J AM ACAD DERMATOL
Letters 831
VOLUME 71, NUMBER 4
pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823-6. 3. Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189-94. 4. Ben-David G, Sheiner E, Hallak M, Levy A. Pregnancy outcome in women with psoriasis. J Reprod Med 2008;53:183-7. 5. Bae YS, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Young M, et al. Review of treatment options for psoriasis in pregnant or lactating women: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol 2012;67:459-77. http://dx.doi.org/10.1016/j.jaad.2014.04.078
Tumor necrosis factor-alfa inhibitors in pregnancy: To prescribe, or not to prescribe, that is the question To the Editor: We are in complete agreement with the commentary by Kivelevitch et al. Two upcoming publications by the Organization of Teratology Information Specialists from large patient registries of pregnant women on etanercept and adalimumab will provide substantially more data regarding safety in pregnancy. However, what recommendations should we make to our patients in the meantime? Two publications by Carter et al1,2 expressed concern over the trend toward congenital anomalies in the spectrum of vertebral abnormalities, anal atresia, cardiac defect, and tracheoesophageal, renal, and limb abnormalities, yet there was much controversy regarding their analysis.3,4 Similarly, Verstappen et al5 reported an increased rate of spontaneous abortion in patients with rheumatoid arthritis, for whom high disease activity relates to adverse pregnancy outcomes.6 So the concerns regarding an increased risk of congenital anomalies and spontaneous abortion remain controversial until we have more data. Often, smaller initial studies indicate cause for concern not supported in later larger studies. For example, diphenhydramine was reported by Saxen7 in The Lancet in 1974 to have an increased rate of cleft palate formation, not confirmed in subsequent studies. Now, physicians routinely recommend diphenhydramine in the first trimester. The goal of this CME article was to succinctly summarize the available body of literature, allowing the dermatologist and the patient to make case-by-case decisions. Importantly, the dermatologist needs to discuss the risks and potential consequences of no therapy during pregnancy.8 In addition to the increased risk of recurrent abortions in patients with psoriasis, Yang et al9 revealed that patients with severe psoriasis have a 1.5-fold risk of low-birth-weight infants, not seen in patients with mild to moderate psoriasis. Psoriasis often clears as a result of the pregnancy itself. We published a study prospectively observing
the change of body surface area of psoriasis in pregnant patients, revealing that the majority of patients (55%) experience dramatic improvement, with an average lesion resolution of 84%.10 Is it in the best interest of the patient to stop her biologic during the first trimester, undergo topical therapy and narrowband ultraviolet B therapy with adequate folic acid supplementation, and see if the psoriasis slowly ameliorates, or is it best for her to continue her tumor necrosis factor inhibitor?11 This decision involves a discussion between patient and dermatologist on a case-by-case basis. Finally, we ask that dermatologists use caution when interpreting the US Food and Drug Administration pregnancy class B designation for medications new to market. Class B does not necessarily imply that the medication is ‘‘safe’’; it states that there are inadequate data to date to make a recommendation.12,13 The biologic efalizumab was given a pregnancy class C designation because newborn animals were unable to generate an antibody response at birth; similarly, an infant of a pregnant mother who used infliximab (class B) died of disseminated bacillus Calmette-Guerin after receiving the BCG vaccine at 3 months of age.14 As experience grows with the medication, it can often be moved to the C and D categories, and it remains to be seen how the tumor necrosis factor inhibitors will be classified. Jenny E. Murase, MD,a,b and Daniel C. Butler, MDc,d Department of Dermatology, University of California, San Franciscoa; Department of Dermatology, Palo Alto Foundation Medical Group, Mountain View, Californiab; Department of Medicine, University of Arizona, Tucsonc; and Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusettsd Funding sources: None. Conflicts of interest: None declared. Correspondence to: Jenny E. Murase, MD, Department of Dermatology, Palo Alto Foundation Medical Group, 701 E El Camino Real (31-104), Mountain View, CA 94040 E-mail: [email protected] REFERENCES 1. Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635-41. 2. Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 2006;33:1014-7.
