A
B
patient had taken tranexamic acid for one week, even after purplish macular rashes appeared. In the following days, the lesions spread out to develop into TEN and the patient died, despite treatment with corticosteroid. We should be aware that tranexamic acid, although generally safe, is associated with the potential risk of a life-threatening drug eruption. Disclosure. Financial support: none. Conflict of interest: none.
C
D
Figure 1. A, B) Skin pigmentation at the initial presentation. C, D) Disseminated erythematous macules after the oral challenge test.
Skin tests and DLST are minimally invasive methods and are the first-line diagnostic procedure when drug eruption is suspected. If these tests are negative or not available, an oral challenge test is the only way to rule out allergy [7]. Given the low positivity rate of patch testing in fixed drug eruption, it is sometimes difficult to identify the causative agent. According to our review, most of the tranexamic acid-induced drug eruptions showed negative results in both patch testing and DLST, requiring an oral challenge test to confirm the diagnosis. In cases with drug eruption by tranexamic acid, regardless of the type, an oral challenge test may thus be necessary. In general, an oral challenge test should begin with a low dose, with careful increases of the dose, which is stopped as soon as the first objective symptoms occur. If no symptoms appear, the maximum single dose will be achieved [8]. On the basis of this patient’s history and symptoms, we first thought that she was suffering from not-so-severe fixed drug eruption. We therefore started the oral challenge test with a regular dose, resulting in a severe flare-up with numerous generalized new eruptions. We should have initiated the challenge test with an appropriate lower dose. In addition to prescribed drugs, various over-the-counter drugs such as cold remedies and supplements for cosmetics contain tranexamic acid, so exposure to it is common in daily life. However, this potential daily exposure may go unnoticed. Indeed, Hayakawa et al. reported a case of fixed drug eruption due to toothpaste containing tranexamic acid [6]. We should suspect tranexamic acid as a possible causative agent in cases with no apparent drug history. Repeated episodes of fixed drug eruption can lead to a more severe type, namely, generalized bullous fixed drug eruption [9]. Peter et al. reported a case of toxic epidermal necrolysis (TEN) induced by tranexamic acid. Their EJD, vol. 24, n◦ 3, May-June 2014
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Yumiko KAKU Takamichi ITO Kyoko KUDO Makiko KIDO-NAKAHARA Takeshi NAKAHARA Yoichi MOROI Masutaka FURUE
1. Imbesi S, Nettis E, Minciullo P, et al. Hypersensitivity to tranexamic acid: a wide spectrum of adverse reactions. Pharm World Sci 2010; 32: 416-9. 2. Pretel Irazabal M, Marques Martin M, Aguado Gil L, Idoate Gastarena MA. Tranexamic acid-induced toxic epidermal necrolysis. Ann Phamacother 2013; 47: e16. 3. Lucas-Polomeni MM, Delaval Y, Menestret P, Delaval P, Ecoffey C. A case of anaphylactic shock with tranexamic acid (Exacy1). Ann Fr Aneth Reaim 2004; 23: 607-9. 4. Kavanagh GM, Sansom JE, Harrison P, Warwick JA, Peachey RD. Tranexamic acid (Cyklokapron)-induced fixed drug eruption. Br J Dermatol 1993; 128: 229-30. 5. Carrion-Carrion C, del Pozo-Losada J, Gutierrez-Ramos R, et al. Bullous eruption induced by tranexamic acid. Ann Pharmacother 1994; 28: 1305-6. 6. Hayakawa R, Suzuki M, Ogino Y. Fixed drug eruption due to tranexamic acid. Environ Dermatol 1995; 2: 100-4. 7. Lammintausta K, Kortekangas-Savolainen O. Oral challenge in patients with cutaneous adverse drug reactions: findings in 784 patients during a 25-year-period. Acta Derm Venereol 2005; 85: 491-6. 8. Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity. Allergy 2003; 38: 854-63. 9. Mockenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009; 2: 142-60. doi:10.1684/ejd.2014.2354
Primary cutaneous meningioma combined with dermal melanocytosis and vascular malformation An 8-year-old boy presented with a depressed plaque on the vertebral region of his middle back since birth. The lesion remained fairly stable and had never ulcerated. Physical examination revealed a depressed, blue-to-black plaque (approximate diameter, 2 cm) surrounded by a red patch (approximate diameter, 5 cm) on his back (figure 1A). Magnetic resonance imaging (MRI) examination showed no spina bifida or other abnormities.
