Erythropoietic protoporphyria in the Netherlands: Clinical features, psychosocial impact and the effect of afamelanotide

Erythropoietic protoporphyria (EPP) patients experience severe burning pain after light exposure, which results in a markedly reduced quality of life. However, there is limited information on the psychosocial aspects of EPP. To investigate the clinical features and social aspects of living with EPP, before and during afamelanotide treatment in the Netherlands. A single‐center prospective longitudinal study of adult patients with EPP attending the Erasmus MC Rotterdam. Patients completed questionnaires, comprising demographic, clinical and social details, including two generic (DS‐14 and SF‐36) and a disease specific (EPP‐QoL) QoL questionnaires. 121 adult EPP patients were included. The educational level of EPP patients seemed higher compared to the Dutch population (36% vs. 30% high‐education, 42% vs. 37% middle‐education). At baseline 5% of the EPP patients were unemployed, none were unemployed during afamelanotide treatment. Full‐ and part‐time employment rate increased from 59.5% to 69.9% on afamelanotide treatment (p > 0.05). EPP‐QoL improved from 44% to 75% on afamelanotide treatment (p < 0.001). Type‐D personality was present in 27.4% of patients; their social inhibition scores improved significantly on afamelanotide treatment (p = 0.019). EPP patients scored low on the social functioning domain (SF‐36) compared to the Dutch population (74.4 ± 27.3 vs. 84.0 ± 22.4; respectively), and improved during afamelanotide treatment (84.3 ± 20.9, p = 0.001). EPP has a significant negative impact on social aspects, with less employment despite a higher education level. Afamelanotide treatment improves quality of life, social functioning and possibly employment rate. It is important to recognize the impact of EPP on social life, although, more research is needed.

gene (in the majority of cases), which result in decreased activity of the ferrochelatase enzyme. Around 96% of EPP patients are compound heterozygote for a pathogenic variant (loss of function mutations) and a second low-expression pathogenic variant (c.315-48T>C; also known as IVS3-48T>C, which is an hypomorphic mutation that is prevalent in several populations), the combination results in decreased ferrochelatase activity. 3 This leads to protoporphyrin IX (PPIX) accumulation in erythroid cells and other tissues. 4 PPIX in erythrocytes and the skin absorb blue light, inducing reactive oxygen species, leading to endothelial and dermal damage. 5 Severe liver damage is possible with a risk of acute cholestatic hepatitis in 1-5% of the patients. 6 The prevalence of EPP differs between populations, and is estimated to be 1:75 000 in the Netherlands. 7 A recent study suggests that the prevalence of EPP is underestimated due to underdiagnoses and diagnostic delay. 8 From a young age patients develop light avoiding behavior due to the early onset and severity of the pain after sunlight exposure. They learn to recognize early symptoms, often referred to as prodromes, 9 as a warning signal to immediately go out of direct light. This is likely to result in impairment of social activities and career perspectives.
Since 2016 adult EPP patients may be treated with afamelanotide, a potent α-melanocyte-stimulating hormone (α-MSH) synthetic analog, which increases the production of eumelanin by agonistically binding to the melanocortin-1 receptor (MC1R). 10 Several studies investigated the effect of afamelanotide in EPP patients, and demonstrated statistically significant improvements in pain-free time spent in direct sun light, 11 associations with increased duration of sun exposure and less severe phototoxic reactions, 12 and improved quality of life. [11][12][13] However, there is limited information on the psychosocial aspects of EPP, both untreated and on treatment with afamelanotide. In previous studies the EPP-QoL questionnaire was used to assess quality of life in EPP patients. Although, the domain regarding wellbeing has been dropped out of the questionnaire based on an analysis that explores aspects of the performance of the measure based on available data from the trials. 14 A common questionnaire used as an instrument to determine the general health related quality of life is the SF-36, which has shown good clinical validity, internal consistency, and reliability in many conditions. 15,16 We investigated the clinical features and social aspects of living with EPP, before and during afamelanotide treatment. With the aid of questionnaires we recorded the education level, employment rate and investigated the outcome of the SF-36 questionnaire and the prevalence of type-D, or distressed, personality. Type-D personality is associated with depressive symptoms, anxiety, and chronic stress, 17,18 and therefore this could be relevant to how EPP patients cope with their disease. 2 We hypothesize that EPP patients have a higher prevalence of type-D personality and that EPP has a substantial negative impact on social aspects of life, with improves by treatment with afamelanotide.

