Journal of Dermatology 2016; 43: 207–209
doi: 10.1111/1346-8138.13009
CONCISE COMMUNICATION
Pirfenidone-induced photoleukomelanoderma in a patient with idiopathic pulmonary fibrosis Aoi TSURUTA, Ken WASHIO, Atsushi FUKUNAGA, Chikako NISHIGORI Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan,
ABSTRACT This is believed to be the first report of pirfenidone-induced photoleukomelanoderma. We discuss the male predominance of photosensitivity induced by pirfenidone. Both ultraviolet (UV)-A and UV-B seemed to be included within the action spectrum of this disorder. Although pirfenidone is a key drug for the treatment of idiopathic pulmonary fibrosis, clinicians should be aware of the high prevalence of photosensitivity and perform sufficient patient education for comprehensive photoprotection before prescription.
Key words: pirfenidone.
drug eruption, idiopathic pulmonary fibrosis, photoleukomelanoderma, photosensitivity,
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease with inevitable loss of lung function. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is a novel synthetic molecule for the treatment of IPF.1 It inhibits the activity of inflammatory cytokines such as tumor necrosis factor-a, interleukin (IL)-1 and IL-6, as well as increasing the production of anti-inflammatory cytokine IL-10.1 It is also reported that pirfenidone has an antifibrotic effect through platelet-derived growth factors and tumor growth factor-b. Although pirfenidone is a promising drug for the treatment of IPF, adverse effects of rash and photosensitivity often emerge.1,2 Here, we describe a patient with IPF who presented with severe photosensitivity and photoleukomelanoderma after the dose of pirfenidone had been increased. We also discuss the male predominance for such severe photosensitivity events related to pirfenidone. Clinicians should be aware of its phototoxicity and recommend comprehensive photoprotection to their patients, especially for male patients.
CASE REPORT A 73-year-old man was referred to our dermatology department with scaly erythema of the face and hands. He had been diagnosed with IPF in another hospital respiratory department 18 months before. One year later, he had started to take pirfenidone (600 mg/day), and its dose was increased to 1800 mg/ day 2 weeks due to the aggravation of dyspnea. Since then, he had noticed facial and manual pruritus. Although he had been treated with topical corticosteroid ointment, his symptoms became worse and he presented himself to our hospital. Figure 1(a,b) demonstrates the facial and manual erythema
with scales. Erosive erythema with fissures was also found on the lower lip. Laboratory tests indicated an increased number of white blood cells (9600/lL), high serum lactate dehydrogenase (280 IU/L) and high titer of antinuclear antibody (91280, speckled + nucleolar pattern). A skin biopsy was performed on the dorsal surface of the hand. The epidermis exhibited hyperkeratosis, acanthosis and liquefaction degeneration. Numerous necrotic keratinocytes were also seen. In the reticular dermis, a perivascular lymphocytic inflammatory cell infiltrate with melanin was also present (Fig. 2). Direct immunofluorescence (DIF) demonstrated no specific deposition of immunoglobulins or complements on the basement membrane or vessel walls. A photosensitivity test for ultraviolet (UV)-A and UV-B was performed and showed a markedly decreased minimum erythema dose (MED) of 20 mJ/cm2 with UV-B and positive response by UV-A with minimum response dose (MRD) of 12 J/cm2. At 1 month after discontinuation of pirfenidone, UV-B MED was elevated to 80 mJ/cm2 and irradiation of 12 J/cm2 UV-A induced no erythema. The clinical presentation of the patients at this time is seen in Figure 1(c,d); facial and digital welldemarcated depigmented maculae were prominent. At 3 months after discontinuation of pirfenidone, regeneration of pigmented spots was recognized within these depigmented areas. We recommended the patient and respiratory doctors to restart the administration of pirfenidone under comprehensive photoprotection in fear of a poor prognosis of IPF; however, the patient refused to use pirfenidone anymore because he was afraid of the aggravation of leukoderma on the face.
DISCUSSION Idiopathic pulmonary fibrosis remains a progressive and fatal disorder. The development of IPF was originally thought to be
Correspondence: Atsushi Fukunaga, M.D., Ph.D., Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan. Email: [email protected] Received 31 March 2015; accepted 20 May 2015.
© 2015 Japanese Dermatological Association
207
A. Tsuruta et al.
(a)
(b)
(c)
(d)
Figure 2. Hyperkeratosis, acanthosis and liquefaction degeneration with numerous necrotic keratinocytes were seen in the epidermis. In the reticular dermis, perivascular lymphocytic inflammatory cell infiltration with incontinence of melanin and solar elastosis was also present (hematoxylin–eosin; bar, 200 lm; original magnification, 9200). The image was recorded by digital microscopy (BZ-X700; Keyence, Osaka, Japan).