409
Histopathological examination showed proliferation of epithelioid cells surrounded by sclerotic collagen in the deep dermis (figure 1B). The cells showed round-tooval nuclei, dot-like nucleoli, homogenous chromatin and eosinophilic cytoplasm (figure 1C). Immunohistochemical analyses revealed positive staining for epithelial membrane antigen (EMA) (figure 1D) and vimentin, and negative staining for S100, keratin, CD31, CD34 and smooth muscle actin. In the superficial dermis, ectasis of the small vessels was observed, which was very similar to the histopathology of nevus flammeus (figure 1E). Moreover, proliferation of highly pigmented bipolar melanocytes in the dermis was observed, consistent with the diagnosis of dermal melanocytosis (figure 1F). According to the clinical, histopathological and immunohistochemical findings, the case was diagnosed as cutaneous meningioma with associated dermal melanocytosis and vascular malformation. Cutaneous meningioma is a rare disease that can be either acquired or congenital and commonly occurs on the scalp. It can be divided into three subtypes, based on the different etiologies [1]: Type I cutaneous meningiomas are congenital lesions commonly occurring on the scalp, face or paravertebral region. They are thought to arise from ectopic arachnoid cells presenting in the cutaneous tissue, or to result from delayed closure of the neural tube with consequent herniation of the meninges, or from premature closure of the neural tube with the meningeal tissue being “pinched
A
B
C
D
off” into the skin [1]. Type II cutaneous meningiomas are acquired lesions occurring around the sensory organs of the head and represent cutaneous extensions from ectopic soft tissue meningiomas. Type III cutaneous meningiomas represent extensions into the skin from central nervous system meningiomas. Primary cutaneous meningioma can be associated with other diseases, such as pheochromocytoma [2], sinus pericranii [3], ovarian fibroma [4] and neurofibromatosis [5]. According to the observed clinical features, we believe that our case should be classified as type I, which is usually not associated with systemic symptoms and has a good prognosis. Dermal melanocytosis is a relatively common disease in Asians and includes subtypes such as Mongolian spots, nevus of Ota, nevus of Ito, nevus fusco-caeruleus zygomaticus and dermal melanocytosis of other anatomical sites [6]. Since both melanocytes and meningocytes are differentiated from the neural crest, the combination of cutaneous meningioma and dermal melanocytosis may represent a defect in the neural crest during early embryonic development. The abnormal ectatic vessels in the dermis observed in our case represented a vascular malformation, which, with the exception of the size being relatively small, was very similar to nevus flammeus. The combination of vascular abnormalities and melanocytic nevi is defined as phacomatosis pigmentovascularis [7, 8]. Our case was similar to phacomatosis pigmentovascularis type II, which represents a combination of nevus flammeus and Mongolian spots. Cases similar to ours should be differentiated from pigmented dermatofibrosarcoma protuberans. In this case, the positive staining of EMA and negative staining of CD34 ruled out dermatofibrosarcoma protuberans. Moreover, the red patch around the depressed plaque should be used for differentiation from the Meyerson phenomenon, which has been previously reported in melanocytic nevi and also in nevus flammeus [9]. However, in our case, the erythema was congenital and, histopathologically, no extravascular red blood cells or inflammation were observed. In conclusion, we report a rare case of cutaneous meningioma combined with dermal melanocytosis and vascular malformation. To our knowledge, this phenomenon has not been previously described. Disclosure. Financial support: none. Conflict of interest: none.
E
F Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Rd, Xi’an 710032, China
Figure 1. A) A depressed blue-to-black plaque surrounded by a red patch on the back B) Scanning magnification showing proliferation of cells with sclerosis in the deep dermis C) High magnification showing proliferated epithelioid cells and sclerotic collagen around the cells D) Immunohistochemical staining of the epithelioid cells revealing positive EMA expression E) Proliferation of small ectatic vessels similar to nevus flammeus in the superficial dermis F) Proliferation of bipolar melanocytes with heavy pigmentation between the collagen.