J AM ACAD DERMATOL
832 Letters
OCTOBER 2014
3. Winger EE, Reed JL. Was risk properly assessed in Carter, et al’s safety assessment of tumor necrosis factor antagonists during pregnancy? J Rheumatol 2009;36:2122; author reply 2123. 4. Koren G, Inoue M. Do tumor necrosis factor inhibitors cause malformations in humans? J Rheumatol 2009;36:465-6. 5. Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL; BSRBR Control Center Consortium, BSR Biologics Register. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823-6. 6. de Man YA, Dolhain RJ, Hazes JM. Disease activity or remission of rheumatoid arthritis before, during and following pregnancy. Curr Opin Rheumatol 2014;26:329-33. 7. Saxen I. Cleft palate and maternal diphenhydramine intake [letter]. Lancet 1974;1:407-8. 8. Gupta R, High WA, Butler D, Murase JE. Medicolegal aspects of prescribing dermatological medications in pregnancy. Semin Cutan Med Surg 2013;32:209-16. 9. Yang YW, Chen CS, Chen YH, Lin HC. Psoriasis and pregnancy outcomes: a nationwide population-based study. J Am Acad Dermatol 2011;64:71-7. 10. Murase JE, Chan KK, Garite TJ, Cooper DM, Weinstein GD. Hormonal effect on psoriasis in pregnancy and post partum. Arch Dermatol 2005;141:601-6. 11. Park KK, Murase JE. Narrowband UV-B phototherapy during pregnancy and folic acid depletion. Arch Dermatol 2012;148:132-3. 12. Millsop JW, Heller MM, Murase JE. Safety classification systems used in dermatological medication risk counseling of pregnant and lactating patients: a case for an evidence-based approach. Dermatol Ther 2013;26:347-53. 13. Wong JW, Heller MM, Murase JE. Caution advised in interpretation of US FDA risk classification for dermatological medications during pregnancy. Dermatol Online J 2012;18:15. 14. Heller MM, Wu JJ, Murase JE. Fatal case of disseminated BCG infection after vaccination of an infant with in utero exposure to infliximab. J Am Acad Dermatol 2011;65:870. http://dx.doi.org/10.1016/j.jaad.2014.06.029
Allergic contact dermatitis to topical brimonidine tartrate gel 0.33% for treatment of rosacea To the Editor: We read with interest the recent publication by Del Rosso regarding the use of brimonidine tartrate gel 0.33% (Mirvaso, Galderma
Laboratories, Fort Worth, TX) in the treatment of rosacea.1 In prescribing this new therapy, dermatologists should be aware of the potential for allergic contact dermatitis. We recently saw a 75-year-old woman with a 3month history of pruritic dermatitis on her malar cheeks and nose. The dermatitis began within a few days of initiating treatment of rosacea with brimonidine tartrate gel 0.33%. She had no prior history of reactions to cosmetics or jewelry but did have a history of intolerance to eye drops used to treat her glaucoma. She was patch tested to the following series: North American Contact Dermatitis Standard, vehicle/emulsifiers, preservatives, nail acrylates, and 10 personal items including brimonidine tartrate gel. Final reactions included strong (11) reactions to Balsam of Peru and sodium metabisulfite. Mild (1) reactions were noted to fragrance mix II, neomycin, Finacea gel, and Elidel cream. Fragrance ingredients and related allergens (benzyl alcohol in Elidel cream and benzoic acid in Finacea gel) were thought to be possibly clinically relevant. Because of the high suspicion for brimonidine allergy, we performed a use test (application twice daily to the upper arm) to brimonidine tartrate gel as well as brimonidine ophthalmic solution (Alphagan, Allergan, Irvine, CA), which the patient was suspicious caused previous issues. On day 3 of the use test, a red, raised, vesicular dermatitis developed in response to both Mirvaso gel and Alphagan eye drops. Neither of these products contained ingredients known to be allergenic for this patient (Table I). Mirvaso was approved by the US Food and Drug Administration in August 2013 for treatment of persistent facial erythema in adults with rosacea. Brimonidine tartrate is a highly selective 2-adrenergic receptor agonist that targets the smooth muscle of superficial cutaneous blood vessels to cause vasoconstriction.1 A 1-year open-label study in 345
Table I. Active and inactive ingredients of Mirvaso and Alphagan Mirvaso
Active ingredient Brimonidine tartrate Inactive ingredients Carbomer homopolymer Type B (acrylic acid) Glycerin Methylparaben* Phenoxyethanol* Propylene glycol* Sodium hydroxide Titanium dioxide*
*Individual patch tests to purified substance negative.