Figure 1. Pirfenidone-induced photoleukomelanoderma. (a) Facial erythema with scales was seen on the day of the initial visit to our hospital. (b) Manual erythema with scales and fissures was evident. (c) Clinical presentation after discontinuation of pirfenidone; well-demarcated depigmented maculae were seen on the face and neck, surrounded by a hyperpigmented area. (d) Depigmented maculae with surrounding hyperpigmentations were also seen on the hands. due to alveolar inflammation followed by fibrosis and scarring. Treatment historically comprised oral steroids and several immunosuppressants, but the effect of these drugs was limited or minimal.3 Pirfenidone is a newly developed antifibrotic
synthetic molecule for the treatment of IPF and several studies have shown its clinical efficacy.1,4 The most common sideeffects of pirfenidone are gastrointestinal discomfort and photosensitivity, although pirfenidone is a safe drug and generally well tolerated.1,2,4 Our patient manifested severe photoleukomelanoderma after the dose of pirfenidone was increased, and his face had an unattractive appearance, with decreased quality of life. The negative DIF result and the fact that discontinuation of pirfenidone improved the hypersensitivity of UV-A and UV-B supported the diagnosis of pirfenidone induced phototoxicity rather than photoallergy or photosensitive autoimmune disease. However, it could be possible that a high titer of antinuclear antibody (91280) was associated with severe photoleukomelanoderma in our patient after a phototoxic reaction was caused by pirfenidone as shown in vitiligo cases.5 Photoleukomelanoderma is a severe photosensitivity reaction that is often induced by drugs such as thiazides.6 This is believed to be the first report of pirfenidone-induced photoleukomelanoderma. Table 1 summarizes pirfenidone-induced
Table 1. Clinical characteristics of pirfenidone-induced photosensitivity in Japanese patients
Patients
Study or subgroup
Age
Sex
Period of use of pirfenidone before events
1 2 3 4 5 6
Umemoto et al.8 Senzaki et al.7 Senzaki et al.7 Natsuaki et al.9 Higashida et al.10 This report
69 75 67 69 77 73
Male Male Male Male Male Male
6 2 2 3 7 5
months months months months months months
Pirfenidone dose on onset of photosensitivity (mg/day)
UV-A MRD (J/cm2)
UV-B MED (mJ/cm2)
1800 1800 600 N.I. 1800 1800
5 2.3 N.D. 1.42 N.D. 6
20 N.D. N.D. 19.2 N.D. 20
N.D., not done; N.I., not informed.
208
© 2015 Japanese Dermatological Association
Pirfenidone-induced photoleukomelanoderma
photosensitivity in Japanese patients.7–10 Of note, all patients were male. The mean and median period of time between the initiation of pirfenidone and clinical manifestation of photosensitivity was 4.17 and 4 months, respectively. The dose of pirfenidone at onset of photosensitivity was high (1800 mg/day) in most patients, whereas Senzaki et al.7 reported a case of pirfenidone-induced photosensitivity with a relatively low dose (600 mg/day) of pirfenidone. Both UV-A and UV-B seemed to be included within the range of action spectrum. Although the male-to-female ratio of IPF partly accounts for the male-predominant nature of photosensitivity induced by pirfenidone, it does not provide an adequate explanation of such excessive male dominancy. We hypothesize that women’s habitual behavior, such as applying makeup or carrying a parasol, prevents them from exposure to direct sunlight. Also, sunscreen cream is not widely used among Japanese men. It should be noted that in the clinical trial of pirfenidone, 3% of Japanese patients discontinued pirfenidone due to the adverse effects of photosensitivity,11 whereas only 0.9% of patients declined due to photosensitivity in CAPACITY trials held in Australia, Europe and North America.1 In fact, our patient had been urged to use sunscreen cream or to wear hats by respiratory physicians, but he usually went on a walk without any protection from sunlight. The severe photosensitivity reaction induced by pirfenidone may be reduced by strict avoidance of direct sunlight. Furthermore, it is possible for the patients to restart the pirfenidone under complete photoprotection after he or she has experienced the photosensitivity reaction due to pirfenidone because the photosensitivity of pirfenidone is mostly caused by phototoxic mechanisms rather than photoallergy12 and IPF has an overall poor prognosis.4 To conclude, we report the first case of pirfenidone-induced photoleukomelanoderma. Clinicians should pay more attention to photoprotection, before they use pirfenidone for the treatment of IPF.