410
Lei WANG Tianwen GAO Gang WANG
1. Lopez DA, Silvers DN, Helwig EB. Cutaneous meningioma–a clinicopathologic study. Cancer 1974; 34: 728-44. 2. Tanaka S, Okazaki M, Egusa G, et al. A case of pheochromocytoma associated with meningioma. J Intern Med 1991; 229: 371-3. 3. Zeikus P, Robinson-Bostom L, Stopa E. Primary cutaneous meningioma in association with a sinus pericranii. J Am Acad Dermatol 2006; 54: S49-50. 4. Junaid TA, Nkposong EO, Kolawole TM. Cutaneous meningiomas and an ovarian fibroma in a three-year-old girl. J Pathol 1972; 108: 165-7. EJD, vol. 24, n◦ 3, May-June 2014
5. Pfeifer JD, Ashley Hill D, Ramos CV, et al. Meningioma presenting as an intraoral mass in a patient with neurofibromatosis type 1. Arch Pathol Lab Med 2000; 124: 898-901. 6. Harrison-Balestra C, Gugic D, Vincek V. Clinically distinct form of acquired dermal melanocytosis with review of published work. J Dermatol 2007; 34: 178-82. 7. Hasegawa Y, Yasuhara M. Phakomatosis pigmentovascularis type IVa. Arch Dermatol 1985; 121: 651-5. 8. Happle R. Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol 2005; 141: 385-8. 9. Hofer T. Meyerson phenomenon within a nevus flammeus. The different eczematous reactions within port-wine stains. Dermatology 2002; 205: 180-3. doi:10.1684/ejd.2014.2348
Ischemic skin necrosis caused by glatiramer acetate in multiple sclerosis patients Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. In developed countries, it is one of the main causes of non-traumatic permanent disability in early adulthood. Nearly 85% of MSpatients evolve by relapses, having the relapse-remitting (RR) form of the disease. Disease-modifying treatment (DMT) includes immunomodulatory drugs, mainly injectable, which have proved to reduce the number of relapses and disability progression [1]. Glatiramer acetate (GA; Copolymer 1; Copaxone® ) is a first line DMT used in RR-MS. Cutaneous adverse reactions to this daily subcutaneous drug are frequent and have clinical implications, as they can reduce treatment adherence and quality of life. Up to 90% of patients develop mild and transient local skin reactions (erythema, induration, swelling, hemorrhage, pain, pruritus) which do not require cessation of DMT [2]. Severe cutaneous reactions are much rarer. Particularly, severe necrotizing cutaneous reactions have mostly been described for all types of beta-interferon (another first-line DMT, intramuscular or subcutaneous) and as far as we know there are only six cases related to GA reported in the literature [3-7]. From the 64 patients treated with GA in our Neuroimmunology Clinic, we report four cases of exuberant cutaneous adverse reactions, two of them with documented necrotizing lesions in skin biopsy. We present four female patients, now aged 35-43 years, with a mean disease duration of 8.25 years and an Expanded Disability Status Scale [8] between 2.0-3.5. Three of them had previously been treated with subcutaneous beta-interferon, which was discontinued in one case for therapeutic failure and in the remaining for hepatitis. Cutaneous adverse reactions to GA occurred at 10 months to 4 years of effective treatment. Injection techniques had been considered adequate so far. In three of the four cases, the skin lesion was abdominal and in the remaining it appeared in the thigh. Abnormally intense pain was unanimous. The appearance of the cutaneous lesions was similar: maculo-papular, heterogeneous and violaceous, measuring at least 2 × 4 cm. Two patients had a skin biopsy, which revealed ischemic skin necrosis EJD, vol. 24, n◦ 3, May-June 2014
secondary to superficial and deep vascular plexus thrombosis (figure 1). Patients were treated with topical corticosteroids and emollients, non-steroidal anti-inflammatories and antibiotics (in one case). The lesions healed in 1-4 weeks. One of the patients was referred to Plastic Surgery, as her lesion was particularly extensive. In fact, she also had elevated serum creatine kinase. The two patients submitted to skin biopsy discontinued GA: one started intramuscular interferon-beta and the other one was offered oral second-line therapy (Fingolimod). The two patients who maintained the drug had no more skin reactions. Several etiopathogenic mechanisms of cutaneous reactions related to GA have been proposed, the injection itself or drug toxicity (through its immunomodulation mechanisms or an acute hypersensitivity reaction), and this distinction is useful in deciding whether therapy must be stopped [9]. Our cases probably fit the Nicolau syndrome – embolia cutis medicamentosa – as the drug injection was immediately followed by acute intense local pain and in a few minutes cyanotic/livedoid lesions appeared, in which, histologically, intravascular thrombosis causing cutaneous necrosis could be observed, probably resulting from an accidental peri- or intravascular injection of the drug. As the cutaneous adverse reactions occurred after several innocuous GA injections, and as there were no more similar events in patients who continued treatment, an injection-related mechanism is more probable, but a drug-specific effect cannot be totally excluded, especially in those who stopped treatment. Interestingly, with increased duration of therapy, many DMT-related adverse events tend to decrease in frequency but skin reactions tend to persist, sometimes making it difficult to maintain treatment with an effective drug. Asking patients about any ongoing problems with the injections, particularly abnormal intense pain, and periodically reviewing the injection technique and examining the inoculation areas remain crucial [10]. Dermatologists should be aware of the various cutaneous reactions that have been reported with GA and their possible subjacent mechanisms in order to help in the decision about maintaining treatment or not. In fact, as we showed in this Patient 1
Patient 2
*
* Patient 3
Patient 4
Figure 1. Macroscopy and histology (H+E) of the cutaneous lesions. Only patients 1 and 3 were submitted to skin biopsy. Macroscopy: Maculo-papular, heterogeneous and violaceous lesions, measuring at least 2 × 4 cm, localized in the abdomen (patients 1, 2, 3) and in the thigh (patient 4). Histology: Skin ischemic necrosis secondary to superficial and deep vascular plexus thrombosis. Notice epidermal ulceration (arrow), intravascular thrombi (arrowhead) and perivascular inflammatory infiltrates (star).
411
B
patient had taken tranexamic acid for one week, even after purplish macular rashes appeared. In the following days, the lesions spread out to develop into TEN and the patient died, despite treatment with corticosteroid. We should be aware that tranexamic acid, although generally safe, is associated with the potential risk of a life-threatening drug eruption. Disclosure. Financial support: none. Conflict of interest: none.
C
D
Figure 1. A, B) Skin pigmentation at the initial presentation. C, D) Disseminated erythematous macules after the oral challenge test.
Skin tests and DLST are minimally invasive methods and are the first-line diagnostic procedure when drug eruption is suspected. If these tests are negative or not available, an oral challenge test is the only way to rule out allergy [7]. Given the low positivity rate of patch testing in fixed drug eruption, it is sometimes difficult to identify the causative agent. According to our review, most of the tranexamic acid-induced drug eruptions showed negative results in both patch testing and DLST, requiring an oral challenge test to confirm the diagnosis. In cases with drug eruption by tranexamic acid, regardless of the type, an oral challenge test may thus be necessary. In general, an oral challenge test should begin with a low dose, with careful increases of the dose, which is stopped as soon as the first objective symptoms occur. If no symptoms appear, the maximum single dose will be achieved [8]. On the basis of this patient’s history and symptoms, we first thought that she was suffering from not-so-severe fixed drug eruption. We therefore started the oral challenge test with a regular dose, resulting in a severe flare-up with numerous generalized new eruptions. We should have initiated the challenge test with an appropriate lower dose. In addition to prescribed drugs, various over-the-counter drugs such as cold remedies and supplements for cosmetics contain tranexamic acid, so exposure to it is common in daily life. However, this potential daily exposure may go unnoticed. Indeed, Hayakawa et al. reported a case of fixed drug eruption due to toothpaste containing tranexamic acid [6]. We should suspect tranexamic acid as a possible causative agent in cases with no apparent drug history. Repeated episodes of fixed drug eruption can lead to a more severe type, namely, generalized bullous fixed drug eruption [9]. Peter et al. reported a case of toxic epidermal necrolysis (TEN) induced by tranexamic acid. Their EJD, vol. 24, n◦ 3, May-June 2014
