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Brief Report |

Novel Treatment Using Cimetidine for Erythropoietic Protoporphyria in Children ONLINE FIRST

Joanna H. Tu, BA1,2; Sarah L. Sheu, MD1; Joyce M. Teng, MD, PhD1
[+] Author Affiliations
1Department of Dermatology, Stanford University, Stanford, California
2Columbia University College of Physicians and Surgeons, New York, New York
JAMA Dermatol. Published online July 13, 2016. doi:10.1001/jamadermatol.2016.2303
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Importance  Erythropoietic protoporphyria (EPP) is a rare hereditary disease of heme biosynthesis that manifests as severe photosensitivity and hepatotoxicity. There have been no effective treatments to date. Cimetidine has been shown to inhibit heme biosynthesis and results in symptomatic improvement in patients with acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT). There is only 1 report in the literature describing the use of cimetidine in the effective treatment of an adult patient with EPP.

Objective  To describe the successful use of cimetidine in pediatric patients with EPP.

Design, Setting, and Participants  Retrospective medical record review carried out in a pediatric dermatology practice at an academic institution of patients diagnosed with EPP who were younger than 18 years and treated with systemic cimetidine in the past 3 years.

Interventions  Systemic cimetidine.

Main Outcomes and Measures  Resolution of skin photodamage was evaluated on clinical examination. Subjective measures including tolerability to sun exposure, ability to participate in outdoor activities, and objective evaluation including serum erythrocyte protoporphyrin levels and liver function tests following treatment were assessed.

Results  All 3 cases reported a rapid reduction in photosensitivity within weeks following initiation of systemic therapy. Their skin photodamage were also improved or resolved completely on subsequent examination. Laboratory study results also revealed reduction in serum erythrocyte protoporphyrin levels and improved liver function. None of the patients have reported any adverse effects of the systemic treatment after more than 2 years of treatment.

Conclusions and Relevance  Children with EPP currently have limited therapeutic options and experience substantial disease impact on their quality of life. This is the first case series demonstrating that cimetidine, a readily available oral medication, can be a promising treatment for children with EPP.

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Figure 1.
Painful, Blistering Photosensitivity of the Hands in a Young Child

A, Child’s hands at baseline before treatment. B, Reduction of photosensitivity of the child’s hands noted at approximately 1 month following initiation of cimetidine treatment.

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Figure 2.
A Case of Erythropoietic Protoporphyria in a Young Child

A, Child’s face at baseline before treatment. B, Clinical improvement of photosensitivity of the child’s face after 1 month of cimetidine therapy.

