Review
Cutaneous porphyrias part II: treatment strategies Suzanne Tintle1, MD, MPH, Ali Alikhan2, MD, Mary E. Horner3, MD, Jennifer L. Hand2,4,5, MD, and Dawn Marie R. Davis2,4, MD
1 Department of Dermatology, Tufts Medical Center, Boston, MA, USA, 2Department of Dermatology, Mayo Clinic, Rochester, MN, USA, 3Department of Dermatology, Baylor University Medical Center, Dallas, TX, USA, 4Department of Pediatrics, Mayo Clinic, Rochester, MN, USA, and 5 Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA
Correspondence Ali Alikhan, MD Department of Dermatology, Mayo Clinic 200 First Street SW Rochester MN 55905 USA E-mail: [email protected]
Abstract The porphyrias are diverse in pathophysiology, clinical presentation, severity, and prognosis, presenting a diagnostic and therapeutic challenge. Although not easily curable, the dermatological manifestations of these diseases, photosensitivity and associated cutaneous pathology, can be effectively prevented and managed. Sun avoidance is essential, and patient education regarding the irreversibility of photocutaneous damage is a necessary corollary. Beyond preventative measures, the care of fragile, vulnerable skin, and pain management, each of the porphyrias has a limited number of unique additional therapeutic options. Many of the treatments have been published only in small case series or anecdotal reports and do not have well-understood nor proven mechanisms of action. This article presents a comprehensive review of available therapeutic options and longterm management recommendations for the cutaneous porphyrias.
Funding: None. Conflicts of interest: None.
Introduction
Sun avoidance in the porphyrias
The treatment of porphyrias is challenging: each porphyria has a unique pathogenesis; several of the subtypes are quite rare, and the degree of clinical symptomatology varies greatly among patients. As a result of these characteristics, and of the lack of defined clinical endpoints, there are very few randomized controlled trials on therapeutic approaches to the porphyrias. Most reports are small case series that lack controls, and several commonly used historic therapies lack clear mechanisms of action. However, the basic tenets of therapy in all the porphyrias are sun avoidance and care of vulnerable skin. Given the potential complications of these diseases, a heightened awareness about the porphyrias is important, especially when a patient presents with concerns of photosensitivity. The complicated and progressive nature of these diseases causes substantial patient morbidity, which emphasizes the importance of effective patient education and appropriate, dedicated long-term management. Recommendations for the general management of porphyrias are shown in Table 1.
Patients with porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP), hereditary coproporphyria (HCP), and variegate porphyria (VP) experience photosensitivity, although the degree of light restriction required varies according to disease severity. For patients in whom diagnosis is delayed, certain cutaneous manifestations, such as hyperpigmentation, hypertrichosis, and sclerodermoid skin changes, may not show complete resolution.1 In the photosensitive porphyrias, either excess porphyrins that have accumulated in the skin and dermal vessels (in PCT, HEP, HCP, and VP), or porphyrin-laden erythrocytes in dermal vessels (in EPP and CEP) are catalyzed and produce singlet oxygen molecules upon skin exposure to visible light (predominantly wavelengths of 400–410 nm [the Soret band], as well as four additional absorption bands of decreasing intensity in the range of 500–700 nm). Consequent oxidative damage leads to clinical phototoxicity manifesting as skin fragility; patients develop vesicles, blisters, and bullae when sun-exposed skin is subject to 3
ª 2013 The International Society of Dermatology
International Journal of Dermatology 2014, 53, 3–24
4
Review
Cutaneous porphyrias: treatment strategies
Table 1 General management of porphyrias Avoidance of sunlight (protective clothing, opaque sunscreens, window filters, PCT, VP, HCP, HEP, CEP) Avoidance of skin trauma with appropriate wound care and infection prevention (PCT, VP, HCP, HEP, CEP) Avoidance of exacerbating factors (alcohol, tobacco, estrogens, iron supplementation, PCT, HEP) Avoidance of precipitating factors of acute porphyric attacks (fasting/low-caloric intake, smoking, infections, porphyrinogenic drug exposure,a hormonal fluctuations, AIP, ADP, HCP, VP, HEP) Antiviral treatment for hepatitis Screening for hemochromatosis (PCT) Vitamin D supplementation in photosensitive porphyrias (PCT, VP, HCP, HEP, CEP) Annual examinations to check plasma, urinary and fecal porphyrins appropriate for each type of porphyria and hepatic function; more frequent follow-up in severe cases
AIP, acute intermittent porphyria; ADP, ALA-dehydratase deficiency porphyria; CEP, congenital erythropoietic porphyria; HCP, hereditary coproporphyria; HEP, hepatoerythropoietic porphyria; PCT, porphyria cutanea tarda; VP, variegate porphyria. a For a list of medications that are safe and unsafe, see http: // www.drugs-porphyria.org in Europe, South Africa, and Canada and http://www.porphyriafoundation.com in the USA.