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Yumiko KAKU Takamichi ITO Kyoko KUDO Makiko KIDO-NAKAHARA Takeshi NAKAHARA Yoichi MOROI Masutaka FURUE
1. Imbesi S, Nettis E, Minciullo P, et al. Hypersensitivity to tranexamic acid: a wide spectrum of adverse reactions. Pharm World Sci 2010; 32: 416-9. 2. Pretel Irazabal M, Marques Martin M, Aguado Gil L, Idoate Gastarena MA. Tranexamic acid-induced toxic epidermal necrolysis. Ann Phamacother 2013; 47: e16. 3. Lucas-Polomeni MM, Delaval Y, Menestret P, Delaval P, Ecoffey C. A case of anaphylactic shock with tranexamic acid (Exacy1). Ann Fr Aneth Reaim 2004; 23: 607-9. 4. Kavanagh GM, Sansom JE, Harrison P, Warwick JA, Peachey RD. Tranexamic acid (Cyklokapron)-induced fixed drug eruption. Br J Dermatol 1993; 128: 229-30. 5. Carrion-Carrion C, del Pozo-Losada J, Gutierrez-Ramos R, et al. Bullous eruption induced by tranexamic acid. Ann Pharmacother 1994; 28: 1305-6. 6. Hayakawa R, Suzuki M, Ogino Y. Fixed drug eruption due to tranexamic acid. Environ Dermatol 1995; 2: 100-4. 7. Lammintausta K, Kortekangas-Savolainen O. Oral challenge in patients with cutaneous adverse drug reactions: findings in 784 patients during a 25-year-period. Acta Derm Venereol 2005; 85: 491-6. 8. Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity. Allergy 2003; 38: 854-63. 9. Mockenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009; 2: 142-60. doi:10.1684/ejd.2014.2354
Primary cutaneous meningioma combined with dermal melanocytosis and vascular malformation An 8-year-old boy presented with a depressed plaque on the vertebral region of his middle back since birth. The lesion remained fairly stable and had never ulcerated. Physical examination revealed a depressed, blue-to-black plaque (approximate diameter, 2 cm) surrounded by a red patch (approximate diameter, 5 cm) on his back (figure 1A). Magnetic resonance imaging (MRI) examination showed no spina bifida or other abnormities.
409
Histopathological examination showed proliferation of epithelioid cells surrounded by sclerotic collagen in the deep dermis (figure 1B). The cells showed round-tooval nuclei, dot-like nucleoli, homogenous chromatin and eosinophilic cytoplasm (figure 1C). Immunohistochemical analyses revealed positive staining for epithelial membrane antigen (EMA) (figure 1D) and vimentin, and negative staining for S100, keratin, CD31, CD34 and smooth muscle actin. In the superficial dermis, ectasis of the small vessels was observed, which was very similar to the histopathology of nevus flammeus (figure 1E). Moreover, proliferation of highly pigmented bipolar melanocytes in the dermis was observed, consistent with the diagnosis of dermal melanocytosis (figure 1F). According to the clinical, histopathological and immunohistochemical findings, the case was diagnosed as cutaneous meningioma with associated dermal melanocytosis and vascular malformation. Cutaneous meningioma is a rare disease that can be either acquired or congenital and commonly occurs on the scalp. It can be divided into three subtypes, based on the different etiologies [1]: Type I cutaneous meningiomas are congenital lesions commonly occurring on the scalp, face or paravertebral region. They are thought to arise from ectopic arachnoid cells presenting in the cutaneous tissue, or to result from delayed closure of the neural tube with consequent herniation of the meninges, or from premature closure of the neural tube with the meningeal tissue being “pinched
A
B
C
D
off” into the skin [1]. Type II cutaneous meningiomas are acquired lesions occurring around the sensory organs of the head and represent cutaneous extensions from ectopic soft tissue meningiomas. Type III cutaneous meningiomas represent extensions into the skin from central nervous system meningiomas. Primary cutaneous meningioma can be associated with other diseases, such as pheochromocytoma [2], sinus pericranii [3], ovarian fibroma [4] and neurofibromatosis [5]. According to the observed clinical features, we believe that our case should be classified as type I, which is usually not associated with systemic symptoms and has a good prognosis. Dermal melanocytosis