| ME THODS
In this single-center prospective longitudinal study, all adult EPP patients attending the outpatient clinic of the Porphyria Expert Center Rotterdam at the Erasmus MC were eligible for inclusion. All included patients had a confirmed diagnosis of EPP, based on clinical phototoxic symptoms with protoporphyrin IX levels in erythrocytes >4 times the upper limit of normal and two pathogenic mutations in the FECH gene or a gain-of-function mutation in the ALAS2 gene.
Since 2016, afamelanotide (SCENESSE, Clinuvel Pharmaceuticals Ltd.) treatment was part of standard care, and was given as a subcutaneous controlled release 16 mg implant, with a maximum of four implants per year. 12 This study adheres to the principals of the Declaration of Helsinki. All patients gave written informed consent for the use of their data for analysis and publication prior to the study. The study was approved by the Medical Ethics Review Board of the Erasmus Medical Center Rotterdam.

| Data collection and questionnaires
Data collection occurred during routine visits at the outpatient clinic according to local standard healthcare practice. Blood samples for PPIX levels were collected during outpatient clinic visits. A baseline questionnaire was completed before treatment with afamelanotide, and a follow-up questionnaire was completed in 2019. The questionnaire covered several topics including medical history, clinical features including diagnosis and symptoms, and social information like marital status, family composition, education level, employment status, vacation type, questions about lifestyle, VAS scale for perceived health (scale from 0 to 100) and family history. We distinguished three educational categories: low (pre-vocational secondary education, elementary-school or none), medium (senior-general secondary education, pre-university education and secondary vocational education), and high (higher professional education and university education). We used CBS Statline, 19 which provides publicly available data on the national level of education in the Netherlands, to provide reference data. The disposable income of patients (income after deduction of income taxes) was estimated based on their 4-digit postal code, also derived from the CBS Statline database.
Quality of life was investigated with the disease specific EPP-QoL questionnaire 11,13,14 and the generic SF-36 questionnaire.
Results of the EPP-QoL are expressed as percentage of maximum score, with 100% being the best and 0% the worst possible QoL.

| Demographics
Details of the baseline characteristics of the EPP patients and reference values of the Dutch population are presented in Table 1. The marital status of EPP patients appears comparable to the Dutch population; 42.5% of the EPP patients were married, 30% were unmarried, 18.3% were living together and 7.5% were divorced. In total 52.6% of the patients has children, and in patients older than 30 years, 75.0% (60/80) has children. None of the patients younger than 30 years old has children (0/34).
The educational level of EPP patients seems higher compared to the Dutch population, 36% vs. 30% had a high educational level, and 42% vs. 37% had a middle educational level. 19 Five percent of the patients (6/121) were medical practitioners, compared to 0.44% in the Dutch population. 23 The EPP patients consumed a median of 4 units of alcohol per week (IQR 2-7), and 5.7% of EPP patients consumed excessive alcohol which is lower compared to the Dutch population with 8.2%. 19 Of the EPP patients 21.4% had ever tried drugs compared to 35.1% in the general population. 19 Current drug use was reported by 5.1% of the patients, mostly cannabis (66.7%) ( Table 1).

| Employment and income
At baseline 59.5% of the EPP patients worked full-time or part-time.
Of all EPP patients 5.0% reported to be unable to work due to their EPP and light exposure limitations. That EPP influenced their career choice was reported by 60.4% of patients, and specific adjustments at work to prevent EPP symptoms was reported by 58.7% (e.g. workplace far away from windows, yellow foil on windows and options TA B L E 1 Baseline characteristics of patients with erythropoietic protoporphyria in comparison to the general Dutch population.

