Letters to the Editor
(a)
523
(b)
Figure 2 Case 2: Post ustekinumab treatment (11/2013). (a) Near complete clearance of psoriasis on the left arm. (b) No change in eczematous plaques on the knee flexures.
phenotype during the chronic phase. Recently, a role for T helper cell subsets such as Th17 and Th22 cells has been suggested, yet the evidence is conflicting.1 By blocking IL-12 and IL-23, ustekinumab can regulate both Th1 and Th17 pathways, which are reportedly active in AD. Unfortunately, our patients did not experience therapeutic benefits seen in previous reports.2–5 Possibly the IL-17 pathway is less relevant in patients with elevated IgE,6 yet responsive patients with elevated IgE have been reported. It may be that IL-17 is only a bystander effect, reflecting an inflammatory state and not an important contributor to AD pathogenesis.1 Another explanation for the disparity in outcomes is that the short follow up period in previous reports2,5 may not have captured a significant loss of efficacy over time as was observed in Patient 1. This patient flared after a staphylococcal infection and did not respond to continued ustekinumab. IL-17 has been shown to play a crucial role in host defense against S. aureus skin infections.7 Blocking this pathway with ustekinumab in atopic patients already prone to staphylococcal skin infection8 may inhibit response or cause a persistent flare. Atopic dermatitis is a complex disease in which a variety of pathogenic pathways may lead to disease expression, reflecting divergent response rates toward specific therapies. Optimized, randomized controlled trials are necessary to evaluate the utility of ustekinumab in treating patients with AD. L.P. Samorano,1,* J.M. Hanifin,2 E.L. Simpson,2 Y.A. Leshem2 1 ~o Department of Dermatology, Hospital das Clınicas, University of Sa Paulo Medical School, Sao Paulo, Brazil, 2Department of Dermatology, Oregon Health and Science University, Portland, OR, USA *Correspondence: L.P. Samorano. E-mail: [email protected]
References 1 Milner JD. IL-17 producing cells in host defense and atopy. Curr Opin Immunol 2011; 23: 784–788.
JEADV 2016, 30, 446–556
2 Agusti-Mejias A, Messeguer F, Garcıa R, Febrer I. Severe refractory atopic dermatitis in an adolescent patient successfully treated with ustekinumab. Ann Dermatol 2013; 25: 368–370. 3 Fernandez-Ant on Martınez MC, Alfageme Roldan F, Ciudad Blanco C, Suarez Fernandez R. Ustekinumab in the treatment of severe atopic dermatitis: a preliminary report of our experience with 4 patients. Actas Dermosifiliogr 2014; 105: 312–313. 4 Puya R, Alvarez-L opez M, Velez A, Casas Asuncion E, Moreno JC. Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol 2012; 51: 115–116. 5 Eyerich S, Onken AT, Weidinger S et al. Mutual antagonism of T cells causing psoriasis and atopic eczema. N Engl J Med 2011 Jul 21; 365: 231–238. 6 Suarez-Fari~ nas M, Dhingra N, Gittler J et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013; 132: 361–370. 7 Ishigame H, Kakuta S, Nagai T et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009 Jan 16; 30: 108–119. 8 Ong PY, Leung DY. The infectious aspects of atopic dermatitis. Immunol Allergy Clin North Am 2010 Aug; 30: 309–321. DOI: 10.1111/jdv.12918
Local reaction after subcutaneous injection of methotrexate: uncommon side effect Editor In February 2014, a 37-year-old man was referred to our outpatient Department with a 20-year history of severe plaque psoriasis that was poorly controlled with topical treatments (PASI 12.2), requiring in different moments of his evolution cyclosporine, methotrexate and acitretin with moderate response, and finally he began treatment with etanercept achieving PASI 0 in week 36. In that moment, we removed the medication but 7 months later he presented a recurrence (PASI 8.2) and we decided to introduce again subcutaneous methotrexate with a progressive increase in the dose. He reached PASI 0 with 15 mg/ week of methotrexate 1 year later. However, at 15 months of having reintroduced the medication the patient suffered a local reaction at the subcutaneous administration site of methotrexate. He presented several oedematous and erythematous papules, with crusting and laminar scaling that healed without scars (Fig. 1). These lesions began to appear with the last five doses of methotrexate, when the accumulated dose was 0.635 g. Because of this, we changed subcutaneous administration of methotrexate to oral administration and we prescribed treatment with fusidic acid and betamethasone topically. Lesions healed and good control of psoriasis was maintained with good tolerance and without other side-effects associated.