mild trauma. In addition to protection from light, complete management of porphyria includes awareness of vitamin D deficiency, which is common and often severe in porphyria patients,2 and counseling for patients of all ages to address the psychosocial effects of light avoidance.3 Protection from visible light spectra
Only physical block sunscreens containing zinc oxide or titanium dioxide are effective in protecting against light wavelengths of >400 nm. Non-micronized zinc oxide provides more complete protection in the ultraviolet (UV) A range and at wavelengths of >400 nm and is therefore preferred over titanium dioxide.4 Zinc oxide and titanium dioxide pastes are available in most major drugstores but may be impractical or cosmetically unacceptable for daily application for many patients. Micronized (ultrafine) forms (packaging is typically labeled as such) may be more translucent and easily applied than the non-micronized pastes. However, the finer particles in micronized pastes reflect less light and provide only partial protection at best.5–7 Protection from ultraviolet light spectra
In the cutaneous porphyrias, protection against UVA wavelengths (320–400 nm) is particularly important; wavelengths as low as 360 nm can cause patient phototoxicity.3 The majority of available sunscreens provide adequate UVB protection. By contrast, the lack of photostability of International Journal of Dermatology 2014, 53, 3–24
Tintle et al.
UVA filters (e.g. avobenzone) has historically limited sufficient protection against UVA light.7,8 The best protection against UVA and UVB is still provided by physical blockers such as non-micronized zinc oxide and titanium dioxide. Additionally, photostable UVA filters that do not degrade when exposed to radiation have recently been discovered. These include ecamsule (Mexoryl SX), drometrizole trisiloxane (Mexoryl XL), and bemotrizinol (Tinosorb S), which are found in sunscreens marketed under the trade names of Anthelios SX+XL® (Vichy, France), Anthelios XL,® and Daylong® (Spirig Pharma AG, Egerkingen, Switzerland). Mexoryl SX is currently the only one of these three filters to be approved for use in the USA.4 Self-tanning agents containing dihydroxyacetone, which can block longer UVA wavelengths and visible light to a degree,9 may provide some benefit to patients (but usually provide only ancillary protection).10 Use of UV protection factor clothing and UV-protective window films should be encouraged. Plastic films that attenuate the transmission of portions of the visible light and UVA spectra are available and can be applied to window or windshield glass. Use of hats, gloves, and lip balm with sunscreen should be encouraged. Eyeglasses with UV film can prevent conjunctival damage and scleromalacia (sunglasses with the UV400 label, readily available in the USA, should filter the complete UV range).3,9 Artificial lighting, including incandescent, halogen, fluorescent, and newer compact fluorescent lighting, may emit a small amount of UVA light and cause cutaneous toxicity in sensitive patients, especially at close distances.11 Studies have shown that incandescent and halogen lights emit more UVA and UVB light than fluorescent lighting, which in most commercial spaces is contained in protective coated tubing. Newer, energy-efficient fluorescent lights, which are replacing traditional incandescent bulbs in the USA, have also shown lower UVA and UVB output than incandescent and halogen lamps (of the compact fluorescent lamps, shielded versions are probably the most protective).11 a-Melanocyte-stimulating hormone analogs
a-Melanocyte-stimulating hormone (a-MSH) analogs, which act by binding to the melanocortin-1 receptor on melanocytes to induce the synthesis of melanin, may have promise in photosensitive diseases, including the porphyrias.12 The synthetic analog Nle4-d-Phe7-a-MSH (afamelanotide) may be up to 100 times more active than the native hormone in its ability to induce melanin synthesis, thereby reducing epidermal cell damage.13,14 Afamelanotide is administered through subcutaneous injection and is currently available for off-label use. As a slow-release formulation, the drug induced a long-lasting increase in melanin pigmentation in healthy human volunteers, including ª 2013 The International Society of Dermatology
Tintle et al.