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Novel Treatment Using Cimetidine for Erythropoietic Protoporphyria in Children. A Comment
Posted on August 16, 2016
Elisabeth I. Minder, Jasmin Barman-Aksözen, Prof. Dr.Jean-Charles Deybach, Xiaoye Schneider-Yin
Stadtspital Triemli, APZ Porphyria Outpatient Clinic & Institute of Laboratory Medicine, 3) Biochimie et Génétique moléculaire; Centre Français des Porphyries; European Porphyr
Conflict of Interest: EIM was the principal investigator in both phase II and III trials (CUV010 and/or CUV017) of afamelanotide in the prevention of phototoxicity in erythropoietic protoporphyria. Later she acted as physician during a subsequent compassionate use phase and special access scheme for afamelanotide in EPP. The trials and the compassionate use programs were sponsored by Clinuvel Pharmaceuticals Ltd., Australia. EIM has received an unrestricted research grant 2009, an educational grant 2015 and support for the organisation of the international congress of porphyrins and porphyrias 2013 from Clinuvel Pharmaceuticals Ltd., Australia.
JCD was the principal investigator during two phase III trials (CUV017 and CUV029).
The authors declare that neither Clinuvel Pharmaceuticals Ltd., Australia, nor any other pharmaceutical company had any influence on the content of this manuscript.
To the editor,
The publication of Tu JH et al emphasizes the necessity to effectively prevent the excruciatingly painful phototoxic skin reactions of erythropoietic protoporphyria (EPP) in children (1). We agree with the authors that inhibition of erythrocytic aminolevulinate synthase (ALAS2), the rate-limiting step in erythrocyte heme formation, could improve EPP symptoms (2). However, the authors’ hypothesis that cimetidine inhibits ALAS2, is ill-founded: Cimetidine has no direct effect on liver aminolevulinate synthase, but rather it inhibits liver heme oxygenase (HO) and thereby increases liver heme concentration(3). Heme in turn exerts a negative feedback on the ubiquitous aminolevulinate synthase (ALAS1) in the liver. The effect of cimetidine has not been studied in erythropoiesis. HO is no longer expressed in the late erythropoiesis when EPP-related protoporphyrin accumulation occurs. The influence of the heme level on ALAS2 activity may be both positive and negative, presumably dependent on the developmental stage of erythrocyte precursors (4-6).
In case 3 of the publication of Tu et al. (1), no erythrocyte protoporphyrin level is reported - a significant increase of which is essential to confirm the diagnosis ‘EPP’. Instead, the authors mention “mutations in FECH2 gene”. Actually, no FECH2 gene has been described until now. The neonatal hyperbilirubinemia and phototherapy-induced skin burning described in this case are well-known complications of congenital erythropoietic porphyria (CEP), and they have never been described in EPP. The scars with depigmentation on the right hand displayed in figure 1A support a diagnosis of CEP instead of EPP.
Finally, cimetidine application has been studied for a limited treatment period of seven days only (https://www.drugs-com/dosage/cimetidine.html). However, for a genetic disease such as EPP, a life-long treatment would be required. Furthermore, the applied dosage of 30-40 mg/kg/day, appropriate only for short-term usage in children, exceeds by a factor two the dose recommended for long-term treatment of childhood cystic fibrosis (7). On prolonged application, cimetidine inhibits its own metabolism, which leads to accumulation of the parent drug and its metabolites. Specific adverse effects, including anti-androgenic effects, psychiatric disorders, a decrease in triiodothyronine/thyronine ratio and delayed hypersensitivity effects are associated with chronic exposure (8). These known adverse effects of cimetidine, especially at higher doses, could disqualify this drug for the long-term treatment of the inherited disease EPP.
We conclude that the application of excessive doses of cimetidine in children with EPP should be subjected to a thorough evaluation, before it can be recommended for prevention of phototoxic skin reactions in EPP.

Reference List

(1) Tu JH, Sheu SL, Teng JM. Novel Treatment Using Cimetidine for Erythropoietic Protoporphyria in Children. JAMA Dermatol 2016.
(2) Minder EI, Barman-Aksozen J. Iron and erythropoietic porphyrias. Blood 2015;126:130-132.
(3) Marcus DL, Halbrecht JL, Bourque AL, Lew G, Nadel H, Freedman ML. Effect of cimetidine on delta-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver. Biochem Pharmacol 1984;33:2005-2008.
(4) Hoffman R, Ibrahim N, Murnane MJ, Diamond A, Forget BG, Levere RD. Hemin control of heme biosynthesis and catabolism in a human leukemia cell line. Blood 1980;56:567-570.
(5) Smith SJ, Cox TM. Translational control of erythroid delta-aminolevulinate synthase in immature human erythroid cells by heme. Cell Mol Biol (Noisy -le-grand) 1997;43:103-114.
(6) Mu A, Li M, Tanaka M et al. Enhancements of the production of bilirubin and the expression of beta-globin by carbon monoxide during erythroid differentiation. FEBS Lett 2016;590:1447-1454.
(7) Ziemniak JA, Assael BM, Padoan R, Schentag JJ. The bioavailability and pharmacokinetics of cimetidine and its metabolites in juvenile cystic fibrosis patients: age related differences as compared to adults. Eur J Clin Pharmacol 1984;26:183-189.
(8) Prandota J, Smith IJ, Wilson JT. Dosage regimen of cimetidine reviewed. Possible drug accumulation after multiple oral doses. Eur J Clin Pharmacol 1988;34:539-542.


