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Dermatology has a long-standing affinity for acronyms. From AGEP (acute generalized exanthematous pustulosis) to XP (xeroderma pigmentosum), acronyms have become a part of our dermatology lexicon, perhaps occasionally to the consternation of our colleagues in other specialties. In this issue, Brau-Javier et al1 describe a patient with a severe pustular skin disease called “DIRA”—an acronym for “deficiency of the interleukin 1 (IL-1) receptor antagonist,” which we first described in 9 pediatric patients in 2009.2 As its name suggests, DIRA is a new autoinflammatory disease linked to activation of the IL-1 pathway (Figure), joining the ranks of other IL-1–associated conditions with a prominent dermatologic component, foremost the cryopyrin-associated periodic fever syndromes (CAPS)—familial cold–induced autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID).3
CAPS is caused by gain of function mutations that lead to oversecretion of the well-established fever causing cytokine IL-1Β, and all 3 disorders manifest in the skin as neutrophilic urticaria. In contrast, DIRA presents in the neonatal period with a severe neutrophilic “pustular” skin eruption, skin pathergy, and nail dystrophy, as well as elevated acute-phase reactants, sterile osteomyelitis, and periostitis. DIRA is caused by loss of function of the IL-1 receptor (IL-1R) antagonist, the first endogenous cytokine receptor antagonist identified that blocks IL-1 signaling (Figure). Absence of the IL-1R antagonist results in unopposed proinflammatory signaling via the cytokines IL-1α and IL-1β on the IL-1R type I (IL-1R1).
DIRA is a rare condition that you may never encounter in your practice, so why bother filing away another acronym in the deep recesses of your dermatologic cortex? First, as Brau-Javier et al1 demonstrate, just as with CAPS, DIRA is exquisitely responsive to IL-1 blockade. Responses are similar to those seen following anti–IL-1 treatment for NOMID, the most severe form of CAPS; children who have been ill since infancy now feel well for the first time; others confined to wheelchairs because of disabling joint pain are able to walk; and growth curves begin to arc upward again for the first time in years. Interleukin 1–blocking therapy is now the standard of care for CAPS, and 3 Food and Drug Administration–approved agents, anakinra, rilonacept, and canakinumab, are currently available that provide targeted inhibition of IL-1 signaling.4
Second, understanding DIRA may yield new insights into the mechanism of other challenging pustular skin conditions. The cutaneous and systemic features of DIRA bear similarity to features seen in pustular psoriasis and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), suggesting that IL-1 signaling may play a role in these conditions as well.
The scientific rationale to explore the IL-1 family in skin inflammation has recently been bolstered by 2 studies that identified mutations in the gene encoding the IL-36 receptor (IL-36R) antagonist, IL-36RN, in familial5 and sporadic6 cases of generalized pustular psoriasis. This condition has been termed DITRA, an acronym for deficiency of the IL-36R antagonist (IL-36Ra). Interleukin 36Ra is an IL-1 family member that antagonizes the proinflammatory signals of IL-36α, IL-36β, and IL-36γ at the IL-36R in a manner analogous to the effect of IL-1Ra inhibition on IL-1 responses (Table and Figure).7,8
IL-36RN and the genes encoding the IL-36 agonist isoforms (IL36A, IL36B, and IL36G) sit in close proximity to IL-1RN on chromosome 2. In contrast to patients with DIRA from Newfoundland, Holland, Lebanon, and Brazil, who harbor isolated founder mutations in IL-1RN,2,9 patients with DIRA of Puerto Rican descent harbor a genomic deletion on chromosome 2, which encompasses IL-1RN as well as 5 adjacent genes: IL36RN (IL1F5), IL36A (IL1F6), IL36B (IL1F8), IL36G (IL1F9), and IL38 (IL1F10). The estimated allele frequency of this founder deletion in the harbor area of Arecibo in the northern part of Puerto Rico is 1.3%.2,10
Deletion of IL36RN in addition to IL-1RN raises the question of whether IL-36 signaling plays an independent role in the development of skin pustulosis in the Puerto Rican patients with DIRA. Interestingly, treatment with anakinra in 2 patients with the Puerto Rican founder mutation, including the Puerto Rican patient described by Brau-Javier et al,1 did not lead to complete normalization of inflammatory markers. However, another reported patient homozygous for the Puerto Rican mutation who initiated anti–IL-1 therapy at a much younger age10 and our subsequent experience in 2 other Puerto Rican children who began treatment at a young age, confirms that complete response to anti–IL-1 therapy is achievable in the Puerto Rican patients with DIRA. Furthermore, the genomic deletion in Puerto Rican patients with DIRA also encompasses the 3 IL-36R agonists (IL-36α, IL-36β, and IL-36γ) and likely cancels out the deleterious effect of loss of IL-36Ra (Figure). The ramifications of the loss of IL-38 in Puerto Rican patients with DIRA is unclear because little is known about the function of the cytokine or its receptor; however, severe bony overgrowth such as that described by Brau-Javier et al1 has only been described in Puerto Rican patients with DIRA, raising the possibility of a role for the cytokine in the development of the osseus deformities.
Interleukin 1R1 and IL-1Ra are ubiquitously expressed,11 whereas expression of IL-36R is restricted to epithelial cells in direct contact with the environment, including the skin,12,13 which may explain the lack of bone involvement in DITRA in contrast to DIRA. However, the clinical and histological similarities of skin involvement raise the possibility of a common downstream pathway to pustular skin inflammation.
Several years prior to the discovery of DITRA, the role of IL-36 in skin inflammation was examined in a murine model that overexpressed IL-36α (il1f6) in the epidermis under a keratin promoter.14 The transgenic mice developed pustular skin lesions, and when bred onto a genetic background that lacks the IL-36Ra (il1f5), the disease worsened, independent of T-cell involvement. An increase in IL-36α expression in psoriasis vulgaris also suggests that the IL-36 isoforms may play a pivotal role in pustular and plaque-type psoriasis.15 The IL-36 isoforms are potent inducers of a proinflammatory cytokine network that is also up-regulated in psoriatic skin disease and can initiate the recruitment of inflammatory cells into the skin, including neutrophils, T-cells, and myeloid dendritic cells, thereby fueling and perpetuating the inflammatory response.15–17 Interestingly, when the IL36α/IL1F6 transgenic mice were crossed onto an IL1R1-deficient background, disease severity was not attenuated, suggesting the IL-1R is not required to mediate the IL-36 model pustular phenotype.14 These results would predict that in contrast to DIRA, patients with DITRA may not respond to IL-1 blockade; however, clinical confirmation is needed.
Both IL-1Ra18 and IL-36Ra19 are highly expressed in keratinocytes. It is conceivable that the IL-36 isoforms may modulate skin pustulosis downstream of IL-1 in DIRA as well as other genetically undefined pustular skin diseases. However, the Puerto Rican patients with DIRA manifest prominent skin pustulosis despite the absence of all the IL-36 isoforms, suggesting that IL-1 and IL-36 may act independently in skin inflammation.
Can the knowledge we have gained by understanding 2 rare monogenic diseases, DIRA and DITRA, be generalized to other neutrophilic disorders? In a second Cutting Edge article in this issue, Lutz and Lipsker20 test the hypothesis that IL-1 blockade may have utility in pustular psoriatic disease in a patient with no genetically characterized abnormality. The authors describe a 59-year-old woman with acrodermatitis of Hallopeau and recurrent fevers unresponsive to multiple therapies, including psoralen UV-A, acitretin, methotrexate, and 3 tumor necrosis factor inhibitors. Treatment with anakinra, initially in combination with acitretin and subsequently as monotherapy, led to resolution of pustules within 24 hours and normalization of C-reactive protein within 5 days.20 Similar results were recently reported in 2 patients with generalized pustular psoriasis following anakinra treatment.21 In this earlier report, elevated serum IL-6 (283 ng/L; reference range, 0–8.6 ng/L) and IL-1Β (22.4 ng/L; reference range, 0–15 ng/L) levels in one of the patients returned to normal during therapy.
Anecdotal reports have also described efficacy of anti–IL-1 therapy in Sweet syndrome,22 neutrophilic urticarial dermatosis,23 and neutrophilic panniculitis.24 However, this approach is unlikely to be a panacea for all neutrophilic skin disease, including one of the most common, plaque-type psoriasis. Despite rapid improvement in skin pustule formation and systemic inflammation, the patient described by Lutz and Lipsker20 did not have improvement in the papulosquamous component of her skin disease. Similarly, in a study of anakinra for psoriatic arthritis, only 2 of 8 patients with significant skin involvement had improvement. In addition, skin disease worsened in 4 of 8, and 1 patient developed new-onset psoriasis during anakinra treatment.25
The monogenic diseases DIRA and DITRA, albeit rare, are important “experiments in nature” that enhance our understanding of pathways leading to skin inflammation. Dramatic responses to IL-1 blockade in DIRA provide a tantalizing opportunity to consider other dermatologic applications, particularly challenging neutrophilic disorders. If IL-1 and IL-36 independently contribute to skin inflammation, one might expect that patients with pustular skin inflammation triggered primarily by IL-1 will respond to IL-1 blockade. Others may require treatment targeting IL-36 directly or common downstream pathways. Regardless, understanding these rare monogenic diseases brings us one step closer to moving from acronyms to answers for patients with severe skin disease.
Financial Disclosure: Dr Goldbach-Mansky has received grant support from Regeneron, Novartis, and Biovitrum.