those with fair skin, without significant adverse effects.15,16 However, the long-term risks of the drug are unknown,17 and recent reports have described an increased incidence of new or changing dysplastic nevi in patients taking afemelanotide.17,18 In a 2009 study, afamelanotide was administered to five EPP patients (see Erythropoietic protoporphyria, Afamelanotide), who experienced considerable clinical improvement in light tolerance.14,19 Side effects included short-term nausea and headache, and no laboratory abnormalities were observed. The authors had previously reported the use of the a-MSH analog in a patient with CEP, who experienced a reduction in cutaneous sensitivity and an improvement in quality of life, and described a plan to use the drug in a patient with HEP (results not yet reported).20 To our knowledge, the use of afamelanotide has not yet been reported in patients with other types of porphyria. Porphyria cutanea tarda General maintenance and prevention of PCT exacerbations
The simplest treatment of PCT involves the avoidance of exogenous exacerbating factors, although only rarely will this be enough to induce clinical remission.21 Alcohol and tobacco use should be prohibited; both products are major precipitating factors of PCT,22,23 as well as independent risk factors for hepatocellular carcinoma (HCC),24,25 a major cause of morbidity in PCT patients. Patients may improve dramatically with alcohol abstinence,26,27 but response is often unpredictable or slow.21 Estrogen is another independent risk factor for PCT. Estrogen exposure through oral contraceptives, postmenopausal hormone therapy, or pregnancy is the sole risk factor in up to 25% of female patients with PCT.22,28 Clinical and biochemical remission has been reported in women who terminate the use of estrogens but only when exposure was not prolonged.29 In one report, suppression of endogenous postmenopausal estrogen levels by the aromatase inhibitor anastrazole, administered for breast cancer prophylaxis, resulted in improvement in PCT symptoms.30 Patients may be advised to limit manual labor as much as possible to minimize mechanical trauma that causes erosions and blistering. Skin lesions can be managed with simple wound care to promote healing, and the judicious treatment of bacterial infections may prevent cutaneous scarring.31 Antimalarial medications (low-dose chloroquine or hydroxychloroquine)
The safety and efficacy of low-dose chloroquine (12532,33 to 250 mg34–36 administered orally twice per week) and ª 2013 The International Society of Dermatology
Cutaneous porphyrias: treatment strategies
Review
hydroxychloroquine (100 mg, orally, two or three times per week) are comparable with those of phlebotomy treatment in PCT, but these forms of therapy are much more convenient and less expensive and thus are preferred at some centers.37–42 Importantly, antimalarials do not cause significant iron depletion and may not be appropriate for PCT patients with significant iron overload.43 Likewise, patients with insufficient renal function to excrete the high levels of porphyrin complexes formed by antimalarial medications require alternative therapies (see Additional therapies for PCT). The exact mechanism of the antimalarials in PCT remains unknown.44 The medications have been reported to form complexes with uroporphyrin, promoting its release from the liver and causing urinary excretion of porphyrins.45 Chloroquine also accumulates in the skin, in which it absorbs both UVA and UVB light and prevents UV-induced erythema.46 Clinical improvement of skin fragility with antimalarial treatment typically takes 4–6 months, and complete remission can be achieved in 10–12 months, similarly to phlebotomy.32,34,36,47 Remission typically lasts 17–24 months, although complete remission is possible.48 Clinically, the two medications achieve similar results except that hydroxychloroquine (given at 200 mg twice weekly in these studies) may have provided a shorter remission period than chloroquine.40,47 Of note, normal doses of chloroquine used for antimalarial or photoprotective indications (e.g. 200 mg/d) can result in excessive porphyrin release from the liver, paradoxically leading to acute hepatic damage.49 Marked increases in ferritin, liver transaminases, and other liver function tests may occur, along with nausea, fever, malaise, and fatigue. In addition, cutaneous manifestations may acutely increase. Standard dosing of chloroquine has been reported to unmask previously unrecognized cases of PCT.50,51 Lower dosing allows porphyrins to be gradually mobilized from the liver without increasing plasma porphyrin levels or inducing hepatocellular damage.52,53 Prior to initiation of treatment with antimalarials, patients should be tested for glucose 6-phosphate dehydrogenase deficiency. Monthly monitoring of liver function tests is recommended, and patient response to treatment can be followed by monthly plasma or urine porphyrin levels.33 Common side effects of antimalarials in the normal population include gastrointestinal upset, allergic skin reactions, headache, and lightheadedness.54 The most feared complication is retinopathy, which results in loss of vision.55 Its exact incidence is unknown, but retinopathy is more likely in patients receiving higher doses of medication for long periods.56 The American Academy of Ophthalmology screening guidelines recommend that International Journal of Dermatology 2014, 53, 3–24