Alphagan
Active ingredient Brimonidine tartrate Inactive ingredients Sodium carboxymethylcellulose Sodium borate Boric acid Calcium chloride Magnesium chloride Sodium hydroxide Hydrochloric acid Stabilized oxychloro complex (sodium chlorite)
Letters 831
VOLUME 71, NUMBER 4
pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823-6. 3. Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189-94. 4. Ben-David G, Sheiner E, Hallak M, Levy A. Pregnancy outcome in women with psoriasis. J Reprod Med 2008;53:183-7. 5. Bae YS, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Young M, et al. Review of treatment options for psoriasis in pregnant or lactating women: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol 2012;67:459-77. http://dx.doi.org/10.1016/j.jaad.2014.04.078
Tumor necrosis factor-alfa inhibitors in pregnancy: To prescribe, or not to prescribe, that is the question To the Editor: We are in complete agreement with the commentary by Kivelevitch et al. Two upcoming publications by the Organization of Teratology Information Specialists from large patient registries of pregnant women on etanercept and adalimumab will provide substantially more data regarding safety in pregnancy. However, what recommendations should we make to our patients in the meantime? Two publications by Carter et al1,2 expressed concern over the trend toward congenital anomalies in the spectrum of vertebral abnormalities, anal atresia, cardiac defect, and tracheoesophageal, renal, and limb abnormalities, yet there was much controversy regarding their analysis.3,4 Similarly, Verstappen et al5 reported an increased rate of spontaneous abortion in patients with rheumatoid arthritis, for whom high disease activity relates to adverse pregnancy outcomes.6 So the concerns regarding an increased risk of congenital anomalies and spontaneous abortion remain controversial until we have more data. Often, smaller initial studies indicate cause for concern not supported in later larger studies. For example, diphenhydramine was reported by Saxen7 in The Lancet in 1974 to have an increased rate of cleft palate formation, not confirmed in subsequent studies. Now, physicians routinely recommend diphenhydramine in the first trimester. The goal of this CME article was to succinctly summarize the available body of literature, allowing the dermatologist and the patient to make case-by-case decisions. Importantly, the dermatologist needs to discuss the risks and potential consequences of no therapy during pregnancy.8 In addition to the increased risk of recurrent abortions in patients with psoriasis, Yang et al9 revealed that patients with severe psoriasis have a 1.5-fold risk of low-birth-weight infants, not seen in patients with mild to moderate psoriasis. Psoriasis often clears as a result of the pregnancy itself. We published a study prospectively observing
the change of body surface area of psoriasis in pregnant patients, revealing that the majority of patients (55%) experience dramatic improvement, with an average lesion resolution of 84%.10 Is it in the best interest of the patient to stop her biologic during the first trimester, undergo topical therapy and narrowband ultraviolet B therapy with adequate folic acid supplementation, and see if the psoriasis slowly ameliorates, or is it best for her to continue her tumor necrosis factor inhibitor?11 This decision involves a discussion between patient and dermatologist on a case-by-case basis. Finally, we ask that dermatologists use caution when interpreting the US Food and Drug Administration pregnancy class B designation for medications new to market. Class B does not necessarily imply that the medication is ‘‘safe’’; it states that there are inadequate data to date to make a recommendation.12,13 The biologic efalizumab was given a pregnancy class C designation because newborn animals were unable to generate an antibody response at birth; similarly, an infant of a pregnant mother who used infliximab (class B) died of disseminated bacillus Calmette-Guerin after receiving the BCG vaccine at 3 months of age.14 As experience grows with the medication, it can often be moved to the C and D categories, and it remains to be seen how the tumor necrosis factor inhibitors will be classified. Jenny E. Murase, MD,a,b and Daniel C. Butler, MDc,d Department of Dermatology, University of California, San Franciscoa; Department of Dermatology, Palo Alto Foundation Medical Group, Mountain View, Californiab; Department of Medicine, University of Arizona, Tucsonc; and Department of Dermatology, Brigham and Women’s Hospital, Boston, Massachusettsd Funding sources: None. Conflicts of interest: None declared. Correspondence to: Jenny E. Murase, MD, Department of Dermatology, Palo Alto Foundation Medical Group, 701 E El Camino Real (31-104), Mountain View, CA 94040 E-mail: [email protected] REFERENCES 1. Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635-41. 2. Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 2006;33:1014-7.
