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Genetic insights inform autoinflammatory therapies


Knowing the genetic basis of monogenic skin diseases may one day help dermatologists treat non-monogenic skin diseases as well.

New knowledge regarding the genetic causes of monogenic autoimmune skin diseases is allowing clinicians to treat these conditions more effectively, and may one day translate into strategies for non-monogenic skin diseases, says an expert who spoke at the 75th American Academy of Dermatology Annual Meeting, Orlando, Fla.

"With genetic advances," says Edward Cowen, M.D., "we are rapidly gaining insights into the underlying nature of new autoinflammatory skin diseases. That includes diseases that cause pustular psoriasis. Hopefully, a better biologic understanding of these diseases will lead to targeted therapies and potentially better therapy for non-monogenic skin diseases." He is senior clinician and head, Dermatology Consultation Service, at the National Institutes of Health.

Dr. Cowen"For most skin diseases, there's still not a genetic underpinning that's been identified. However, we now know the genetic basis for several heritable forms of pustular psoriasis," and this knowledge may help investigators understand how to better treat other forms of psoriasis that possess clinical similarities but not the same genetic basis.

Very rare genetic forms of pustular psoriasis include the autosomal recessive conditions deficiency of interleukin (IL) 1 receptor antagonist (DIRA) and deficiency of IL36 receptor antagonist (DITRA). DIRA presents in the neonatal period with fetal distress, skin pustulosis, joint swelling and pain, and skeletal abnormalities, and DITRA has a more variable age of onset with skin pustulosis and fever, he said.

"The skin manifestations range from groupings of small pustules to a generalized pustulosis. The bone manifestations of DIRA include epiphyseal ballooning of multiple distal and proximal long bones," Dr. Cowen says. Because DIRA does not respond well to conventional therapy, patients' prognosis previously was bleak.

However, "We now understand the biologic mechanism that's driving them based on the gene that was identified – in the case of DIRA, the interleukin IL1 receptor antagonist, and with DITRA, the IL36 receptor antagonist."1

Anakinra is a recombinant form of the IL1 receptor antagonist that is U.S. Food and Drug Administration (FDA)-approved for the treatment of rheumatoid arthritis. This medication replaces the endogenous protein missing in children afflicted by DIRA, he says. "And they respond remarkably well to it."

New interferon-driven skin diseases (interferonopathies) including STING-associated vasculopathy with onset in infancy (SAVI) and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) also are better understood at the genetic level, he says.

"We believe that specifically targeting interferon-mediated signaling with Jak/STAT inhibitors might be the preferred way to treat affected individuals," he adds.

The clinical manifestations of deficiency of adenosine deaminase 2 (DADA2) resemble those of the poorly understood Sneddon syndrome, which is typically seen in adults, Dr. Cowen says. Sneddon syndrome is a syndrome of livedo racemosa on the skin in conjunction with cerebrovascular events.

"There's a bit of imprecision regarding the use of the term livedo. We know that physiologic livedo, causing a net-like pattern on the skin, can be normal, or when fixed, a sign of a variety of conditions. Livedo racemosa describes a different pattern, defined by irregular broken circles, often with wider bands of net-like erythema," he notes.

"DADA2 resembles Sneddon's in cutaneous appearance and risk of cerebrovascular events but occurs in the pediatric age group. In addition, it is associated with systemic inflammation and risk of polyarteritis nodosa. It appears that etanercept might alter the risk of subsequent strokes in affected individuals.  To date, none of the children who have been given etanercept after they've been diagnosed with DADA2 have subsequently had further strokes,"2 he expalins.

In sum, "It's an exciting time in medical dermatology, where we can link clinical phenotypes to specific genes and specific inflammatory pathways. But ultimately the goal is to devise targeted therapies for the monogenic diseases as well as more genetically complex inflammatory skin disease," he says.

Disclosures: Dr. Cowen is principal investigator on a study of anakinra for pustular dermatoses but reports no relevant financial relationships.


1. Aksentijevich IMasters SLFerguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426-37.

2. Pichard DC, Ombrello AK, Hoffmann P, Stone DL, Cowen EW. Early-onset stroke, polyarteritis nodosa (PAN), and livedo racemosa.J Am Acad Dermatol. 2016;75(2):449-53.


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