5
6
Review
Cutaneous porphyrias: treatment strategies
patients should undergo a baseline ophthalmologic examination within one year of starting therapy and should undergo follow-up examinations at intervals of 6–60 months based upon patient risk factors.57 Risk factors include age >60 years, concomitant liver or kidney disease, high doses of drug (>3 mg/kg/d of chloroquine or >6.5 mg/kg/d of hydroxychloroquine), duration of use for 5 years, high body fat percentage, and concomitant retinal disease.57 Phlebotomy
Phlebotomy, which has been used for many conditions and illnesses since antiquity, is the definitive treatment for PCT.58 Withdrawal of blood reduces iron stores and liver iron content, thereby interrupting the pathway of oxidation of hepatic porphyrinogens to porphyrins.26,59,60 Most patients with PCT exhibit a degree of iron overload, and phlebotomy is especially important in patients with hepatitis C, excessive alcohol consumption, and HFE mutations as these patients are at higher risk for the sequelae of hepatic siderosis (e.g. liver cirrhosis and HCC).61 General phlebotomy guidelines suggest the removal of 7 ml of blood per kg body weight, not to exceed 550 ml in one session.62 Phlebotomy may be performed once or twice weekly until serum levels of ferritin reach the lower limit of normal and then once biweekly or monthly as dictated by pretreatment laboratory values and maintenance of a hemoglobin level appropriate for the patient.63–65 Phlebotomies are continued until 24-hour porphyrin excretion falls to normal levels (
Cutaneous porphyrias part II: treatment strategies Suzanne Tintle1, MD, MPH, Ali Alikhan2, MD, Mary E. Horner3, MD, Jennifer L. Hand2,4,5, MD, and Dawn Marie R. Davis2,4, MD
1 Department of Dermatology, Tufts Medical Center, Boston, MA, USA, 2Department of Dermatology, Mayo Clinic, Rochester, MN, USA, 3Department of Dermatology, Baylor University Medical Center, Dallas, TX, USA, 4Department of Pediatrics, Mayo Clinic, Rochester, MN, USA, and 5 Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA
Correspondence Ali Alikhan, MD Department of Dermatology, Mayo Clinic 200 First Street SW Rochester MN 55905 USA E-mail: [email protected]
Abstract The porphyrias are diverse in pathophysiology, clinical presentation, severity, and prognosis, presenting a diagnostic and therapeutic challenge. Although not easily curable, the dermatological manifestations of these diseases, photosensitivity and associated cutaneous pathology, can be effectively prevented and managed. Sun avoidance is essential, and patient education regarding the irreversibility of photocutaneous damage is a necessary corollary. Beyond preventative measures, the care of fragile, vulnerable skin, and pain management, each of the porphyrias has a limited number of unique additional therapeutic options. Many of the treatments have been published only in small case series or anecdotal reports and do not have well-understood nor proven mechanisms of action. This article presents a comprehensive review of available therapeutic options and longterm management recommendations for the cutaneous porphyrias.
Funding: None. Conflicts of interest: None.
Introduction
Sun avoidance in the porphyrias
The treatment of porphyrias is challenging: each porphyria has a unique pathogenesis; several of the subtypes are quite rare, and the degree of clinical symptomatology varies greatly among patients. As a result of these characteristics, and of the lack of defined clinical endpoints, there are very few randomized controlled trials on therapeutic approaches to the porphyrias. Most reports are small case series that lack controls, and several commonly used historic therapies lack clear mechanisms of action. However, the basic tenets of therapy in all the porphyrias are sun avoidance and care of vulnerable skin. Given the potential complications of these diseases, a heightened awareness about the porphyrias is important, especially when a patient presents with concerns of photosensitivity. The complicated and progressive nature of these diseases causes substantial patient morbidity, which emphasizes the importance of effective patient education and appropriate, dedicated long-term management. Recommendations for the general management of porphyrias are shown in Table 1.