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
524
We present this case of intense local reaction after administration of methotrexate subcutaneous because, after reviewing the literature, we have no found similar cases. C.M. Priego-Recio,* F.M. Camacho-Martınez n Clınica de Dermatologıa, Hospital Universitario Virgen Unidad de Gestio Macarena de Sevilla, Avda. Dr Fedriani, n° 3, 41009, Seville, Spain *Correspondence: C.M. Priego Recio. E-mail: [email protected]
References
Figure 1 Edematosquamous papule in abdomen, secondary to the last injection of methotrexate.
Methotrexate is a synthetic analogue of the folic acid that interferes with their metabolic pathway, by blocking the enzyme dihydrofolic-reductase. This inhibits its activation to folinic acid, that it is necessary for the formation of deoxythymidylic acid, which is essential for the synthesis of DNA.1 Since the approval of methotretaxe in 1972 for use as a treatment for plaque psoriasis, it has amply demonstrated its efficacy in this disease and, although it is customary that are mild, it is not free from adverse effects.2 The toxicity produced by methotrexate appears up to 30% of the cases, and can affect different organs and systems.3 The most common side-effects are gastrointestinal disorders, musculoskeletal pain and fever, which appear in the first few hours after its administration and may be cause for suspension of treatment. Other side-effects more severe are liver toxicity (increase transaminases, fibrosis, cirrhosis), blood toxicity (myelosuppression) and lung toxicity (acute interstitial pneumonitis, pulmonary fibrosis). There are even cases of encephalopathy described by methotrexate.4 In regard to the mucocutaneous side-effects, it has been described erosions and/or skin ulcers, generally associated with an underlying severe haematologic toxicity,5–7 although this is an exceptional side-effect. Another well-known sideeffect is photosensitivity induced by methotrexate.8 The way of administration has also been a subject of controversy. Some papers are being published in favour of subcutaneous route compared to the oral. Subcutaneous way has demonstrated a higher bioavailability, in addition to association with a lower occurrence of gastrointestinal effects.9 On the other side, subcutaneous administration is often rejected by the patient. The presence of local reaction at the injection site is an effect reflected in the technical sheet of the medication as ‘very rare’ (less than 1/10 000 patients), with possible formation of sterile abscesses and lipodystrophy.
JEADV 2016, 30, 446–556
1 Puig L. Metotrexato: novedades terapeuticas. Actas Dermosifiliogr 2014; 105: 583–589. 2 Carretero G, Ribera M, Belinch on I et al. Metotrexato: guıa de uso en psoriasis. Actas Dermosifiliogr 2010; 101: 600–613. 3 Weidmann A, Foulkes AC, Kirkham N, Reynolds NJ. Methotrexate toxicity during treatment of chronic plaque psoriasis: a case report and review of the literature. Dermatol Ther (Heidelb), 2014; 4: 145–156. 4 Martınez-Raposo Piedrafita MC, Esteban Jimenez O, Baile Estopa~ nan G, Navarro Peman C. Encephalopathy secondary to methotrexate. Med Clin (Barc). 2010; 134: 662–663. 5 Del Pozo J, Martınez W, Garcıa-Silva J, Almagro M, Pe~ na-Penabad C, Fonseca E. Cutaneous ulceration as a sign of methotrexate toxicity. Eur J Dermatol. 2001; 11: 450–452. 6 Lawrence CM, Dahl MG. Two patterns of skin ulceration induced by methotrexate in patients with psoriasis. J Am Acad Dermatol 1984; 11: 1059–1065. 7 Maro~ nas-Jimenez L, Castellanos-Gonzalez M, Sanz Bueno J, Vanaclocha Sebastian F. Erosiones y u lceras acrales: manifestaci on precoz de toxicidad aguda grave por metotrexato. Actas Dermosifiliogr 2014; 105: 322–323. 8 Fernandez RJ, Jorda PA, Fernandez-Navarro JM, Sales AA, Ramiro AN, Miralles AV. Photoxicity reaction due to methotrexate. An Pediatr (Barc). 2012; 76: 179–180. 9 Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol 2014; 32: 563–571. DOI: 10.1111/jdv.12920
Failure of omalizumab in the treatment of solar urticaria Editor Solar urticaria is a rare IgE-mediated disease resulting in urticae following exposure to UV- or visible light. Wheals develop within minutes of light exposure and resolve spontaneously over hours. Wheals may develop following sun exposure through glass or under clothing. H1-antihistamines and phototherapy are the mainstay of treatment. Beneficial effects have been reported with plasmapheresis, intravenous immunoglobulins, chloroquine, cyclosporine and polypodium leucotomos. Recently, omalizumab, a recombinant humanized monoclonal antibody against the human IgE Ce3 domain has been reported as a promising therapeutic option for refractory solar urticaria.1
© 2014 European Academy of Dermatology and Venereology
(a)
523
(b)
Figure 2 Case 2: Post ustekinumab treatment (11/2013). (a) Near complete clearance of psoriasis on the left arm. (b) No change in eczematous plaques on the knee flexures.