J AM ACAD DERMATOL
832 Letters
OCTOBER 2014
3. Winger EE, Reed JL. Was risk properly assessed in Carter, et al’s safety assessment of tumor necrosis factor antagonists during pregnancy? J Rheumatol 2009;36:2122; author reply 2123. 4. Koren G, Inoue M. Do tumor necrosis factor inhibitors cause malformations in humans? J Rheumatol 2009;36:465-6. 5. Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL; BSRBR Control Center Consortium, BSR Biologics Register. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823-6. 6. de Man YA, Dolhain RJ, Hazes JM. Disease activity or remission of rheumatoid arthritis before, during and following pregnancy. Curr Opin Rheumatol 2014;26:329-33. 7. Saxen I. Cleft palate and maternal diphenhydramine intake [letter]. Lancet 1974;1:407-8. 8. Gupta R, High WA, Butler D, Murase JE. Medicolegal aspects of prescribing dermatological medications in pregnancy. Semin Cutan Med Surg 2013;32:209-16. 9. Yang YW, Chen CS, Chen YH, Lin HC. Psoriasis and pregnancy outcomes: a nationwide population-based study. J Am Acad Dermatol 2011;64:71-7. 10. Murase JE, Chan KK, Garite TJ, Cooper DM, Weinstein GD. Hormonal effect on psoriasis in pregnancy and post partum. Arch Dermatol 2005;141:601-6. 11. Park KK, Murase JE. Narrowband UV-B phototherapy during pregnancy and folic acid depletion. Arch Dermatol 2012;148:132-3. 12. Millsop JW, Heller MM, Murase JE. Safety classification systems used in dermatological medication risk counseling of pregnant and lactating patients: a case for an evidence-based approach. Dermatol Ther 2013;26:347-53. 13. Wong JW, Heller MM, Murase JE. Caution advised in interpretation of US FDA risk classification for dermatological medications during pregnancy. Dermatol Online J 2012;18:15. 14. Heller MM, Wu JJ, Murase JE. Fatal case of disseminated BCG infection after vaccination of an infant with in utero exposure to infliximab. J Am Acad Dermatol 2011;65:870. http://dx.doi.org/10.1016/j.jaad.2014.06.029
Allergic contact dermatitis to topical brimonidine tartrate gel 0.33% for treatment of rosacea To the Editor: We read with interest the recent publication by Del Rosso regarding the use of brimonidine tartrate gel 0.33% (Mirvaso, Galderma
Laboratories, Fort Worth, TX) in the treatment of rosacea.1 In prescribing this new therapy, dermatologists should be aware of the potential for allergic contact dermatitis. We recently saw a 75-year-old woman with a 3month history of pruritic dermatitis on her malar cheeks and nose. The dermatitis began within a few days of initiating treatment of rosacea with brimonidine tartrate gel 0.33%. She had no prior history of reactions to cosmetics or jewelry but did have a history of intolerance to eye drops used to treat her glaucoma. She was patch tested to the following series: North American Contact Dermatitis Standard, vehicle/emulsifiers, preservatives, nail acrylates, and 10 personal items including brimonidine tartrate gel. Final reactions included strong (11) reactions to Balsam of Peru and sodium metabisulfite. Mild (1) reactions were noted to fragrance mix II, neomycin, Finacea gel, and Elidel cream. Fragrance ingredients and related allergens (benzyl alcohol in Elidel cream and benzoic acid in Finacea gel) were thought to be possibly clinically relevant. Because of the high suspicion for brimonidine allergy, we performed a use test (application twice daily to the upper arm) to brimonidine tartrate gel as well as brimonidine ophthalmic solution (Alphagan, Allergan, Irvine, CA), which the patient was suspicious caused previous issues. On day 3 of the use test, a red, raised, vesicular dermatitis developed in response to both Mirvaso gel and Alphagan eye drops. Neither of these products contained ingredients known to be allergenic for this patient (Table I). Mirvaso was approved by the US Food and Drug Administration in August 2013 for treatment of persistent facial erythema in adults with rosacea. Brimonidine tartrate is a highly selective 2-adrenergic receptor agonist that targets the smooth muscle of superficial cutaneous blood vessels to cause vasoconstriction.1 A 1-year open-label study in 345
Table I. Active and inactive ingredients of Mirvaso and Alphagan Mirvaso
Active ingredient Brimonidine tartrate Inactive ingredients Carbomer homopolymer Type B (acrylic acid) Glycerin Methylparaben* Phenoxyethanol* Propylene glycol* Sodium hydroxide Titanium dioxide*
*Individual patch tests to purified substance negative.
Alphagan
Active ingredient Brimonidine tartrate Inactive ingredients Sodium carboxymethylcellulose Sodium borate Boric acid Calcium chloride Magnesium chloride Sodium hydroxide Hydrochloric acid Stabilized oxychloro complex (sodium chlorite)
