Erythropoietic Protoporphyria Life Impact and Genetic Health Trajectory (LIGHT) Study in Europe: A Cross-Sectional Online Questionnaire

Technical Summary: Erythropoietic Protoporphyria Life Impact and Genetic Health Trajectory (LIGHT) Study in Europe

Problem Statement
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (collectively EPP) are rare, inherited metabolic disorders of the heme biosynthetic pathway characterized by severe photosensitivity. Exposure to sunlight or specific artificial light triggers painful phototoxic reactions, including burning, itching, and pain, often leading to significant psychosocial strain and decrements in health-related quality of life (HRQoL). While previous studies in Sweden, the UK, and the Netherlands have documented the burden of EPP, there is a lack of comprehensive data regarding the disease's impact on children, specific healthcare resource utilization (HRU), and the variability of symptoms and HRQoL across a broader European demographic. Furthermore, the delay in diagnosis (often averaging 13 years from symptom onset) exacerbates the disease burden. This study addresses the gap in understanding the real-world symptoms, HRQoL impacts, and healthcare utilization patterns of EPP patients across five major European nations: France, Germany, Italy, Spain, and the UK.

Methodology
The study employed a cross-sectional online questionnaire design conducted between August and October 2025.

• Participants: The sample consisted of 101 individuals (91 adults and 10 adolescents) aged ≥12 years with a self-reported diagnosis of EPP residing in France, Germany, Italy, Spain, or the UK. Recruitment was facilitated through local patient advocacy groups to ensure demographic heterogeneity.
• Data Collection: Participants completed a one-time online questionnaire (approx. 60 minutes) translated into local languages. The instrument included:
  • Validated Patient-Reported Outcome (PRO) measures: EPP Impact Questionnaire (EPIQ), Sunlight Exposure Diary, KIDSCREEN-27 (for adolescents), and Patient-Reported Outcomes Measurement System (PROMIS) scales (Satisfaction with Social Roles and Activities, Peer Relationships, Social Isolation).
  • Original questions assessing physical functioning, emotional well-being (anxiety, depression, frustration), work/school productivity, healthcare utilization (physician visits, ER, hospitalizations), and medication use.
• Analysis: Data were analyzed descriptively. T-scores were calculated for PROMIS and KIDSCREEN measures, standardized against the general population (mean = 50, SD = 10). Differences of ≥3 T-score points (PROMIS) or ≥5 T-score points (KIDSCREEN) were considered meaningful.
• Ethics: Ethics approvals were obtained in Spain, Italy, and the UK. In France, non-opposition was implied by questionnaire completion. Participants provided consent for data use.

Key Results

• Symptom Frequency and Severity:
  • Prodromal Symptoms: 76% of adults and 38% of adolescents reported experiencing prodromal symptoms after ≤30 minutes of direct or indirect sunlight. In the past three months, 36% (Italy) to 67% (Spain) of participants experienced these symptoms ≥5 times.
  • Pain Triggers: 69% of participants experienced pain after <30 minutes of direct sunlight, and over 50% experienced pain from indirect sunlight.
  • Common Symptoms: The most frequent prodromal symptoms were sensitivity to hot/cold (84%), sensitivity to touch (83%), feelings of warmth (78%), burning (70%), itching (69%), and pain (68%).
• Impact on Daily Activities and HRQoL:
  • Activity Limitation: The most recent phototoxic reaction limited daily activities "very much" for 58% of participants (ranging from 40% in Spain to 86% in the UK).
  • Emotional Burden: Participants reported high levels of negative emotions attributed to EPP: frustration (86%), isolation (84%), loneliness (74%), sadness/depression (66%), and anxiety (60%).
  • PRO Scores: Mean T-scores for "Satisfaction with Social Roles and Activities" were below the general population mean (50) for all countries, with the UK scoring lowest (42.0). For "Social Isolation," mean T-scores were above 50 (indicating worse isolation), particularly in the UK (56.1).
• Work and School Productivity:
  • EPP impacted work productivity for 9% (Italy) to 42% (France) of currently working participants.
  • Adolescents missed an average of 3.9 hours of school per month due to EPP; 50% reported at least a "little" impact on school productivity.
• Healthcare Resource Utilization (HRU):
  • Physician visits varied significantly by country, with Italy reporting the highest mean (12.1 visits/year) and Spain the lowest (3.2 visits/year).
  • Emergency room visits and hospitalizations were rare (e.g., 1 ER visit reported in France, Spain, Italy, and the UK each).
  • Comorbidities: Vitamin D deficiency (71% of adults), anemia (55%), and gallstones (30%) were common. Liver disease was reported by 9% of adults and 10% of adolescents.
  • Medications: Vitamin D (75%) was the most common supplement. 24% of adults used Scenesse (afamelanotide). 13% were on investigational drugs (primarily dersimelagon).
• Treatment Preferences: The majority (68%) preferred oral administration (pills) for future treatments, citing ease of administration (48%) and convenience (33%) as primary reasons.

Significance and Claims
The paper claims that this study provides the first comprehensive, multi-country European assessment of EPP burden using a combination of validated PROs and specific EPP-related measures. The findings highlight that Europeans with EPP frequently experience prodromal symptoms and phototoxic reactions that severely restrict daily activities and impose a significant negative burden on emotional and mental well-being.

The study underscores the variability in disease impact across different European nations, particularly regarding work productivity and healthcare utilization. By documenting the high prevalence of negative emotions (frustration, isolation) and the specific limitations on sunlight exposure, the authors conclude that there is an urgent need for early diagnosis and effective treatments to mitigate the significant burden of EPP. The paper modestly notes limitations, including the reliance on self-reported diagnoses and the potential for a recruitment bias toward patients more engaged in disease management. It does not propose new therapeutic interventions but rather characterizes the current landscape to inform future clinical and policy decisions.