Deficiency of Interleukin-1 Receptor Antagonist: A Case with Late Onset Severe Inflammatory Arthritis, Nail Psoriasis with Onychomycosis and Well Responsive to Adalimumab Therapy

Abstract

DIRA (deficiency of the IL-1Ra) is a rare condition that usually presents in the neonatal period. Patients with DIRA present with systemic inflammation, respiratory distress, joint swelling, pustular rash, multifocal osteomyelitis, and periostitis. Previously, we reported a patient with a novel mutation in IL1RN with a healthy neonatal period, a late-onset of pustular dermatosis, inflammatory arthritis, and excellent response to canakinumab treatment. Herein, we are presenting a new case of late-onset DIRA syndrome, carrying a different mutation and showing different clinical findings. This patient is the first one in the literature with the inflammatory arthritis, nail psoriasis, and onychomycosis and with her remarkable response to monoclonal antibodies. The case responded well and fully recovered after treatment with adalimumab, but not with canakinumab. The DIRA disease can lead to death from multiple organ failures and if recognized early, the treatment with replacement of the deficient protein with biologic agents induces rapid and complete remission. Therefore, clinical symptoms should be learned exactly by the pediatricians, pediatric rheumatologists, and immunologists; and molecular analysis targeting this defect must be performed as early as possible.

Intestinal and enthesis innate immunity in early axial spondyloarthropathy

“…IL-1β is a prototypic pro-inflammatory cytokine mainly produced by macrophages in response to PAMPs and exerts pleiotropic effects including immune cell recruitment and activation [ 45 ]. Deficiency of IL-1 receptor antagonist (DIRA) is accompanied by joint swelling and inflammatory arthritis, including axial new bone formation, a finding that parallels the development of spontaneous inflammatory arthritis in murine models deficient in IL-1R antagonist [ 46–48 ]. Moreover, several single-nucleotide polymorphisms (SNPs) involving the IL1 gene cluster have been associated with axSpA, including IL1α, IL1β, IL-1RN (coding for IL-1RA) and IL-1R [ 49 , 50 ].…”

A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)

“…Of note, since canakinumab blocks specifically the serum free IL1β, it is possible that the accumulation of IL1α may lead to independently activate the natural receptor. Indeed, the introduction of recombinant IL-1Ra allowed a complete control of disease activity, as reported on Table 1 [9][10][11].…”

Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features

“…One is Majeed syndrome which is the focus of this review. The other is the deficiency of the interleukin-1 receptor antagonist (DIRA) in which , sterile multifocal osteomyelitis/osteitis and skin pustulosis are the dominant phenotypes [34,35,[67][68][69][70][71][72][73][74][75][76][77][78]. Patients with DIRA present in infancy with systemic inflammation, severe multifocal osteomyelitis and pustulosis of the skin.…”

“…Patients with DIRA present in infancy with systemic inflammation, severe multifocal osteomyelitis and pustulosis of the skin. It is caused by either deficiency or loss of function mutations in the gene that encodes the IL-1 receptor antagonist leading to unfettered IL-1 signaling and results in a systemic inflammatory disorder that if left untreated is often fatal [34,35,[67][68][69][70][71][72][73][74][75][76][77][78]. While a direct connection to IL-1 signaling is evident in DIRA, that connection had been less clear in the Majeed syndrome which is caused by pathogenic variants in LPIN2, in which the encoded protein plays a central role in lipid metabolism.…”