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Letters 829
VOLUME 71, NUMBER 4
surgical excision of dermatofibrosarcoma protuberans. J Dermatol Surg Oncol 1994;20:687-9. 6. Kelley LC, Starkus L. Immunohistochemical staining of lentigo maligna during Mohs micrographic surgery using MART-1. J Am Acad Dermatol 2002;46:78-84. 7. Cherpelis BS, Turner L, Ladd S, Glass LF, Fenske NA. Innovative 19-minute rapid cytokeratin immunostaining of nonmelanoma skin cancer in Mohs micrographic surgery. Dermatol Surg 2009; 35:1050-6. http://dx.doi.org/10.1016/j.jaad.2014.05.043
Comments on ‘‘Diet and psoriasis, part I: Impact of weight loss interventions’’ To the Editor: We read with great interest the review on weight loss in psoriasis recently published online in the Journal.1 The authors concluded that weight loss may be a useful preventive and adjunctive therapy for the treatment of psoriasis but ‘‘larger, prospective clinical studies are needed to further delineate the efficacy of diet and weight loss interventions in psoriasis improvement.’’ We have recently completed a randomized clinical trial on weight reduction in overweight or obese psoriatic patients.2 The study included patients with chronic plaque psoriasis, aged 18 to 80 years, with body mass index 25 or higher and a Psoriasis Area and Severity Index (PASI) score of 10 or higher, who had started a systemic therapy for psoriasis not achieving clearance after 4 weeks of continuous treatment. A total of 588 patients were initially screened and 303 were finally randomized. The impact of a dietetic plan associated with advice on physical exercise was compared with a simple informative counseling about the utility of weight loss during a 20-week period. The dietetic plan was based on the exchange system, in which foods are divided into groups, and, within each group, the maximum food allowance is defined based on the amount of calories involved. The main outcome was any reduction of PASI score from baseline at week 20. The target weight reduction was a loss equal to or greater than 5% of baseline weight at week 20. Outcome parameters were evaluated by an assessor, different from the treating physician, blind to the patient treatment allocation. Only 29 enrolled patients (6.9%) withdrew before the end of the study. Intention-to-treat analysis showed a median PASI score reduction of 48% in the dietary intervention arm and 25.5% in the information-only arm (P ¼ .02). The weight-loss target was reached by 29.8% of patients in the dietary intervention arm and 14.5% in the information-only arm (P ¼ .001). Interestingly, there was a clear correlation between the amount of weight loss and the improvement of psoriasis expressed as percent reduction of PASI
value, both in the intervention arm and in the information-only arm. All in all, our study documented that, in the short term, even limited weight loss could help reduce psoriasis severity in overweight or obese patients, increasing the efficacy of systemic treatment. Interestingly, similar to metabolic control in diabetes,3 we showed that even a small reduction in body weight may have a large clinical influence on disease activity. The long-term impact of a dietetic intervention on psoriasis remains to be documented, and we are exploring the possibility of promoting a larger international collaboration focusing on the impact of dietetic interventions in the long-term management of psoriasis and its comorbidities, possibly by nesting randomized trials within existing disease registries. Simone Cazzaniga, PhD,a Andrea Conti, MD,b Luigi Naldi, MD,a,c on behalf of the Psoriasis Emilia Romagna Study Group Centro Studi Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED), Bergamo, Italya; Department of Dermatology, Azienda Ospedaliero-Universitaria-Policlinico, Modena, Italyb; and Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italyc Supported by a research grant from the Emilia Romagna region (Programma di Ricerca Regione Universit a 2007-2009, AREA 2 Ricerca per il governo clinico). Conflicts of interest: None declared. Correspondence to: Luigi Naldi, MD, Centro Studi GISED, Via Garibaldi 13/15, 24122 Bergamo, Italy E-mail: [email protected] REFERENCES 1. Debbaneh M, Millsop JW, Bhatia BK, Koo J, