Erythropoietic protoporphyria: case reports for clinical and therapeutic hints.

BACKGROUND: Erythropoietic protoporphyria is a rare disorder which represents an important health problem in children, causing painful photosensitivity. Little is known on the correlation between genetic profile and clinical manifestations. The standard of care for Erythropoietic protoporphyria is based on avoiding sun and using sun protections, but recent literature has suggested that cimetidine may have a role in improving sun sensitivity. Herein we report our case series describing the successful use of cimetidine and analyzing potential phenotype-genotype correlations. CASE PRESENTATION: This case series describes five patients presented to our Rheumatology Service complaining sun sensitivity. Blood exams and genetic analysis were consistent with the diagnosis of erythropoietic protoporphyria. Four of 5 patients received cimetidine in addition to standard therapies and the effect of treatment was evaluated by Erythropoietic Protoporphyria - Quality of Life questionnaire. CONCLUSIONS: Erythropoietic protoporphyria usually manifests in early childhood after a short sun exposure. Skin manifestations are the main reason for investigations, although sometimes they can be more subtle, leading to a significant diagnostic delay. Skin diseases in children can have profound effects on their family and social relationships. A treatment with cimetidine appears to be an excellent therapeutic option in children with Erythropoietic protoporphyria.

Development and content validation of a sunlight exposure diary in patients with erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria is a rare, inherited disorder presenting in early childhood with severe, painful phototoxicity. EPP has significant impacts on health-related quality of life, though there is variable disease severity. Accurately capturing how much time individuals with EPP can spend outdoors before they develop symptoms is critical to understanding HRQoL and measuring therapeutic response. Therefore, the goal of this study was to develop a comprehensive and content valid sun exposure diary to assess the efficacy of new therapies in individuals with EPP. METHODS: Qualitative interviews were conducted with adult and adolescent EPP participants, as well as five clinical experts, to obtain their input on the content of an existing sun exposure diary. Revisions to the diary were made based on evidence generated in cognitive debriefing interviews analyzed in eight consecutive groups of EPP participant. RESULTS: Interviews were conducted with 17 adults and 6 adolescents with EPP. The average age of adults was 40 years and of adolescents was 14 years. Clinical experts thought the original diary needed clarification on the description of symptoms, how time outdoors was captured, and the distinction between direct vs. indirect sunlight. Participants with EPP also noted these items needed revision, and that the distinction between prodromal symptoms and full reaction symptoms should be clarified. In the final diary version, participants with EPP found most items to be clear and easy to complete/think about. Seventy-six percent of participants (13/17) asked thought the diary was easy to complete. The remainder thought the majority of the diary was easy to complete with the exception of select questions. CONCLUSIONS: Evaluating a new treatment for EPP requires accurately capturing time in sunlight and symptoms in this unique disorder. The newly developed sun exposure diary is content valid and can be used to assess important aspects of symptoms and daily life and therefore evaluate clinically meaningful therapeutic response.

Into the Light: Afamelanotide and the Treatment of Erythropoietic Protoporphyria in the United States.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare disease that causes disabling cutaneous photosensitivity with pain and burning sensations. In 2019, afamelanotide, an α-melanocyte-stimulating hormone analogue, was approved in the United States for treatment of EPP. In this study, patients receiving afamelanotide filled out questionnaires assessing the benefit of treatment. Outcomes measured included: return to normal activities, experience of phototoxic reactions, effect on patient confidence, and more. Patients ranked their experience on a descriptive scale ranging from "very much" to "never". RESULTS: Prior to treatment, 75% of patients indicated that EPP affected their lives "very much" or "a lot". This number fell to 11% after the 1st implant and to 0% after each subsequent implant. The number of patients that willingly ventured outside increased with each subsequent implant. CONCLUSION: The results of this study clearly show that afamelanotide treatment can dramatically and positively impact the lives of EPP patients.  Citation: Resnik SR, Targett D, Resnik BI. Into the light: afamelanotide and the treatment of erythropoietic protoporphyria in the United States. J Drugs Dermatol. 2023;22(9):941-949. doi:10.36849/JDD.7126R1.

Light-Related Cutaneous Symptoms of Erythropoietic Protoporphyria and Associations With Light Sensitivity Measurements.

Importance: Erythropoietic protoporphyria (EPP) is a rare and underdiagnosed genetic disease characterized by painful sensitivity to light. A better understanding and characterization of its light-induced cutaneous symptoms may aid in the identification of EPP in patients. Objectives: To describe the cutaneous symptoms of erythropoietic protoporphyria (EPP) and to determine if these symptoms are associated with the degree of light sensitivity. Design, Setting, and Participants: This was a cross-sectional study of adolescent and adult (≥15 years) patients with EPP across the US conducted by a single academic hospital via a remotely administered survey, measurements of light sensitivity by light dosimetry and by text message symptom assessments. Data analyses were conducted from November 2020 to April 2022. Exposures: Sunlight exposure. Main Outcomes and Measures: Self-reported symptoms and association with measured light sensitivity. Results: The study sample consisted of 35 patients with EPP (mean [SD] age, 39.1 (15.5) years; 21 [60%] female; 14 [40%] male; 35 [100%] White individuals). The patients' median [range] skin tone was 3.0 (1.0-8.0), based on self-reporting from 1 (lightest) to 12 (darkest). A total of 24 participants completed the light dosimeter measurements. Phototoxic reactions were characterized by pain (97%; 34 patients), burning (97%; 34), tingling (97%; 34), pruritus (83%; 29), allodynia (89%; 31), improvement of symptoms with cold (89%; 31), achiness (24%; 12), fatigue (46%; 16), mild swelling (83%; 29), severe swelling (63%; 22), erythema (51%; 18), petechiae (40%; 14), skin cracking (43%; 15), scabbing (46%; 16), scarring (66%; 23), and other chronic skin changes (40%; 14). Patients with EPP reported that their hands, feet, and face were most sensitive to light and that their shoulders and legs were least sensitive; 25.7% (9 patient) reported no chronic skin changes, and 5.7% (2 patients) reported never having had any visible symptoms. None of these findings varied with the degree of light sensitivity except that lower overall light sensitivity was associated with lower ranked sensitivity of the neck and arms. Conclusions and Relevance: The findings of this cross-sectional study suggest that patients with EPP have distinctive cutaneous symptoms that may aid in identification of this underdiagnosed disease. Characteristic EPP symptoms include light-induced cutaneous burning pain and occasional swelling, particularly over the hands, with a prodrome of pruritus and paresthesias. Minimal skin changes or the absence of visible skin changes during reactions to light, including lack of erythema, do not exclude an EPP diagnosis nor suggest low EPP disease burden.