© 2015 Japanese Dermatological Association
CONFLICT OF INTEREST:
The authors declare no finan-
cial or other conflict of interest.
REFERENCES 1 Noble PW, Albera C, Bradford WZ et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760–1769. 2 Jiang C, Huang H, Liu J, Wang Y, Lu X, Xu Z. Adverse events of pirfenidone for the treatment of pulmonary fibrosis: a meta-analysis of randomized controlled trials. PLoS ONE 2012; 7: e47024. 3 Costabel U, Bendstrup E, Cottin V et al. Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events. Adv Ther 2014; 31: 375–391. 4 Cottin V. Changing the idiopathic pulmonary fibrosis treatment approach and improving patient outcomes. Eur Respir Rev 2012; 21: 161–167. 5 Sheth VM, Guo Y, Qureshi AA. Comorbidities associated with vitiligo: a ten-year retrospective study. Dermatology 2013; 227: 311– 315. 6 Masuoka E, Bito T, Shimizu H, Nishigori C. Dysfunction of melanocytes in photoleukomelanoderma following photosensitivity caused by hydrochlorothiazide. Photodermatol Photoimmunol Photomed 2011; 27: 328–330. 7 Senzaki S, Hirose K, Ishigami T, Murao K, Kubo N, Nishioka Y. Two cases of photosensitive drug eruption due to pirfenidone. Rinsho Hihuka (Japanese) 2012; 66: 945–948. 8 Umemoto J, Uchida T, Takase N et al. A case of photosensitivity due to pirfenidone. Hihuka no Rinsho (Japanese) 2013; 55: 140–141. 9 Natsuaki Y, Hashimoto T. Prevention and management of photosensitivity due to pirfenidone. Vis Dermatol 2014; 13: 180–182. 10 Higashida Y, Ueno M, Ogawa M, Nagano T, Otsuka K, Tomii K. A case of photosensitivity due to pirfenidone. Hihuka no Rinsho (Japanese) 2012; 54: 794–795. 11 Taniguchi H, Ebina M, Kondoh Y et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35: 821–829. 12 Seto Y, Inoue R, Kato M, Yamada S, Onoue S. Photosafety assessments on pirfenidone: photochemical, photobiological, and pharmacokinetic characterization. J Photochem Photobiol, B 2013; 120: 44–51.
209
doi: 10.1111/1346-8138.13009
CONCISE COMMUNICATION
Pirfenidone-induced photoleukomelanoderma in a patient with idiopathic pulmonary fibrosis Aoi TSURUTA, Ken WASHIO, Atsushi FUKUNAGA, Chikako NISHIGORI Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan,
ABSTRACT This is believed to be the first report of pirfenidone-induced photoleukomelanoderma. We discuss the male predominance of photosensitivity induced by pirfenidone. Both ultraviolet (UV)-A and UV-B seemed to be included within the action spectrum of this disorder. Although pirfenidone is a key drug for the treatment of idiopathic pulmonary fibrosis, clinicians should be aware of the high prevalence of photosensitivity and perform sufficient patient education for comprehensive photoprotection before prescription.
Key words: pirfenidone.
drug eruption, idiopathic pulmonary fibrosis, photoleukomelanoderma, photosensitivity,
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease with inevitable loss of lung function. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is a novel synthetic molecule for the treatment of IPF.1 It inhibits the activity of inflammatory cytokines such as tumor necrosis factor-a, interleukin (IL)-1 and IL-6, as well as increasing the production of anti-inflammatory cytokine IL-10.1 It is also reported that pirfenidone has an antifibrotic effect through platelet-derived growth factors and tumor growth factor-b. Although pirfenidone is a promising drug for the treatment of IPF, adverse effects of rash and photosensitivity often emerge.1,2 Here, we describe a patient with IPF who presented with severe photosensitivity and photoleukomelanoderma after the dose of pirfenidone had been increased. We also discuss the male predominance for such severe photosensitivity events related to pirfenidone. Clinicians should be aware of its phototoxicity and recommend comprehensive photoprotection to their patients, especially for male patients.
