DIRA: A New Autoinflammatory Disease

Summary and Comment |
June 3, 2009

DIRA: A New Autoinflammatory Disease

  1. Craig A. Elmets, MD

Deficiency of the interleukin-1–receptor antagonist disrupts the function of skin (and other systems).

  1. Craig A. Elmets, MD

The proinflammatory cytokine interleukin (IL)-1β has many biological activities, including fever, anorexia, and leukocytosis; it also stimulates other cytokines, chemokines, and acute-phase reactants. Its multiplicity of actions necessitates tight control of IL-1β functions, including control by the IL-1–receptor antagonist. IL-1β dysregulation can cause autoinflammatory disease, often with cutaneous manifestations. Unlike autoimmune diseases, autoinflammatory diseases tend to be episodic, associated with exogenous triggers, and unrelated to the major histocompatibility complex. Autoinflammatory disease responds to anakinra, a recombinant IL-1–receptor antagonist. Among the known autoinflammatory disorders are familial Mediterranean fever, Muckle-Wells syndrome, neonatal-onset multi-inflammatory disease (NOMID), and TNF-receptor–associated periodic syndrome (TRAPS). Now, authors describe a new autoinflammatory syndrome — deficiency of IL-1–receptor antagonist (DIRA) — in nine children with mutations of IL1RN, the IL-1–receptor antagonist gene. (A short report in the same issue discusses another such patient.)

Within the first 3 weeks of life, patients had fetal distress, joint swelling, oral mucosal lesions, and painful movement. Other skin symptoms developed, including severe pustulosis and ichthyosiform lesions. Onychomadesis and psoriasis-like changes also occurred. Histological features included a pronounced epidermal and dermal infiltrate of neutrophils, especially along hair follicles, as well as acanthosis and hyperkeratosis. Bone lesions were the other prominent feature, including widening of the anterior rib endings and periosteal elevation along the long bones.

In in vitro assays, IL-1β–treated monocytes from these patients secreted exaggerated amounts of IL-6 and other IL-1–responsive cytokines. These patients were not febrile but had elevated erythrocyte sedimentation rates and C-reactive protein levels. All six patients treated with anakinra responded rapidly, with resolution of skin and bone lesions that flared on drug discontinuation.


DIRA is a new addition to the spectrum of autoinflammatory disorders. A rare condition, DIRA will not be encountered often, but its origin highlights the importance of IL-1β in skin function. Dermatologists and pediatricians should be aware of DIRA, because it may enter into the differential diagnosis of pustular eruptions in newborns. Moreover, study of DIRA might inform understanding of more-common skin and bone diseases; for example, some evidence suggests that Behçet syndrome can be traced to dysregulated IL-1 production. An editorialist proposes that imbalances between IL-1β and the IL-1–receptor antagonist will be shown to contribute to many other disorders in various systems.


Reader Comments (1)

Hartmut Michels

The destription of DIRA including its feature "sterile multifocal osteomyelitis" and its successful treatment with anakinra might lead to applying anakinra or other IL-1 inhibiting substances also to treatment- resistant cases of "chronic recurrent multifocal osteomyelitis" (CRMO).

Competing interests: None declared

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