is a relatively common disease in Asians and includes subtypes such as Mongolian spots, nevus of Ota, nevus of Ito, nevus fusco-caeruleus zygomaticus and dermal melanocytosis of other anatomical sites [6]. Since both melanocytes and meningocytes are differentiated from the neural crest, the combination of cutaneous meningioma and dermal melanocytosis may represent a defect in the neural crest during early embryonic development. The abnormal ectatic vessels in the dermis observed in our case represented a vascular malformation, which, with the exception of the size being relatively small, was very similar to nevus flammeus. The combination of vascular abnormalities and melanocytic nevi is defined as phacomatosis pigmentovascularis [7, 8]. Our case was similar to phacomatosis pigmentovascularis type II, which represents a combination of nevus flammeus and Mongolian spots. Cases similar to ours should be differentiated from pigmented dermatofibrosarcoma protuberans. In this case, the positive staining of EMA and negative staining of CD34 ruled out dermatofibrosarcoma protuberans. Moreover, the red patch around the depressed plaque should be used for differentiation from the Meyerson phenomenon, which has been previously reported in melanocytic nevi and also in nevus flammeus [9]. However, in our case, the erythema was congenital and, histopathologically, no extravascular red blood cells or inflammation were observed. In conclusion, we report a rare case of cutaneous meningioma combined with dermal melanocytosis and vascular malformation. To our knowledge, this phenomenon has not been previously described. Disclosure. Financial support: none. Conflict of interest: none.
E
F Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Rd, Xi’an 710032, China
Figure 1. A) A depressed blue-to-black plaque surrounded by a red patch on the back B) Scanning magnification showing proliferation of cells with sclerosis in the deep dermis C) High magnification showing proliferated epithelioid cells and sclerotic collagen around the cells D) Immunohistochemical staining of the epithelioid cells revealing positive EMA expression E) Proliferation of small ectatic vessels similar to nevus flammeus in the superficial dermis F) Proliferation of bipolar melanocytes with heavy pigmentation between the collagen.
410
Lei WANG Tianwen GAO Gang WANG
1. Lopez DA, Silvers DN, Helwig EB. Cutaneous meningioma–a clinicopathologic study. Cancer 1974; 34: 728-44. 2. Tanaka S, Okazaki M, Egusa G, et al. A case of pheochromocytoma associated with meningioma. J Intern Med 1991; 229: 371-3. 3. Zeikus P, Robinson-Bostom L, Stopa E. Primary cutaneous meningioma in association with a sinus pericranii. J Am Acad Dermatol 2006; 54: S49-50. 4. Junaid TA, Nkposong EO, Kolawole TM. Cutaneous meningiomas and an ovarian fibroma in a three-year-old girl. J Pathol 1972; 108: 165-7. EJD, vol. 24, n◦ 3, May-June 2014
5. Pfeifer JD, Ashley Hill D, Ramos CV, et al. Meningioma presenting as an intraoral mass in a patient with neurofibromatosis type 1. Arch Pathol Lab Med 2000; 124: 898-901. 6. Harrison-Balestra C, Gugic D, Vincek V. Clinically distinct form of acquired dermal melanocytosis with review of published work. J Dermatol 2007; 34: 178-82. 7. Hasegawa Y, Yasuhara M. Phakomatosis pigmentovascularis type IVa. Arch Dermatol 1985; 121: 651-5. 8. Happle R. Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol 2005; 141: 385-8. 9. Hofer T. Meyerson phenomenon within a nevus flammeus. The different eczematous reactions within port-wine stains. Dermatology 2002; 205: 180-3. doi:10.1684/ejd.2014.2348
Ischemic skin necrosis caused by glatiramer acetate in multiple sclerosis patients Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. In developed countries, it is one of the main causes of non-traumatic permanent disability in early adulthood. Nearly 85% of MSpatients evolve by relapses, having the relapse-remitting (RR) form of the disease. Disease-modifying treatment (DMT) includes immunomodulatory drugs, mainly injectable, which have proved to reduce the number of relapses and disability progression [1]. Glatiramer acetate (GA; Copolymer 1; Copaxone® ) is a first line DMT used in RR-MS. Cutaneous adverse reactions to this daily subcutaneous drug are frequent and have clinical implications, as they can reduce treatment adherence and quality of