phenotype during the chronic phase. Recently, a role for T helper cell subsets such as Th17 and Th22 cells has been suggested, yet the evidence is conflicting.1 By blocking IL-12 and IL-23, ustekinumab can regulate both Th1 and Th17 pathways, which are reportedly active in AD. Unfortunately, our patients did not experience therapeutic benefits seen in previous reports.2–5 Possibly the IL-17 pathway is less relevant in patients with elevated IgE,6 yet responsive patients with elevated IgE have been reported. It may be that IL-17 is only a bystander effect, reflecting an inflammatory state and not an important contributor to AD pathogenesis.1 Another explanation for the disparity in outcomes is that the short follow up period in previous reports2,5 may not have captured a significant loss of efficacy over time as was observed in Patient 1. This patient flared after a staphylococcal infection and did not respond to continued ustekinumab. IL-17 has been shown to play a crucial role in host defense against S. aureus skin infections.7 Blocking this pathway with ustekinumab in atopic patients already prone to staphylococcal skin infection8 may inhibit response or cause a persistent flare. Atopic dermatitis is a complex disease in which a variety of pathogenic pathways may lead to disease expression, reflecting divergent response rates toward specific therapies. Optimized, randomized controlled trials are necessary to evaluate the utility of ustekinumab in treating patients with AD. L.P. Samorano,1,* J.M. Hanifin,2 E.L. Simpson,2 Y.A. Leshem2 1 ~o Department of Dermatology, Hospital das Clınicas, University of Sa Paulo Medical School, Sao Paulo, Brazil, 2Department of Dermatology, Oregon Health and Science University, Portland, OR, USA *Correspondence: L.P. Samorano. E-mail: [email protected]
References 1 Milner JD. IL-17 producing cells in host defense and atopy. Curr Opin Immunol 2011; 23: 784–788.
JEADV 2016, 30, 446–556
2 Agusti-Mejias A, Messeguer F, Garcıa R, Febrer I. Severe refractory atopic dermatitis in an adolescent patient successfully treated with ustekinumab. Ann Dermatol 2013; 25: 368–370. 3 Fernandez-Ant on Martınez MC, Alfageme Roldan F, Ciudad Blanco C, Suarez Fernandez R. Ustekinumab in the treatment of severe atopic dermatitis: a preliminary report of our experience with 4 patients. Actas Dermosifiliogr 2014; 105: 312–313. 4 Puya R, Alvarez-L opez M, Velez A, Casas Asuncion E, Moreno JC. Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol 2012; 51: 115–116. 5 Eyerich S, Onken AT, Weidinger S et al. Mutual antagonism of T cells causing psoriasis and atopic eczema. N Engl J Med 2011 Jul 21; 365: 231–238. 6 Suarez-Fari~ nas M, Dhingra N, Gittler J et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013; 132: 361–370. 7 Ishigame H, Kakuta S, Nagai T et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009 Jan 16; 30: 108–119. 8 Ong PY, Leung DY. The infectious aspects of atopic dermatitis. Immunol Allergy Clin North Am 2010 Aug; 30: 309–321. DOI: 10.1111/jdv.12918
Local reaction after subcutaneous injection of methotrexate: uncommon side effect Editor In February 2014, a 37-year-old man was referred to our outpatient Department with a 20-year history of severe plaque psoriasis that was poorly controlled with topical treatments (PASI 12.2), requiring in different moments of his evolution cyclosporine, methotrexate and acitretin with moderate response, and finally he began treatment with etanercept achieving PASI 0 in week 36. In that moment, we removed the medication but 7 months later he presented a recurrence (PASI 8.2) and we decided to introduce again subcutaneous methotrexate with a progressive increase in the dose. He reached PASI 0 with 15 mg/ week of methotrexate 1 year later. However, at 15 months of having reintroduced the medication the patient suffered a local reaction at the subcutaneous administration site of methotrexate. He presented several oedematous and erythematous papules, with crusting and laminar scaling that healed without scars (Fig. 1). These lesions began to appear with the last five doses of methotrexate, when the accumulated dose was 0.635 g. Because of this, we changed subcutaneous administration of methotrexate to oral administration and we prescribed treatment with fusidic acid and betamethasone topically. Lesions healed and good control of psoriasis was maintained with good tolerance and without other side-effects associated.