Novel Treatment Using Cimetidine for Erythropoietic Protoporphyria in Children. A Comment
Posted on August 16, 2016
Elisabeth I. Minder, Jasmin Barman-Aksözen, Prof. Dr.Jean-Charles Deybach, Xiaoye Schneider-Yin
Stadtspital Triemli, APZ Porphyria Outpatient Clinic & Institute of Laboratory Medicine, 3) Biochimie et Génétique moléculaire; Centre Français des Porphyries; European Porphyr
Conflict of Interest: EIM was the principal investigator in both phase II and III trials (CUV010 and/or CUV017) of afamelanotide in the prevention of phototoxicity in erythropoietic protoporphyria. Later she acted as physician during a subsequent compassionate use phase and special access scheme for afamelanotide in EPP. The trials and the compassionate use programs were sponsored by Clinuvel Pharmaceuticals Ltd., Australia. EIM has received an unrestricted research grant 2009, an educational grant 2015 and support for the organisation of the international congress of porphyrins and porphyrias 2013 from Clinuvel Pharmaceuticals Ltd., Australia.
JCD was the principal investigator during two phase III trials (CUV017 and CUV029).
The authors declare that neither Clinuvel Pharmaceuticals Ltd., Australia, nor any other pharmaceutical company had any influence on the content of this manuscript.
To the editor,
The publication of Tu JH et al emphasizes the necessity to effectively prevent the excruciatingly painful phototoxic skin reactions of erythropoietic protoporphyria (EPP) in children (1). We agree with the authors that inhibition of erythrocytic aminolevulinate synthase (ALAS2), the rate-limiting step in erythrocyte heme formation, could improve EPP symptoms (2). However, the authors’ hypothesis that cimetidine inhibits ALAS2, is ill-founded: Cimetidine has no direct effect on liver aminolevulinate synthase, but rather it inhibits liver heme oxygenase (HO) and thereby increases liver heme concentration(3). Heme in turn exerts a negative feedback on the ubiquitous aminolevulinate synthase (ALAS1) in the liver. The effect of cimetidine has not been studied in erythropoiesis. HO is no longer expressed in the late erythropoiesis when EPP-related protoporphyrin accumulation occurs. The influence of the heme level on ALAS2 activity may be both positive and negative, presumably dependent on the developmental stage of erythrocyte precursors (4-6).
In case 3 of the publication of Tu et al. (1), no erythrocyte protoporphyrin level is reported - a significant increase of which is essential to confirm the diagnosis ‘EPP’. Instead, the authors mention “mutations in FECH2 gene”. Actually, no FECH2 gene has been described until now. The neonatal hyperbilirubinemia and phototherapy-induced skin burning described in this case are well-known complications of congenital erythropoietic porphyria (CEP), and they have never been described in EPP. The scars with depigmentation on the right hand displayed in figure 1A support a diagnosis of CEP instead of EPP.
Finally, cimetidine application has been studied for a limited treatment period of seven days only (https://www.drugs-com/dosage/cimetidine.html). However, for a genetic disease such as EPP, a life-long treatment would be required. Furthermore, the applied dosage of 30-40 mg/kg/day, appropriate only for short-term usage in children, exceeds by a factor two the dose recommended for long-term treatment of childhood cystic fibrosis (7). On prolonged application, cimetidine inhibits its own metabolism, which leads to accumulation of the parent drug and its metabolites. Specific adverse effects, including anti-androgenic effects, psychiatric disorders, a decrease in triiodothyronine/thyronine ratio and delayed hypersensitivity effects are associated with chronic exposure (8). These known adverse effects of cimetidine, especially at higher doses, could disqualify this drug for the long-term treatment of the inherited disease EPP.
We conclude that the application of excessive doses of cimetidine in children with EPP should be subjected to a thorough evaluation, before it can be recommended for prevention of phototoxic skin reactions in EPP.

Reference List

(1) Tu JH, Sheu SL, Teng JM. Novel Treatment Using Cimetidine for Erythropoietic Protoporphyria in Children. JAMA Dermatol 2016.
(2) Minder EI, Barman-Aksozen J. Iron and erythropoietic porphyrias. Blood 2015;126:130-132.
(3) Marcus DL, Halbrecht JL, Bourque AL, Lew G, Nadel H, Freedman ML. Effect of cimetidine on delta-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver. Biochem Pharmacol 1984;33:2005-2008.
(4) Hoffman R, Ibrahim N, Murnane MJ, Diamond A, Forget BG, Levere RD. Hemin control of heme biosynthesis and catabolism in a human leukemia cell line. Blood 1980;56:567-570.
(5) Smith SJ, Cox TM. Translational control of erythroid delta-aminolevulinate synthase in immature human erythroid cells by heme. Cell Mol Biol (Noisy -le-grand) 1997;43:103-114.
(6) Mu A, Li M, Tanaka M et al. Enhancements of the production of bilirubin and the expression of beta-globin by carbon monoxide during erythroid differentiation. FEBS Lett 2016;590:1447-1454.
(7) Ziemniak JA, Assael BM, Padoan R, Schentag JJ. The bioavailability and pharmacokinetics of cimetidine and its metabolites in juvenile cystic fibrosis patients: age related differences as compared to adults. Eur J Clin Pharmacol 1984;26:183-189.
(8) Prandota J, Smith IJ, Wilson JT. Dosage regimen of cimetidine reviewed. Possible drug accumulation after multiple oral doses. Eur J Clin Pharmacol 1988;34:539-542.


