Understanding Increased but Treatments Still Limited for Porphyria, Editorial Says

Although progress has been made, more research is needed to develop effective therapeutic options for cutaneous porphyria, researchers said in a recent editorial, highlighting the latest advancements in the understanding of the disease, as well as possible pharmacological and non-pharmacological treatments.

The editorial, “Shedding light on recent advances in our understanding of cutaneous porphyrias,” published in the British Journal of Dermatology, discusses a collection of recently published porphyria studies in the same journal. The two authors are from Cardiff University in the U.K.

Cutaneous porphyria comprises eight mainly inherited disorders. Clinical manifestations result from the buildup of intermediates in the production of heme, a component of several iron-containing proteins, including hemoglobin — the protein that carries oxygen in the blood. In cutaneous porphyrya, porphyrin molecules accumulate in a skin layer called the dermis, ultimately leading to the characteristic sensitivity to visible light.

Due to this increased light sensitivity, patients require reflectant sunscreens. In addition, the ability of porphyrins to absorb light provides the basis of blood testing, which is the primary first‐line test if cutaneous porphyria is suspected.

The most common type of porphyria — porphyria cutanea tarda (PCT) — manifests as a result of liver dysfunction. Factors such as iron overload, alcohol, hepatitis C virus, prescribed estrogens, and possibly smoking contribute to a deficiency in an enzyme called UROD in the liver. PCT patients may have particularly troublesome itching in affected areas, but their experiences are typically varied.

Providing appropriate information and reassurance to PCT patients is especially relevant. This porphyria type can be treated effectively with either venesection — regular removal of blood — or low‐dose chloroquine, an anti-malarial medication.

Congenital erythropoietic porphyria (CEP) is the rarest form of cutaneous porphyria, usually presenting in infancy but can also manifest in adolescence or early adulthood. This later start is associated with a milder phenotype. Two possible mechanisms for later-onset CEP were proposed in individuals with a known disease-causing mutation in a study, which also highlighted the importance of laboratory testing to distinguish between PCT, CEP, and variegate porphyria.

Most studies in this series focused on erythropoietic protoporphyrias (EPP), characterized by an intense burning pain on exposure to sunlight due to the buildup of protoporphyrin, the final intermediate in the heme pathway. Regular clinic visits to monitor liver function and vitamin D levels are warranted for these patients. Although common, anemia only requires iron therapy if symptomatic. Because iron replacement may worsen photosensitivity, it should not be started without consulting a specialist.

Patients with EPP have a higher prevalence of osteoporosis than the general population. For this reason, lifestyle changes to increase dietary calcium intake, physical activity, and lifelong vitamin D supplementation are recommended to reduce the risk of fractures.

A different study on 115 EPP patients showed that treatment with under-the-skin implants of Scenesse (afamelanotide), by Clinuvel — approved in the EU but not in the U.K. or U.S. yet — significantly increased quality of life from 32% to 74%, as assessed by an EPP‐specific questionnaire. Scenesse, which was administered every two months, had low discontinuation rates over a long observation period of eight years.

After more than 1,000 implants, the researchers concluded that Scenesse “exhibits good clinical effectiveness and good safety in EPP under long‐term routine conditions.”

Additionally, in EPP patients, repeated sunlight exposure led to an improvement in sunlight tolerance in 40% of 89 patients from France. Sunnier areas of the country were associated with less pain during flare‐ups and higher sunlight tolerance.

However, caution must be taken before advising natural sunlight exposure for these patients, as overexposure on one day can lead to a much more severe reaction to light on the following day, according to the editorial.

The genetic basis of EPP — commonly characterized by inheriting a polymorphism (variation) in the copies of the FECH gene — was explored in a study from Japan, where this genetic variation has a particularly high incidence. The researchers described rare cases of three patients with mild photosensitivity who were homozygous (both gene copies are altered) for a particular FECH variation.

Additionally, a 2016 study used, for the first time, noninvasive measurements of skin protoporphyrin in EPP patients. The team used a hand‐held device that analyzes fluorescence light, which revealed that protoporphyrin levels depend on the concentration of protoporphyrin in red blood cells and can be increased with light exposure. The researchers suggest that this approach “can be used for objective monitoring of treatment effect.”

“Thus, for patients with EPP in 2018, although we know much more than previously, we have a range of treatments with little evidence of efficacy and a licensed treatment that is not widely available at present. In short, there remains much still to be done,” the authors wrote in the editorial.