Patients with porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP), hereditary coproporphyria (HCP), and variegate porphyria (VP) experience photosensitivity, although the degree of light restriction required varies according to disease severity. For patients in whom diagnosis is delayed, certain cutaneous manifestations, such as hyperpigmentation, hypertrichosis, and sclerodermoid skin changes, may not show complete resolution.1 In the photosensitive porphyrias, either excess porphyrins that have accumulated in the skin and dermal vessels (in PCT, HEP, HCP, and VP), or porphyrin-laden erythrocytes in dermal vessels (in EPP and CEP) are catalyzed and produce singlet oxygen molecules upon skin exposure to visible light (predominantly wavelengths of 400–410 nm [the Soret band], as well as four additional absorption bands of decreasing intensity in the range of 500–700 nm). Consequent oxidative damage leads to clinical phototoxicity manifesting as skin fragility; patients develop vesicles, blisters, and bullae when sun-exposed skin is subject to 3
ª 2013 The International Society of Dermatology
International Journal of Dermatology 2014, 53, 3–24
4
Review
Cutaneous porphyrias: treatment strategies
Table 1 General management of porphyrias Avoidance of sunlight (protective clothing, opaque sunscreens, window filters, PCT, VP, HCP, HEP, CEP) Avoidance of skin trauma with appropriate wound care and infection prevention (PCT, VP, HCP, HEP, CEP) Avoidance of exacerbating factors (alcohol, tobacco, estrogens, iron supplementation, PCT, HEP) Avoidance of precipitating factors of acute porphyric attacks (fasting/low-caloric intake, smoking, infections, porphyrinogenic drug exposure,a hormonal fluctuations, AIP, ADP, HCP, VP, HEP) Antiviral treatment for hepatitis Screening for hemochromatosis (PCT) Vitamin D supplementation in photosensitive porphyrias (PCT, VP, HCP, HEP, CEP) Annual examinations to check plasma, urinary and fecal porphyrins appropriate for each type of porphyria and hepatic function; more frequent follow-up in severe cases
AIP, acute intermittent porphyria; ADP, ALA-dehydratase deficiency porphyria; CEP, congenital erythropoietic porphyria; HCP, hereditary coproporphyria; HEP, hepatoerythropoietic porphyria; PCT, porphyria cutanea tarda; VP, variegate porphyria. a For a list of medications that are safe and unsafe, see http: // www.drugs-porphyria.org in Europe, South Africa, and Canada and http://www.porphyriafoundation.com in the USA.
mild trauma. In addition to protection from light, complete management of porphyria includes awareness of vitamin D deficiency, which is common and often severe in porphyria patients,2 and counseling for patients of all ages to address the psychosocial effects of light avoidance.3 Protection from visible light spectra
Only physical block sunscreens containing zinc oxide or titanium dioxide are effective in protecting against light wavelengths of >400 nm. Non-micronized zinc oxide provides more complete protection in the ultraviolet (UV) A range and at wavelengths of >400 nm and is therefore preferred over titanium dioxide.4 Zinc oxide and titanium dioxide pastes are available in most major drugstores but may be impractical or cosmetically unacceptable for daily application for many patients. Micronized (ultrafine) forms (packaging is typically labeled as such) may be more translucent and easily applied than the non-micronized pastes. However, the finer particles in micronized pastes reflect less light and provide only partial protection at best.5–7 Protection from ultraviolet light spectra
In the cutaneous porphyrias, protection against UVA wavelengths (320–400 nm) is particularly important; wavelengths as low as 360 nm can cause patient phototoxicity.3 The majority of available sunscreens provide adequate UVB protection. By contrast, the lack of photostability of International Journal of Dermatology 2014, 53, 3–24
Tintle et al.