| Clinical features
The median age of first EPP symptoms was reported to be 1.

| Quality of life, health and personality questionnaires
The

| DISCUSS ION
This large single-center cohort study provides novel insights into the impact of EPP on daily social functioning, which is often mentioned in publications on EPP but has never objectively been assessed. In The probable higher education level in this cohort of EPP patients, compared to the general population, could be the result of having to spend more time indoors during childhood, and more time to study. However, in healthy children more outdoor time has been found to support self-regulatory capacities and cognitive development. 24 The educational level of the patients' parents was not taken into account in the presented study, and could be a confounding factor. 25 A higher education level of parents could result in an earlier diagnosis, 26 and it is possible that an EPP patient remains undiagnosed or untreated when the patients' parents stop seeking medical care.
The study confirms that afamelanotide treatment can improve tolerance to direct sunlight. 9,[11][12][13] However, this is the first study that reports that treatment can possibly have a positive impact on employment rate. Treatment resulted in more patients reporting a full-or part-time job, and requiring less adjustment at work (e.g. blinding windows, special working hours, wearing protective clothing on their way to work), and also enabled some patients to consider a career switch. This finding can be biased by a decrease in overall unemployment rate in the Netherlands over the study period, from 6.0% in 2016 to 3.4% in 2019. 19 F I G U R E 1 Erythropoietic protoporphyria patients reported age periods with the highest burden of their disease. Patients were asked the following question: "At which age did you experience the highest burden of your EPP (you can answer multiple age categories)".

F I G U R E 2
Reported erythropoietic protoporphyria symptoms per season. Patients where asked the following question: "During which periods do you experience EPP symptoms?" *p < 0.05.
The low QoL of EPP patients has been reported many times. 2,13,27,28 EPP patients in the present study, reported an EPP-QoL score of 44% which increased to 75% on treatment, this effect is comparable to reported outcome in phase III trials and observational studies. Afamelanotide treatment had positive effects on their vacations, which could positively contribute to improved QoL. 29 Patients with a type-D personality tend to experience negative emotions (high NA-score) and to inhibit self-expression in social interaction (high SI-score). 30 The type-D personality was present in 27.8% of the EPP patients, which is higher than in the general Dutch population (21%), 22 but similar to patients with coronary heart disease (28%), 22 and diabetes (27%). 31 The higher prevalence of type-D personality can be explained by the negative impact of EPP on social wellbeing from an early age. The SF36 confirmed the negative impact of EPP on social functioning. EPP patients report a high physical score on the SF36, higher than the Dutch population. 21 It is encouraging to see that afamelanotide treatment results in significant improvements on social functioning, giving EPP patients the opportunity to finally participate in more 'normal' activities. The findings of this study are in line with previous studies regarding the quality of life in photodermatosis in general, which has shown a very large impact on QoL, with particular effects on employment and social and leisure activities, next to suggested higher anxiety and depression levels. 32,33 This EPP cohort is comparable in age, contribution of males and females, and ethnicity to previously reported cohorts. 2,28,34,35 It is important to note that more than a third of the patients also report The majority of the presented cohort are fair-skinned subjects, skin type I/II according to Fitzpatrick scale, we were unable to TA B L E 3 Reported outcomes based on quality of life and type D-personality questionnaires, in patients with erythropoietic protoporphyria, before and on afamelanotide treatment.

| CON CLUS ION
This large cohort study demonstrated that Dutch EPP patients appear to have a higher unemployment rate, despite a higher education level, that EPP has a negative impact on holidays, quality of life and social functioning. These differences diminished after initiation of afamelanotide treatment, with residual unmet need. Further research to obtain more details regarding these psychosocial consequences is needed.

FU N D I N G I N FO R M ATI O N
No funding.

Dr. Langendonk reports contracts for phase III and IV trials with
Clinuvel (the producer of afamelanotide), and Alnylam. Dr. Wilson reports travel fees from Clinuvel during the conduct of the phase III study. No disclosures were reported by Wensink and Wagenmakers.