New Therapeutic Approach in Malignant Atrophic Papulosis

Background/Purpose: Malignant atrophic papulosis (MAP, synonym Köhlmeier-Degos disease) is an extremely rare multisystemic vasculopathy of unknown etiology, characterized by skin lesions and multiple possible organ manifestations including the central nervous system. Until now, multiple therapeutic approaches have been unsuccessful.

Methods: Whole-exome sequencing (WES) was performed with DNA from the patient and her parents to identify the genetic cause of MAP. Clinical workup (skin/brain biopsy, brain imaging) and extensive blood tests including interferon signature were performed repeatedly.

Results: A 10-year-old girl presented with MAP symptoms, including characteristic skin lesions as well as cognitive decline, progressive flaccid tetraparesis, focal-onset seizures, glaucoma, optic nerve atrophy, and hearing impairment. WES identified a heterozygous de novo nonsense variant c.830G>A (p.W277*) in the interferon-α/β receptor subunit 1 gene (IFNAR1, NM_000629.2), resulting in a truncated, soluble protein. Baricitinib treatment initially led to a clinical stabilization. After a partial radiological progression, hydroxychloroquine and subsequently cyclophosphamide were added, but were unable to prevent disease progression. Given the identified IFNAR1 variant and the hypothesized increased activation of a soluble aberrant protein, the monoclonal IFNAR1 antibody anifrolumab was applied as a monthly infusion in addition to daily oral baricitinib. This resulted in a rapid neurological stabilization and normalization of the previously highly elevated interferon signature.

Conclusion: This case report provides evidence that MAP can be caused by a variant in the IFN pathway with an elevated interferon signature linking it to monogenetic type I interferonopathies. Furthermore, we present data that therapeutic inhibition of this pathway with baricitinib and anifrolumab can stabilize severe disease progression and normalize the hyperinflammatory state.

Publication History

Article published online:
28 October 2021