UVA filters (e.g. avobenzone) has historically limited sufficient protection against UVA light.7,8 The best protection against UVA and UVB is still provided by physical blockers such as non-micronized zinc oxide and titanium dioxide. Additionally, photostable UVA filters that do not degrade when exposed to radiation have recently been discovered. These include ecamsule (Mexoryl SX), drometrizole trisiloxane (Mexoryl XL), and bemotrizinol (Tinosorb S), which are found in sunscreens marketed under the trade names of Anthelios SX+XL® (Vichy, France), Anthelios XL,® and Daylong® (Spirig Pharma AG, Egerkingen, Switzerland). Mexoryl SX is currently the only one of these three filters to be approved for use in the USA.4 Self-tanning agents containing dihydroxyacetone, which can block longer UVA wavelengths and visible light to a degree,9 may provide some benefit to patients (but usually provide only ancillary protection).10 Use of UV protection factor clothing and UV-protective window films should be encouraged. Plastic films that attenuate the transmission of portions of the visible light and UVA spectra are available and can be applied to window or windshield glass. Use of hats, gloves, and lip balm with sunscreen should be encouraged. Eyeglasses with UV film can prevent conjunctival damage and scleromalacia (sunglasses with the UV400 label, readily available in the USA, should filter the complete UV range).3,9 Artificial lighting, including incandescent, halogen, fluorescent, and newer compact fluorescent lighting, may emit a small amount of UVA light and cause cutaneous toxicity in sensitive patients, especially at close distances.11 Studies have shown that incandescent and halogen lights emit more UVA and UVB light than fluorescent lighting, which in most commercial spaces is contained in protective coated tubing. Newer, energy-efficient fluorescent lights, which are replacing traditional incandescent bulbs in the USA, have also shown lower UVA and UVB output than incandescent and halogen lamps (of the compact fluorescent lamps, shielded versions are probably the most protective).11 a-Melanocyte-stimulating hormone analogs
a-Melanocyte-stimulating hormone (a-MSH) analogs, which act by binding to the melanocortin-1 receptor on melanocytes to induce the synthesis of melanin, may have promise in photosensitive diseases, including the porphyrias.12 The synthetic analog Nle4-d-Phe7-a-MSH (afamelanotide) may be up to 100 times more active than the native hormone in its ability to induce melanin synthesis, thereby reducing epidermal cell damage.13,14 Afamelanotide is administered through subcutaneous injection and is currently available for off-label use. As a slow-release formulation, the drug induced a long-lasting increase in melanin pigmentation in healthy human volunteers, including ª 2013 The International Society of Dermatology
Tintle et al.
those with fair skin, without significant adverse effects.15,16 However, the long-term risks of the drug are unknown,17 and recent reports have described an increased incidence of new or changing dysplastic nevi in patients taking afemelanotide.17,18 In a 2009 study, afamelanotide was administered to five EPP patients (see Erythropoietic protoporphyria, Afamelanotide), who experienced considerable clinical improvement in light tolerance.14,19 Side effects included short-term nausea and headache, and no laboratory abnormalities were observed. The authors had previously reported the use of the a-MSH analog in a patient with CEP, who experienced a reduction in cutaneous sensitivity and an improvement in quality of life, and described a plan to use the drug in a patient with HEP (results not yet reported).20 To our knowledge, the use of afamelanotide has not yet been reported in patients with other types of porphyria. Porphyria cutanea tarda General maintenance and prevention of PCT exacerbations
The simplest treatment of PCT involves the avoidance of exogenous exacerbating factors, although only rarely will this be enough to induce clinical remission.21 Alcohol and tobacco use should be prohibited; both products are major precipitating factors of PCT,22,23 as well as independent risk factors for hepatocellular carcinoma (HCC),24,25 a major cause of morbidity in PCT patients. Patients may improve dramatically with alcohol abstinence,26,27 but response is often unpredictable or slow.21 Estrogen is another independent risk factor for PCT. Estrogen exposure through oral contraceptives, postmenopausal hormone therapy, or pregnancy is the sole risk factor in up to 25% of female patients with PCT.22,28 Clinical and biochemical remission has been reported in women who terminate the use of estrogens but only when exposure was not prolonged.29 In one report, suppression of endogenous postmenopausal estrogen levels by the aromatase inhibitor anastrazole, administered for breast cancer prophylaxis, resulted in improvement in PCT symptoms.30 Patients may be advised to limit manual labor as much as possible to minimize mechanical trauma that causes erosions and blistering. Skin lesions can be managed with simple wound care to promote healing, and the judicious treatment of bacterial infections may prevent cutaneous scarring.31 Antimalarial medications (low-dose chloroquine or hydroxychloroquine)
