ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 0617

Hereditary C1q Deficiency Is Associated with Type 1 Interferon-pathway Activation and a High Risk of Central Nervous System Inflammation

Clément triaille1, Neha Mohan Rao2, Gillian Rice3, Luis Seabra4, Sutherland Fraser5, Vincent Bondet6, Darragh duffy6, Andrew Gennery7, Benjamin Fournier8, Brigitte Bader-Meunier9, Christopher Troedson10, Gavin CLeary11, Helena Buso12, Jacqueline Dalby-Payne13, Ranade Prajakta14, Katrien Jansen15, Lien De Somer16, Marie-Louise Fremond17, Pimple Pallavi14, Melanie Wong18, Russel Dale10, Carine Wouters16, PIERRE QUARTIER19, Raju Khubchandani20 and Yanick Crow5, 1Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium, Brussels, Belgium, 2NH SRCC hospital, Department of Pediatric Rheumatology, Mumbai, Maharashtra, India, Mumbai, 3Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom, Manchester, 4Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, INSERM UMR1163, Paris, France, Paris, France, 5MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom, Edinburgh, United Kingdom, 6Translational Immunology Unit, Institut Pasteur, Université Paris-Cité, Paris, France, Paris, France, 7: Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom, Newcastle, United Kingdom, 8Paediatric Immunology-Hematology and Rheumatology Unit, Necker Hospital, APHP Centre, Université Paris-Cité, Paris, France, Paris, France, 9Necker Hospital, Assistance Publique Hopitaux de Paris, Paris, France, 10T. Y. Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Westmead, New South Wales, and University of Sydney, Australia, Sydney, Australia, 11: Paediatric Rheumatology, Alder Hey Children's Hospital, Liverpool, United Kingdom, Liverpool, United Kingdom, 12Department of Medicine - DIMED, University of Padova, Padova, Italy, Padova, Italy, 13Specialty of Child and Adolescent Health, Faculty of Medicine, The University of Sydney, Australia, Sydney, Australia, 14NH SRCC hospital, Department of Pediatric Rheumatology, Mumbai, Maharashtra, India, Mumbai, India, 15Division of Pediatric Neurology, Department of Pediatrics, University Hospitals Leuven, Belgium, Leuven, Belgium, 16Division of Pediatric Rheumatology, Department of Pediatrics, University Hospitals Leuven, Belgium, Leuven, Belgium, 17Paediatric Immunology-Hematology and Rheumatology Unit, Necker Hospital, APHP Centre, Université Paris-Cité, Paris, France, Paris, United Kingdom, 18Department of Allergy and Immunology, Children's Hospital at Westmead, Westmead, Australia, Westmead, Australia, 19Université Paris-Cite, IMAGINE Institute, Necker Children’s Hospital, Paris Cedex 15, France, 20SRCC Childrens Hospital, Mumbai, India

Meeting: ACR Convergence 2024

Keywords: , , ,

Session Information

Date: Saturday, November 16, 2024

Title: SLE – Diagnosis, Manifestations, & Outcomes Poster I

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: To report on the largest cohort of C1Q deficient (C1QDef ) patients; to investigate the activation of Type 1 interferon pathway in the blood  and cerebrospinal fluid (CSF) of C1QDef patients; and to describe response to Janus Kinase Inhibitor (JAKi) in three C1QDef patients.

Methods: Patients were recruited through an international collaborative effort. Phenotypic and genotypic data were retrospectively collected. Expression of ISGs in the peripheral blood of patients and controls was assessed using quantitative reverse transcription polymerase chain reaction or a NanoString. ISGs expression from canonical monogenic interferonopathies were used for comparison. Measurement of IFNα levels in serum and CSF was performed using SIMOA (single molecule array) technology.

Results: Twelve C1QDef patients were recruited (10/12 with biallelic mutations in C1QA, one in C1QB and one in C1QC). All patients received multiple immune suppressive therapies (n=12/12), fresh-frozen plasma transfusion (n=2/12), plasma-exchange (n=1/12) or stem-cell transplantation (n=2/12). After a median follow-up period of 83.5 months (range 48-168), 4/12 patients had died, and another 7/12 had developed mild to severe neurological sequalae.

Most patients demonstrated mucocutaneous manifestations (11/12). CNS involvement was recorded in 11/12 (basal ganglia calcification, CNS vasculitis, moyamoya disease, encephalitis involving the basal ganglia, cerebral atrophy and pachy-meningitis). Renal disease and major infections were rare (2/12). Most patients tested positive for ANA (anti-nuclear antibodies) and anti-Ro antibodies (10/12 and 9/12, respectively).

We assessed ISG expression in the whole blood of 10 patients, recording an elevated expression in all patients. The interferon signature was found to be in the range of the canonical monogenic interferonopathies Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy. In addition, IFNα protein measurement in serum and CSF of two patients with CNS involvement were also elevated.

Three patients in our cohort were treated with JAKi, with differing outcomes. One patient displayed a dramatic improvement in cutaneous and meningeal inflammation. A second patient displayed a moderately positive response on skin disease. The last patient with severe disease flare did not respond.

Conclusion: Altogether, our data illustrate the severity of C1QDef, which is associated with significant morbidity (in particular, relating to CNS involvement) and increased mortality. C1QDef patients display biological, clinical and radiological similarities with canonical monogenic interferonopathies. Finally, we report a variable therapeutic response to JAKi, thereby emphasising the need for further research to better tailor therapy.

Disclosures: C. triaille: None; N. Mohan Rao: None; G. Rice: None; L. Seabra: None; S. Fraser: None; V. Bondet: None; D. duffy: None; A. Gennery: None; B. Fournier: None; B. Bader-Meunier: None; C. Troedson: None; G. CLeary: None; H. Buso: None; J. Dalby-Payne: None; R. Prajakta: None; K. Jansen: None; L. De Somer: None; M. Fremond: None; P. Pallavi: None; M. Wong: None; R. Dale: None; C. Wouters: None; P. QUARTIER: Abbvie, 2, 5, 6, BMS, 2, 5, 6, Chugai-Roche, 2, 5, 6, Novartis, 2, 5, 6, Pfizer, 2, 5, 6, Sweedish Orphan Biovitrum, 2, 5, 6; R. Khubchandani: None; Y. Crow: None.

To cite this abstract in AMA style:

triaille C, Mohan Rao N, Rice G, Seabra L, Fraser S, Bondet V, duffy D, Gennery A, Fournier B, Bader-Meunier B, Troedson C, CLeary G, Buso H, Dalby-Payne J, Prajakta R, Jansen K, De Somer L, Fremond M, Pallavi P, Wong M, Dale R, Wouters C, QUARTIER P, Khubchandani R, Crow Y. Hereditary C1q Deficiency Is Associated with Type 1 Interferon-pathway Activation and a High Risk of Central Nervous System Inflammation [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/hereditary-c1q-deficiency-is-associated-with-type-1-interferon-pathway-activation-and-a-high-risk-of-central-nervous-system-inflammation/. Accessed .

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