To the Editor
Posted on August 29, 2016
Manisha Balwani, MD, MS , Karl E. Anderson, MD, Robert J. Desnick, PhD, MD on behalf of the NIH-supported Porphyrias Consortium of the Rare Diseases Clinical Research Network Investigators.
1) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, NY 2 ) Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galvesto
Conflict of Interest: None Declared
We appreciate that the repurposing of FDA-approved drugs for other diseases is attractive, but are concerned by the report by Tu et al (1) on the use of cimetidine to treat children with erythropoietic protoporphyria (EPP).

The Porphyrias Consortium has evaluated over 200 adults and children with biochemically and mutation confirmed EPP (2). Based on our experience, we raise significant issues with this report, including incorrect statements about the clinical presentation (EPP patients have acute pain with sunlight exposure and don’t typically have bullae, erosions and blistering skin lesions), inadequate diagnostic documentation, incorrect nomenclature for the ferrochelatase gene (FECH, not FECH2), and no information on the specific FECH mutations, which are important for diagnostic confirmation.

Diagnostic testing for EPP includes erythrocyte total protoporphyrin, usually reported in mcg/dl, and a predominance of metal-free protoporphyrin (zinc-protoporphyrin predominates in other conditions that increase total protoporphyrin). Some laboratories measure only zinc-protoporphyrin but may misleadingly report results as “erythrocyte protoporphyrin” or “free protoporphyrin” (3). The authors mention both “erythrocyte protoporphyrin” and “serum erythrocyte protoporphyrin” in µmol/L; it is not clear whether they are referring to erythrocyte or serum levels, and amounts of metal-free protoporphyrin, normal ranges and testing methods are not described. In our experience, erythrocyte total protoporphyrin levels can vary significantly over time in EPP and variations in serum (or plasma) porphyrin levels are even greater. The authors’ unconvincing inference that cimetidine is a safe and effective treatment for EPP is based on only baseline and post-treatment protoporphyrin levels in 2 of the 3 cases. ALT and AST levels are intermittently and modestly elevated in some EPP patients, and a decrease may not indicate a therapeutic effect.

In our experience, sunlight tolerance can vary considerably over time in EPP (4), and the subjective improvement reported in these 3 cases is insufficient to indicate efficacy. Cimetidine, which is a known inhibitor of cytochrome P450 enzymes (CYPs), has only been shown to ameliorate an increase in hepatic ALAS1 in rodents treated with a chemical that, to cause porphyria and ALAS1 induction, requires activation by CYPs. In fact, cimetidine did not inhibit hepatic ALAS1 in vitro (5).

For these reasons, we contend that this report, along with other anecdotal reports in the literature, do not provide the rationale or proof-of-concept support for the use of cimetidine in EPP. The last sentence stating that social media provided additional validation of effectiveness in other patients is unreliable in the absence of supporting data.

References
1.Tu JH, Sheu SL, Teng JM. Novel Treatment Using Cimetidine for Erythropoietic Protoporphyria in Children. JAMA Dermatol. 2016 Jul 13. [Epub ahead of print]
2. https://www.rarediseasesnetwork.org/cms/porphyrias
3. Gou EW, Balwani M, Bissell DM et al. Pitfalls in Erythrocyte Protoporphyrin Measurement for Diagnosis and Monitoring of Protoporphyrias. Clin Chem. 2015 Dec;61(12):1453-6.
4. Langendonk JG, Balwani M, Anderson KE et al. Afamelanotide for Erythropoietic Protoporphyria. N Engl J Med. 2015 Jul 2;373(1):48-59.
5. Marcus DL, Halbrecht JL, Bourque AL et al. Effect of cimetidine on delta-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver. Biochem Pharmacol. 1984 Jul 1;33(13):2005-8.

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