The safety and efficacy of low-dose chloroquine (12532,33 to 250 mg34–36 administered orally twice per week) and ª 2013 The International Society of Dermatology
Cutaneous porphyrias: treatment strategies
Review
hydroxychloroquine (100 mg, orally, two or three times per week) are comparable with those of phlebotomy treatment in PCT, but these forms of therapy are much more convenient and less expensive and thus are preferred at some centers.37–42 Importantly, antimalarials do not cause significant iron depletion and may not be appropriate for PCT patients with significant iron overload.43 Likewise, patients with insufficient renal function to excrete the high levels of porphyrin complexes formed by antimalarial medications require alternative therapies (see Additional therapies for PCT). The exact mechanism of the antimalarials in PCT remains unknown.44 The medications have been reported to form complexes with uroporphyrin, promoting its release from the liver and causing urinary excretion of porphyrins.45 Chloroquine also accumulates in the skin, in which it absorbs both UVA and UVB light and prevents UV-induced erythema.46 Clinical improvement of skin fragility with antimalarial treatment typically takes 4–6 months, and complete remission can be achieved in 10–12 months, similarly to phlebotomy.32,34,36,47 Remission typically lasts 17–24 months, although complete remission is possible.48 Clinically, the two medications achieve similar results except that hydroxychloroquine (given at 200 mg twice weekly in these studies) may have provided a shorter remission period than chloroquine.40,47 Of note, normal doses of chloroquine used for antimalarial or photoprotective indications (e.g. 200 mg/d) can result in excessive porphyrin release from the liver, paradoxically leading to acute hepatic damage.49 Marked increases in ferritin, liver transaminases, and other liver function tests may occur, along with nausea, fever, malaise, and fatigue. In addition, cutaneous manifestations may acutely increase. Standard dosing of chloroquine has been reported to unmask previously unrecognized cases of PCT.50,51 Lower dosing allows porphyrins to be gradually mobilized from the liver without increasing plasma porphyrin levels or inducing hepatocellular damage.52,53 Prior to initiation of treatment with antimalarials, patients should be tested for glucose 6-phosphate dehydrogenase deficiency. Monthly monitoring of liver function tests is recommended, and patient response to treatment can be followed by monthly plasma or urine porphyrin levels.33 Common side effects of antimalarials in the normal population include gastrointestinal upset, allergic skin reactions, headache, and lightheadedness.54 The most feared complication is retinopathy, which results in loss of vision.55 Its exact incidence is unknown, but retinopathy is more likely in patients receiving higher doses of medication for long periods.56 The American Academy of Ophthalmology screening guidelines recommend that International Journal of Dermatology 2014, 53, 3–24
5
6
Review
Cutaneous porphyrias: treatment strategies
patients should undergo a baseline ophthalmologic examination within one year of starting therapy and should undergo follow-up examinations at intervals of 6–60 months based upon patient risk factors.57 Risk factors include age >60 years, concomitant liver or kidney disease, high doses of drug (>3 mg/kg/d of chloroquine or >6.5 mg/kg/d of hydroxychloroquine), duration of use for 5 years, high body fat percentage, and concomitant retinal disease.57 Phlebotomy
Phlebotomy, which has been used for many conditions and illnesses since antiquity, is the definitive treatment for PCT.58 Withdrawal of blood reduces iron stores and liver iron content, thereby interrupting the pathway of oxidation of hepatic porphyrinogens to porphyrins.26,59,60 Most patients with PCT exhibit a degree of iron overload, and phlebotomy is especially important in patients with hepatitis C, excessive alcohol consumption, and HFE mutations as these patients are at higher risk for the sequelae of hepatic siderosis (e.g. liver cirrhosis and HCC).61 General phlebotomy guidelines suggest the removal of 7 ml of blood per kg body weight, not to exceed 550 ml in one session.62 Phlebotomy may be performed once or twice weekly until serum levels of ferritin reach the lower limit of normal and then once biweekly or monthly as dictated by pretreatment laboratory values and maintenance of a hemoglobin level appropriate for the patient.63–65 Phlebotomies are continued until 24-hour porphyrin excretion falls to normal levels (
