FAVORABLE RESPONSE TO RITUXIMAB IN A PATIENT WITH HYPOCOMPLEMENTEMIC URTICARIAL VASCULITIS ASSOCIATED WITH A HOMOZYGOUS FRAMESHIFT AGBL3 VARIANT

Background: Last year we described a homozygous AGBL3 variant in a patient with autoinflammatory features and hypocomplementemic urticarial vasculitis. Whole exome sequencing revealed a deleterious homozygous c.769C\u003eT mutation in AGBL3 (ATP/GTP binding protein-like 3) gene, which results in early termination of the protein (p.Gln257Ter) and deletion of the functional carboxypeptidase domain. This protein belongs to metallocarboxypeptidases that mediate both deglutamylation and deaspartylation of target proteins, and AGBL3 is suggested to catalyze the deglutamylation of polyglutamate side chains, especially in proteins such as tubulins. This variant was not found before in all reported databases including 1000 Genomes Project data. Objectives: To define the clinical phenotype and treatment responses of a patient with newly defined monogenic hypocomplementemic urticarial vasculitis associated with a homozygous AGBL3 variant. Methods: We collected all clinical, serologic, and pathological data regarding the clinical findings of the index case as well as recorded all treatment responses throughout the follow-up period during the last 8 years. Results: The index case was 23-year-old male patient of Assyrian origin, who had consanguineous parents. He was evaluated in our clinic because of recurrent attacks of fever, urticarial rash on the extremities and trunk, conjunctival injections and arthralgia, without a trigger or more frequently following an infection. His 2 to 3 days lasting attacks started when he was 13 and recurred more frequently during warm weather conditions or following hot baths. He had highly elevated CRP and ESR during attacks, but his acute phase response did not return to normal values in between the flares. Low C3 and C4 values were also observed during asymptomatic periods. His ANA test became positive during the course of his disease with an increase in titers during the last years. The biopsy of skin lesions revealed findings compatible with urticarial vasculitis. He responded only partially to corticosteroids, canakinumab and anakinra treatments. His treatment was switched to rituximab last year, and a favorable response was observed following the first two infusions. He developed less frequent and milder attacks only after infections, and acute phase response was reduced to near normal values in between attacks. Conclusion: The AGBL3 metallocarboxypeptidase gene was recently idenfied as a novel autoinflammatory gene associated with hypocomplementemic urticarial vasculitis phenotype, and it was different from the previously defined variants including DNASE1L3 mutations. The clinical features of the index case included both autoinflammatory and autoimmune findings including autoantibodies; and his inflammatory attacks did respond to rituximab treatment but not IL-1 blockade. Long term follow-up and search for other patients associated with AGBL3 variants among idiopathic hypocomplementemic urticarial vasculitis are required for better clarification of the AGBL3-associated clinical phenotype. Disclosure of Interests: None declared