CASE REPORT A 73-year-old man was referred to our dermatology department with scaly erythema of the face and hands. He had been diagnosed with IPF in another hospital respiratory department 18 months before. One year later, he had started to take pirfenidone (600 mg/day), and its dose was increased to 1800 mg/ day 2 weeks due to the aggravation of dyspnea. Since then, he had noticed facial and manual pruritus. Although he had been treated with topical corticosteroid ointment, his symptoms became worse and he presented himself to our hospital. Figure 1(a,b) demonstrates the facial and manual erythema
with scales. Erosive erythema with fissures was also found on the lower lip. Laboratory tests indicated an increased number of white blood cells (9600/lL), high serum lactate dehydrogenase (280 IU/L) and high titer of antinuclear antibody (91280, speckled + nucleolar pattern). A skin biopsy was performed on the dorsal surface of the hand. The epidermis exhibited hyperkeratosis, acanthosis and liquefaction degeneration. Numerous necrotic keratinocytes were also seen. In the reticular dermis, a perivascular lymphocytic inflammatory cell infiltrate with melanin was also present (Fig. 2). Direct immunofluorescence (DIF) demonstrated no specific deposition of immunoglobulins or complements on the basement membrane or vessel walls. A photosensitivity test for ultraviolet (UV)-A and UV-B was performed and showed a markedly decreased minimum erythema dose (MED) of 20 mJ/cm2 with UV-B and positive response by UV-A with minimum response dose (MRD) of 12 J/cm2. At 1 month after discontinuation of pirfenidone, UV-B MED was elevated to 80 mJ/cm2 and irradiation of 12 J/cm2 UV-A induced no erythema. The clinical presentation of the patients at this time is seen in Figure 1(c,d); facial and digital welldemarcated depigmented maculae were prominent. At 3 months after discontinuation of pirfenidone, regeneration of pigmented spots was recognized within these depigmented areas. We recommended the patient and respiratory doctors to restart the administration of pirfenidone under comprehensive photoprotection in fear of a poor prognosis of IPF; however, the patient refused to use pirfenidone anymore because he was afraid of the aggravation of leukoderma on the face.
DISCUSSION Idiopathic pulmonary fibrosis remains a progressive and fatal disorder. The development of IPF was originally thought to be
Correspondence: Atsushi Fukunaga, M.D., Ph.D., Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan. Email: [email protected] Received 31 March 2015; accepted 20 May 2015.
© 2015 Japanese Dermatological Association
207
A. Tsuruta et al.
(a)
(b)
(c)
(d)
Figure 2. Hyperkeratosis, acanthosis and liquefaction degeneration with numerous necrotic keratinocytes were seen in the epidermis. In the reticular dermis, perivascular lymphocytic inflammatory cell infiltration with incontinence of melanin and solar elastosis was also present (hematoxylin–eosin; bar, 200 lm; original magnification, 9200). The image was recorded by digital microscopy (BZ-X700; Keyence, Osaka, Japan).
Figure 1. Pirfenidone-induced photoleukomelanoderma. (a) Facial erythema with scales was seen on the day of the initial visit to our hospital. (b) Manual erythema with scales and fissures was evident. (c) Clinical presentation after discontinuation of pirfenidone; well-demarcated depigmented maculae were seen on the face and neck, surrounded by a hyperpigmented area. (d) Depigmented maculae with surrounding hyperpigmentations were also seen on the hands. due to alveolar inflammation followed by fibrosis and scarring. Treatment historically comprised oral steroids and several immunosuppressants, but the effect of these drugs was limited or minimal.3 Pirfenidone is a newly developed antifibrotic
synthetic molecule for the treatment of IPF and several studies have shown its clinical efficacy.1,4 The most common sideeffects of pirfenidone are gastrointestinal discomfort and photosensitivity, although pirfenidone is a safe drug and generally well tolerated.1,2,4 Our patient manifested severe photoleukomelanoderma after the dose of pirfenidone was increased, and his face had an unattractive appearance, with decreased quality of life. The negative DIF result and the fact that discontinuation of pirfenidone improved the hypersensitivity of UV-A and UV-B supported the diagnosis of pirfenidone induced phototoxicity rather than photoallergy or photosensitive autoimmune disease. However, it could be possible that a high titer of antinuclear antibody (91280) was associated with severe photoleukomelanoderma in our patient after a phototoxic reaction was caused by pirfenidone as shown in vitiligo cases.5 Photoleukomelanoderma is a severe photosensitivity reaction that is often induced by drugs such as thiazides.6 This is believed to be the first report of pirfenidone-induced photoleukomelanoderma. Table 1 summarizes pirfenidone-induced
Table 1. Clinical characteristics of pirfenidone-induced photosensitivity in Japanese patients
Patients
Study or subgroup
Age
Sex
Period of use of pirfenidone before events
1 2 3 4 5 6
Umemoto et al.8 Senzaki et al.7 Senzaki et al.7 Natsuaki et al.9 Higashida et al.10 This report
69 75 67 69 77 73
Male Male Male Male Male Male
6 2 2 3 7 5
months months months months months months
Pirfenidone dose on onset of photosensitivity (mg/day)
UV-A MRD (J/cm2)
UV-B MED (mJ/cm2)
1800 1800 600 N.I. 1800 1800
5 2.3 N.D. 1.42 N.D. 6
20 N.D. N.D. 19.2 N.D. 20
N.D., not done; N.I., not informed.