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

Recovery From Severe Systemic Peripheral Neuropathy Secondary to Erythropoietic Protoporphyria by Liver Transplant: A Case Report.

Erythropoietic protoporphyria is a rare inherited metabolic disorder involving the heme biosynthesis pathway and leads to the accumulation of protoporphyrin in the erythrocytes or liver. Although peripheral neuropathy is known to develop occasionally in other types of porphyria, it rarely occurs in patients with erythropoietic protoporphyria. A 16-year-old boy was transferred to our hospital due to end-stage liver disease secondary to erythropoietic protoporphyria. Severe systemic peripheral neuropathy, similar to that presented in Guillain-Barré syndrome, developed; it was promptly managed with mechanical ventilation. Electrophysiological assessment of the presented neuropathy showed no responsiveness, indicating severe axonopathy. Six weeks after the transfer, liver transplant was performed.Postoperatively, hepatorenal syndromes improved immediately, and his erythrocyte protoporphyrin level decreased from 6291 to 174 µg/dL red blood cells.The patient started to move his limbs gradually and was weaned from mechanical ventilation 2 months after liver transplant. Eventually, he was discharged from hospital and was able to ambulate with assistance 10 months after liver transplant. To our knowledge, this is the first report detailing the clinical course in a patient with erythropoietic protoporphyria who recovered from severe systemic peripheral neuropathy after liver transplant.

Ultraviolet A phototest positivity is associated with higher free erythrocyte protoporphyrin IX concentration and lower transferrin saturation values in erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited. METHODS: To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment-naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25-hydroxyvitamin D, and liver enzyme levels. RESULTS: Median FEP concentration at the time of phototesting was 57.50 (IQR: 34.58-102.70) µg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest-positive patients than in those negative (64.37 [IQR: 57.45-121.82] vs 45.35 [IQR: 24.53-74.61] µg/g of Hb, respectively; P = .04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5-84] µg/dL vs 109 [IQR: 63.25-154] µg/dL, respectively; P = .01862) and transferrin saturation values (15.005 [IQR: 7.0775-18.41] % vs 29.645 [IQR: 17.8225-34.3575] %; P = .0109) than those negative. CONCLUSIONS: Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.

Erythropoietic protoporphyria: time to prodrome, the warning signal to exit sun exposure without pain-a patient-reported outcome efficacy measure.

PURPOSE: Patients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the "warning signals" to exit the sun, as prolonged exposure causes an excruciatingly painful phototoxic attack. The unique prodromal cutaneous sensations are reversible and differ from the severe burning pain attack lasting 2-7 days. Previously, afamelanotide treatment was studied using time to pain or time outside as primary outcome measures. Since patients have an ingrained fear of sunlight, these measures did not capture the full treatment effect. We retrospectively characterized and evaluated time to prodrome (TTP) as a safer, patient-reported outcome (PRO) measure in afamelanotide-treated patients. METHODS: Structured interviews recorded TTP before and during afamelanotide treatment in retrospective US and Dutch cohort studies. RESULTS: Thirty-one US and 58 Dutch EPP patients participated. Before afamelanotide treatment, 54.8% US and 39.7% Dutch patients reported TTP onset <10 minutes in direct sunlight. In both studies, patients' TTP's were significantly longer during afamelanotide treatment (p < 0.0001). All US patients' TTP increased; no TTP was <10 minutes. Among Dutch patients 81% improved; only 10.3% reported TTPs < 10 minutes. CONCLUSION: EPP patients reported substantial improvements in TTP during afamelanotide treatment. TTP could provide a safer, PRO-based efficacy endpoint for assessing future EPP treatments.

Alternative Pathway Involvement in Protoporphyria Patients Related to Sun Exposure.

The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it may also be detrimental to healthy cells with a consequent aggravation of symptoms. The protoporphyria (PP) is a rare chronic disease that causes phototoxicity in visible light with local skin pain and general malaise. In order to establish if there is a systemic involvement of the CS during sun exposure, we designed a non-invasive method with a serum collection in winter and summer from 19 PP and 13 controls to detect the levels of CS protein: Properdin, Factor H (FH), and C5. Moreover, the global radiation data were collected from the regional agency of environmental protection (ARPA). The results show growing values for every protein in patients with PP, compared to control, in both seasons, in particular in summer compared to winter. To reinforce the evidence, we have estimated the personal exposure of patients based on the global radiation data. The main factors of the AP increased over the season, confirming the involvement of the AP in relation to light exposure. The systemic response could justify the general malaise of patients after long light exposure and can be exploited to elucidate new therapeutic approaches.

Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.

PURPOSE: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets. METHODS: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed. RESULTS: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin. CONCLUSION: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.

Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP.

The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.