: diagnosis and treatment. , 2013, Best practice & research. Clinical rheumatology.

[20]  K. Kalunian,et al.  Sifalimumab, a Human Anti–Interferon-α Monoclonal Antibody, in Systemic Lupus Erythematosus: A Phase I Randomized, Controlled, Dose-Escalation Study , 2013, Arthritis and rheumatism.

[21]  L. Criswell,et al.  Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus , 2012, Arthritis Research & Therapy.

[22]  A. Davidson,et al.  Taming lupus—a new understanding of pathogenesis is leading to clinical advances , 2012, Nature Medicine.

[23]  V. Werth,et al.  The interferon‐regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score , 2012, The British journal of dermatology.

[24]  D. Lipsker,et al.  Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. , 2012, Archives of dermatology.

[25]  P. Brown,et al.  Interferon and Biologic Signatures in Dermatomyositis Skin: Specificity and Heterogeneity across Diseases , 2012, PloS one.

[26]  T. Tenhave,et al.  Response to antimalarial agents in cutaneous lupus erythematosus: a prospective analysis. , 2011, Archives of dermatology.

[27]  S. Greenberg,et al.  Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway , 2011, Annals of the rheumatic diseases.

[28]  U. Švajger,et al.  Mechanism of Endosomal TLR Inhibition by Antimalarial Drugs and Imidazoquinolines , 2011, The Journal of Immunology.

[29]  Sarah E. Ewald,et al.  Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase , 2011, The Journal of experimental medicine.

[30]  D. Tomasini,et al.  Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner's lymphocytic infiltrate of the skin and cutaneous lupus erythematosus , 2010, Journal of cutaneous pathology.

[31]  M. Marmor,et al.  Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus , 2010, Arthritis care & research.

[32]  J. Kere,et al.  Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus , 2010, Experimental dermatology.

[33]  S. Maschalidi,et al.  Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. , 2009, Immunity.

[34]  L. Cerroni,et al.  Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage. , 2009, Immunobiology.

[35]  Marion Jurk,et al.  Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses1 , 2008, The Journal of Immunology.

[36]  June-Yong Lee,et al.  Dysfunctional interferon-α production by peripheral plasmacytoid dendritic cells upon Toll-like receptor-9 stimulation in patients with systemic lupus erythematosus , 2008, Arthritis Research & Therapy.

[37]  R. Küppers,et al.  CD303 (BDCA‐2) signals in plasmacytoid dendritic cells via a BCR‐like signalosome involving Syk, Slp65 and PLCγ2 , 2007, European journal of immunology.

[38]  T. Bieber,et al.  The expression pattern of interferon‐inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets , 2007, The British journal of dermatology.

[39]  L. Lanier,et al.  BDCA2/FcɛRIγ Complex Signals through a Novel BCR-Like Pathway in Human Plasmacytoid Dendritic Cells , 2007, PLoS biology.

[40]  P. Emery,et al.  The validity of the inclusion of "lupus headache" in the Systemic Lupus Erythematosus Disease Activity Index. , 2007, Arthritis and rheumatism.

[41]  J. Piette,et al.  Hydroxychloroquine in systemic lupus erythematosus , 2007, The Lancet.

[42]  T. Bieber,et al.  CXCR3-mediated recruitment of cytotoxic lymphocytes in lupus erythematosus profundus. , 2007, Journal of the American Academy of Dermatology.

[43]  P. Fitzgerald-Bocarsly,et al.  Receptor Cross-Linking on Human Plasmacytoid Dendritic Cells Leads to the Regulation of IFN-α Production1 , 2006, The Journal of Immunology.

[44]  D. Furst,et al.  Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. , 2006, Arthritis and rheumatism.

[45]  J. Berlin,et al.  The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. , 2005, The Journal of investigative dermatology.

[46]  A. Zlotnik,et al.  Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus. , 2005, Arthritis and rheumatism.

[47]  M. Dall'era,et al.  Type I interferon correlates with serological and clinical manifestations of SLE , 2005, Annals of the rheumatic diseases.

[48]  M. Tomai,et al.  Synthetic TLR Agonists Reveal Functional Differences between Human TLR7 and TLR8 , 2005, The Journal of Immunology.

[49]  D. Golenbock,et al.  Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. , 2005, The Journal of clinical investigation.

[50]  D. Gladman,et al.  Systemic lupus erythematosus disease activity index 2000. , 2002, The Journal of rheumatology.

[51]  S. Miltenyi,et al.  BDCA-2, BDCA-3, and BDCA-4: Three Markers for Distinct Subsets of Dendritic Cells in Human Peripheral Blood , 2000, The Journal of Immunology.

[52]  G. Sturfelt,et al.  Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies , 2000, Lupus.

[53]  N. Kadowaki,et al.  The nature of the principal type 1 interferon-producing cells in human blood. , 1999, Science.

[54]  M. Hochberg,et al.  Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. , 1997, Arthritis and rheumatism.

[55]  U. Mansmann,et al.  Markers in cutaneous lupus erythematosus indicating systemic involvement. A multicenter study on 296 patients. , 1997, Acta dermato-venereologica.

[56]  D. Crosby,et al.  Systemic disease in subacute cutaneous lupus erythematosus: a controlled comparison with systemic lupus erythematosus. , 1994, The Journal of rheumatology.

[57]  R. Day,et al.  Bioavailability of hydroxychloroquine tablets in patients with rheumatoid arthritis. , 1994, British journal of rheumatology.

[58]  L. Golitz,et al.  Clinical, histologic, and immunofluorescent distinctions between subacute cutaneous lupus erythematosus and discoid lupus erythematosus. , 1992, The Journal of investigative dermatology.

[59]  V. Werth,et al.  Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: A retrospective cohort study , 2018, Journal of the American Academy of Dermatology.

[60]  Dennis Andersson,et al.  A retrospective cohort study , 2018 .

[61]  M. Dew,et al.  A Prospective Analysis , 2015 .

[62]  P A Dekker-de Kiefte,et al.  Diagnosis and Treatment , 2020, Diabetes.

[63]  Joan Abbott-chapman,et al.  Longitudinal Cohort Analysis , 1992 .