Background/Purpose: Urticarial skin lesions are well-known features of autoinflammatory disorders associated with NLRP3 and NLRP12 variants. However hereditary forms of hypocomplementemic urticarial vasculitis (HUV) with or without lupus features have been associated with DNASE1L3 variants in limited number of Turkish, Arabic and Italian families. We herein aimed to define the clinical phenotype and treatment responses of a patient with HUV due to a homozygous deleterious variant of a novel gene, AGBL3 (ATP/GTP binding protein-like 3).

Methods: Last year we described a novel gene variant in a patient with autoinflammatory features and HUV, who was negative for DNASE1L3 variants. Whole exome sequencing of the genomic DNA revealed a deleterious homozygous c.769C >T mutation in AGBL3 gene, which results in early termination of the protein (p.Gln257Ter) and deletion of the functional carboxypeptidase domain. The 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. We herein describe the clinical features and treatment responses of the index case.

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 2-3 days lasting attacks started when he was 13 and recurred more frequently at warm 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, but no obvious clinical and laboratory response could be seen with canakinumab and anakinra treatments. Following serologic evolution of the disease, his treatment was switched to rituximab. A favorable response both in clinical and laboratory findings was observed following two cycles of 1g infusions at 2-week intervals. He developed less frequent and milder attacks, which occurred only after infections; and acute phase response was reduced to near normal values in between attacks.

Conclusion: This case reveals AGBL3 metallocarboxypeptidase gene as a novel autoinflammatory gene associated with hypocomplementemic urticarial vasculitis. Potential pathogenic mechanisms and clinical picture are considered to be different from DNASE1L3 variants, which are also associated with monogenic lupus and defects in DNA clearance. Long term follow-up and search for other patients associated with AGBL3 variants among DNASE1L3-variant-negative hypocomplementemic urticarial vasculitis patients are required for better clarification of the AGBL3-associated clinical phenotype.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/agbl3-as-a-novel-gene-associated-with-hereditary-hypocomplementemic-urticarial-vasculitis-and-favorable-response-to-rituximab/