life. Up to 90% of patients develop mild and transient local skin reactions (erythema, induration, swelling, hemorrhage, pain, pruritus) which do not require cessation of DMT [2]. Severe cutaneous reactions are much rarer. Particularly, severe necrotizing cutaneous reactions have mostly been described for all types of beta-interferon (another first-line DMT, intramuscular or subcutaneous) and as far as we know there are only six cases related to GA reported in the literature [3-7]. From the 64 patients treated with GA in our Neuroimmunology Clinic, we report four cases of exuberant cutaneous adverse reactions, two of them with documented necrotizing lesions in skin biopsy. We present four female patients, now aged 35-43 years, with a mean disease duration of 8.25 years and an Expanded Disability Status Scale [8] between 2.0-3.5. Three of them had previously been treated with subcutaneous beta-interferon, which was discontinued in one case for therapeutic failure and in the remaining for hepatitis. Cutaneous adverse reactions to GA occurred at 10 months to 4 years of effective treatment. Injection techniques had been considered adequate so far. In three of the four cases, the skin lesion was abdominal and in the remaining it appeared in the thigh. Abnormally intense pain was unanimous. The appearance of the cutaneous lesions was similar: maculo-papular, heterogeneous and violaceous, measuring at least 2 × 4 cm. Two patients had a skin biopsy, which revealed ischemic skin necrosis EJD, vol. 24, n◦ 3, May-June 2014
secondary to superficial and deep vascular plexus thrombosis (figure 1). Patients were treated with topical corticosteroids and emollients, non-steroidal anti-inflammatories and antibiotics (in one case). The lesions healed in 1-4 weeks. One of the patients was referred to Plastic Surgery, as her lesion was particularly extensive. In fact, she also had elevated serum creatine kinase. The two patients submitted to skin biopsy discontinued GA: one started intramuscular interferon-beta and the other one was offered oral second-line therapy (Fingolimod). The two patients who maintained the drug had no more skin reactions. Several etiopathogenic mechanisms of cutaneous reactions related to GA have been proposed, the injection itself or drug toxicity (through its immunomodulation mechanisms or an acute hypersensitivity reaction), and this distinction is useful in deciding whether therapy must be stopped [9]. Our cases probably fit the Nicolau syndrome – embolia cutis medicamentosa – as the drug injection was immediately followed by acute intense local pain and in a few minutes cyanotic/livedoid lesions appeared, in which, histologically, intravascular thrombosis causing cutaneous necrosis could be observed, probably resulting from an accidental peri- or intravascular injection of the drug. As the cutaneous adverse reactions occurred after several innocuous GA injections, and as there were no more similar events in patients who continued treatment, an injection-related mechanism is more probable, but a drug-specific effect cannot be totally excluded, especially in those who stopped treatment. Interestingly, with increased duration of therapy, many DMT-related adverse events tend to decrease in frequency but skin reactions tend to persist, sometimes making it difficult to maintain treatment with an effective drug. Asking patients about any ongoing problems with the injections, particularly abnormal intense pain, and periodically reviewing the injection technique and examining the inoculation areas remain crucial [10]. Dermatologists should be aware of the various cutaneous reactions that have been reported with GA and their possible subjacent mechanisms in order to help in the decision about maintaining treatment or not. In fact, as we showed in this Patient 1
Patient 2
*
* Patient 3
Patient 4
Figure 1. Macroscopy and histology (H+E) of the cutaneous lesions. Only patients 1 and 3 were submitted to skin biopsy. Macroscopy: Maculo-papular, heterogeneous and violaceous lesions, measuring at least 2 × 4 cm, localized in the abdomen (patients 1, 2, 3) and in the thigh (patient 4). Histology: Skin ischemic necrosis secondary to superficial and deep vascular plexus thrombosis. Notice epidermal ulceration (arrow), intravascular thrombi (arrowhead) and perivascular inflammatory infiltrates (star).
411
