Real-world Assessment of Patient Characteristics, Clinical Features, Treatment Patterns, and Outcomes Associated with Erythropoietic Protoporphyria and X-linked Protoporphyria

Academic Background

Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are two rare inherited metabolic disorders. The prevalence of EPP varies across countries, with an incidence of approximately 1:75,000 in the Netherlands and 1:200,000 in the United Kingdom. XLP accounts for 2% and 10% of porphyria cases in the UK and the United States, respectively. These disorders result from alterations in the activities of the enzymes ferrochelatase (FECH) and aminolevulinic acid synthase-2 (ALAS2), leading to the accumulation of protoporphyrin in the bone marrow, plasma, and red blood cells. When the affected red blood cells are exposed to visible or long-wave ultraviolet light, highly oxidized oxygen species are produced, causing vascular damage and the release of histamines and chemotactic factors, which trigger phototoxic reactions in patients.

Although EPP and XLP are known diseases, data on their management in real-world settings are limited. Currently, most information on the diagnosis and management of these disorders comes from research conducted at academic medical centers, where physicians typically possess specialized knowledge and have access to detailed medical histories. However, there are few experts with expertise in these rare diseases, leading to diagnostic delays and inadequate management. Although guidelines have been published in recent years to standardize care for these conditions, systematic research on the diagnosis and management of EPP and XLP in general clinical settings remains scarce.

Source of the Paper

This paper was co-authored by Samuel M. Silver (University of Michigan Medical School), Katherine Houghton (RTI Health Solutions, Manchester), Abby Hitchens (RTI Health Solutions, North Carolina), Valérie Derrien Ansquer (RTI Health Solutions, Lyon), and Malgorzata Ciepielwska (Mitsubishi Tanabe Pharma America, Inc., New Jersey). The paper was published in 2025 in the Journal of Dermatology under the title “Real-world assessment of the patient profile, clinical characteristics, treatment patterns, and outcomes associated with erythropoietic and x-linked protoporphyria.”

Research Process and Participants

The study was a retrospective, non-interventional medical record review aimed at documenting the characteristics, treatment patterns, and related clinical outcomes of patients diagnosed with EPP or XLP in general clinical settings in the United States. The primary participants were patients diagnosed with EPP or XLP before July 1, 2020. A total of 386 medical records were included, comprising 299 EPP patients and 91 XLP patients. The abstraction of medical records was completed by 136 healthcare professionals (HCPs) recruited through convenience sampling, including dermatologists, general practitioners, and hematologists/oncologists.

Research Steps

1. Patient Characteristics and Diagnostic Pathway:

   • Data on sociodemographic characteristics, clinical history, and diagnostic pathways were collected, including pre-diagnostic symptoms, tests, and referrals.
   • Post-diagnostic treatment recommendations, prescriptions, office visits, emergency department visits, and hospitalizations were recorded.

2. Resource Utilization and Cost Analysis:

   • Data on healthcare resource utilization related to EPP/XLP were collected for the period from symptom onset to 12 months post-diagnosis, including tests, referrals, emergency visits, and hospitalizations.
   • Mean and per-patient costs were calculated using 2022 U.S. healthcare cost standards (e.g., the Centers for Medicare & Medicaid Services Physician Fee Schedule).

Key Findings

1. Patient Characteristics:

   • The mean age at first symptom onset was 19 years, and the mean age at diagnosis was 24 years.
   • 64% of patients had at least one comorbidity, with the most common being vitamin D deficiency (42%), anxiety (38%), and anemia (29%).
   • Most patients (97%) had at least one symptom documented before diagnosis, most commonly skin symptoms such as burning or itching.

2. Diagnostic Pathway:

   • The mean time from the first documented symptom to diagnosis was 2.9 years, with a median of 1.3 years.
   • The most common pre-diagnostic tests included liver function tests, total plasma and erythrocyte protoporphyrin tests, genetic tests, and renal function tests.
   • Patients received an average of 2.8 specialist referrals before diagnosis, primarily to dermatologists (48%) and hematologists (22%).

3. Treatment Recommendations:

   • Patients received an average of 4.4 treatment recommendations pre- and post-diagnosis, with the most common being the use of sunscreen (85%) and lifestyle modifications (83%).

4. Healthcare Resource Utilization and Costs:

   • Within 12 months post-diagnosis, patients had an average of 4.0 office visits and 0.8 emergency department visits.
   • 16% of patients were hospitalized due to EPP/XLP, with an average hospital stay of 7.6 days.
   • The mean diagnostic pathway cost per patient was $601.54, while the average cost of hospitalizations and emergency visits was $2,731.85.

Conclusions and Significance

The study highlights that patients with EPP and XLP in general clinical settings in the United States have multiple unmet needs, including timely and accurate diagnosis, symptom relief, and effective prevention of phototoxic reactions. The findings reveal significant diagnostic delays and inadequate use of diagnostic tests, particularly among general clinicians with limited awareness of EPP and XLP. Additionally, although some patients received recommended treatments (e.g., sunscreen and lifestyle adjustments), a substantial proportion were prescribed ineffective therapies (e.g., beta-carotene and non-steroidal anti-inflammatory drugs), indicating a need for further optimization of treatment choices.

This study provides critical real-world data on the management of EPP and XLP, emphasizing the importance of increasing awareness of these rare diseases and promoting the development of more effective treatments, particularly for pediatric and XLP patients. Furthermore, the results underscore the need for standardized diagnostic and treatment guidelines to reduce diagnostic delays and resource waste.

Research Highlights

• Real-world Data: The study fills the data gap on the management and diagnosis of EPP and XLP in general clinical settings.
• Diagnostic Delays: The research reveals prolonged delays from symptom onset to diagnosis, highlighting the urgency of increasing clinician awareness.
• Resource Utilization and Costs: The study provides the first detailed documentation of healthcare resource utilization and associated costs for EPP and XLP patients, offering a basis for future healthcare policy development.

Other Valuable Insights

The study also found that some patients were misdiagnosed as having both EPP and XLP, and that a higher proportion of XLP patients were female, suggesting the need for stricter validation of diagnostic criteria. Additionally, the study recommends that future research further explore treatment efficacy in pediatric patients and promote the development and accessibility of new therapies.