ABCs in Dermatology: Updates in Erythropoietic Protoporphyria Management for 2026

Erythropoietic protoporphyria (EPP) remains among dermatology's most under-recognized diagnoses, often mistaken for solar urticaria or polymorphic light eruption for years before clinicians identify its hallmark feature: severe burning pain after sun exposure with little or no visible skin change.

In this episode of ABCs in Dermatology, hosts Lindsay Ackerman, MD, and Christopher Bunick, MD, PhD, spoke with Angelika Erwin, MD, PhD, founder and director of the Porphyria Center at Cleveland Clinic, about diagnosing and managing EPP and its X-linked counterpart, XLP.

EPP results from ferrochelatase deficiency, causing free protoporphyrin IX to accumulate in red blood cells, plasma, and skin. Pain typically strikes within minutes of sun exposure, most often on the backs of the hands, and can precede any visible finding. Onset usually occurs between ages 1 and 4, and diagnosis is frequently delayed for years because symptoms resolve before a clinician examines the skin. About 5% of patients develop protoporphyric hepatopathy, which in rare cases progresses to fulminant liver failure requiring transplantation paired with bone marrow transplant, since liver transplant alone is not curative.

Erwin outlined a diagnostic pathway starting with plasma total porphyrins, available through standard commercial labs, followed by erythrocyte protoporphyrin testing at specialized centers such as Mayo Clinic or ARUP to distinguish EPP from XLP based on the ratio of free to zinc-bound protoporphyrin. Urine porphyrins remain normal in both conditions and should not be used for screening. Genetic testing targets the FECH gene in EPP, an autosomal recessive condition typically involving a common low-expression allele paired with a disease-causing mutation, and the ALAS2 gene on the X chromosome in XLP.

Before afamelanotide's 2019 approval, management relied on physical sun avoidance, zinc oxide and titanium dioxide sunscreens, and UV-filtering window films, with limited benefit from oral beta-carotene. Afamelanotide, a subcutaneous implant given every 60 days, increased pain-free sun exposure by a mean of 69 hours over 6 months versus placebo in the US phase 3 trial1, though it is not approved in pediatric patients. Bitopertin, an oral glycine transporter 1 inhibitor now in phase 3 testing, reduces porphyrin production upstream in the heme biosynthetic pathway and has shown promise in patients as young as 12 years in earlier trials2.

Erwin also pointed to earlier-stage candidates, including an ABCG2 inhibitor, ex vivo FECH gene replacement, mRNA-based delivery, and dersimelagon, an oral melanocortin receptor agonist in phase 3 testing. She emphasized that suspected EPP warrants erythrocyte protoporphyrin or plasma porphyrin testing rather than urine studies, and that confirmed cases require coordinated monitoring of liver function and vitamin D levels alongside referral to a specialized porphyria center.

References

1. Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med. 2015;373(1):48-59. doi:10.1056/NEJMoa1411481

2. Yeung AK, Bonkovsky HL, Balwani M, et al. Bitopertin shows efficacy in patients with erythropoietic protoporphyria: results from the randomized, double-blind, placebo-controlled AURORA trial. J Am Acad Dermatol. 2025. doi:10.1016/j.jaad.2025.12.024