© 2014 European Academy of Dermatology and Venereology
Letters to the Editor
524
We present this case of intense local reaction after administration of methotrexate subcutaneous because, after reviewing the literature, we have no found similar cases. C.M. Priego-Recio,* F.M. Camacho-Martınez n Clınica de Dermatologıa, Hospital Universitario Virgen Unidad de Gestio Macarena de Sevilla, Avda. Dr Fedriani, n° 3, 41009, Seville, Spain *Correspondence: C.M. Priego Recio. E-mail: [email protected]
References
Figure 1 Edematosquamous papule in abdomen, secondary to the last injection of methotrexate.
Methotrexate is a synthetic analogue of the folic acid that interferes with their metabolic pathway, by blocking the enzyme dihydrofolic-reductase. This inhibits its activation to folinic acid, that it is necessary for the formation of deoxythymidylic acid, which is essential for the synthesis of DNA.1 Since the approval of methotretaxe in 1972 for use as a treatment for plaque psoriasis, it has amply demonstrated its efficacy in this disease and, although it is customary that are mild, it is not free from adverse effects.2 The toxicity produced by methotrexate appears up to 30% of the cases, and can affect different organs and systems.3 The most common side-effects are gastrointestinal disorders, musculoskeletal pain and fever, which appear in the first few hours after its administration and may be cause for suspension of treatment. Other side-effects more severe are liver toxicity (increase transaminases, fibrosis, cirrhosis), blood toxicity (myelosuppression) and lung toxicity (acute interstitial pneumonitis, pulmonary fibrosis). There are even cases of encephalopathy described by methotrexate.4 In regard to the mucocutaneous side-effects, it has been described erosions and/or skin ulcers, generally associated with an underlying severe haematologic toxicity,5–7 although this is an exceptional side-effect. Another well-known sideeffect is photosensitivity induced by methotrexate.8 The way of administration has also been a subject of controversy. Some papers are being published in favour of subcutaneous route compared to the oral. Subcutaneous way has demonstrated a higher bioavailability, in addition to association with a lower occurrence of gastrointestinal effects.9 On the other side, subcutaneous administration is often rejected by the patient. The presence of local reaction at the injection site is an effect reflected in the technical sheet of the medication as ‘very rare’ (less than 1/10 000 patients), with possible formation of sterile abscesses and lipodystrophy.
JEADV 2016, 30, 446–556
1 Puig L. Metotrexato: novedades terapeuticas. Actas Dermosifiliogr 2014; 105: 583–589. 2 Carretero G, Ribera M, Belinch on I et al. Metotrexato: guıa de uso en psoriasis. Actas Dermosifiliogr 2010; 101: 600–613. 3 Weidmann A, Foulkes AC, Kirkham N, Reynolds NJ. Methotrexate toxicity during treatment of chronic plaque psoriasis: a case report and review of the literature. Dermatol Ther (Heidelb), 2014; 4: 145–156. 4 Martınez-Raposo Piedrafita MC, Esteban Jimenez O, Baile Estopa~ nan G, Navarro Peman C. Encephalopathy secondary to methotrexate. Med Clin (Barc). 2010; 134: 662–663. 5 Del Pozo J, Martınez W, Garcıa-Silva J, Almagro M, Pe~ na-Penabad C, Fonseca E. Cutaneous ulceration as a sign of methotrexate toxicity. Eur J Dermatol. 2001; 11: 450–452. 6 Lawrence CM, Dahl MG. Two patterns of skin ulceration induced by methotrexate in patients with psoriasis. J Am Acad Dermatol 1984; 11: 1059–1065. 7 Maro~ nas-Jimenez L, Castellanos-Gonzalez M, Sanz Bueno J, Vanaclocha Sebastian F. Erosiones y u lceras acrales: manifestaci on precoz de toxicidad aguda grave por metotrexato. Actas Dermosifiliogr 2014; 105: 322–323. 8 Fernandez RJ, Jorda PA, Fernandez-Navarro JM, Sales AA, Ramiro AN, Miralles AV. Photoxicity reaction due to methotrexate. An Pediatr (Barc). 2012; 76: 179–180. 9 Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol 2014; 32: 563–571. DOI: 10.1111/jdv.12920
Failure of omalizumab in the treatment of solar urticaria Editor Solar urticaria is a rare IgE-mediated disease resulting in urticae following exposure to UV- or visible light. Wheals develop within minutes of light exposure and resolve spontaneously over hours. Wheals may develop following sun exposure through glass or under clothing. H1-antihistamines and phototherapy are the mainstay of treatment. Beneficial effects have been reported with plasmapheresis, intravenous immunoglobulins, chloroquine, cyclosporine and polypodium leucotomos. Recently, omalizumab, a recombinant humanized monoclonal antibody against the human IgE Ce3 domain has been reported as a promising therapeutic option for refractory solar urticaria.1
© 2014 European Academy of Dermatology and Venereology