208
© 2015 Japanese Dermatological Association
Pirfenidone-induced photoleukomelanoderma
photosensitivity in Japanese patients.7–10 Of note, all patients were male. The mean and median period of time between the initiation of pirfenidone and clinical manifestation of photosensitivity was 4.17 and 4 months, respectively. The dose of pirfenidone at onset of photosensitivity was high (1800 mg/day) in most patients, whereas Senzaki et al.7 reported a case of pirfenidone-induced photosensitivity with a relatively low dose (600 mg/day) of pirfenidone. Both UV-A and UV-B seemed to be included within the range of action spectrum. Although the male-to-female ratio of IPF partly accounts for the male-predominant nature of photosensitivity induced by pirfenidone, it does not provide an adequate explanation of such excessive male dominancy. We hypothesize that women’s habitual behavior, such as applying makeup or carrying a parasol, prevents them from exposure to direct sunlight. Also, sunscreen cream is not widely used among Japanese men. It should be noted that in the clinical trial of pirfenidone, 3% of Japanese patients discontinued pirfenidone due to the adverse effects of photosensitivity,11 whereas only 0.9% of patients declined due to photosensitivity in CAPACITY trials held in Australia, Europe and North America.1 In fact, our patient had been urged to use sunscreen cream or to wear hats by respiratory physicians, but he usually went on a walk without any protection from sunlight. The severe photosensitivity reaction induced by pirfenidone may be reduced by strict avoidance of direct sunlight. Furthermore, it is possible for the patients to restart the pirfenidone under complete photoprotection after he or she has experienced the photosensitivity reaction due to pirfenidone because the photosensitivity of pirfenidone is mostly caused by phototoxic mechanisms rather than photoallergy12 and IPF has an overall poor prognosis.4 To conclude, we report the first case of pirfenidone-induced photoleukomelanoderma. Clinicians should pay more attention to photoprotection, before they use pirfenidone for the treatment of IPF.
© 2015 Japanese Dermatological Association
CONFLICT OF INTEREST:
The authors declare no finan-
cial or other conflict of interest.
REFERENCES 1 Noble PW, Albera C, Bradford WZ et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760–1769. 2 Jiang C, Huang H, Liu J, Wang Y, Lu X, Xu Z. Adverse events of pirfenidone for the treatment of pulmonary fibrosis: a meta-analysis of randomized controlled trials. PLoS ONE 2012; 7: e47024. 3 Costabel U, Bendstrup E, Cottin V et al. Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events. Adv Ther 2014; 31: 375–391. 4 Cottin V. Changing the idiopathic pulmonary fibrosis treatment approach and improving patient outcomes. Eur Respir Rev 2012; 21: 161–167. 5 Sheth VM, Guo Y, Qureshi AA. Comorbidities associated with vitiligo: a ten-year retrospective study. Dermatology 2013; 227: 311– 315. 6 Masuoka E, Bito T, Shimizu H, Nishigori C. Dysfunction of melanocytes in photoleukomelanoderma following photosensitivity caused by hydrochlorothiazide. Photodermatol Photoimmunol Photomed 2011; 27: 328–330. 7 Senzaki S, Hirose K, Ishigami T, Murao K, Kubo N, Nishioka Y. Two cases of photosensitive drug eruption due to pirfenidone. Rinsho Hihuka (Japanese) 2012; 66: 945–948. 8 Umemoto J, Uchida T, Takase N et al. A case of photosensitivity due to pirfenidone. Hihuka no Rinsho (Japanese) 2013; 55: 140–141. 9 Natsuaki Y, Hashimoto T. Prevention and management of photosensitivity due to pirfenidone. Vis Dermatol 2014; 13: 180–182. 10 Higashida Y, Ueno M, Ogawa M, Nagano T, Otsuka K, Tomii K. A case of photosensitivity due to pirfenidone. Hihuka no Rinsho (Japanese) 2012; 54: 794–795. 11 Taniguchi H, Ebina M, Kondoh Y et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35: 821–829. 12 Seto Y, Inoue R, Kato M, Yamada S, Onoue S. Photosafety assessments on pirfenidone: photochemical, photobiological, and pharmacokinetic characterization. J Photochem Photobiol, B 2013; 120: 44–51.
209
![[Idiopathic Pulmonary Fibrosis].](/assets/img/hold.png)
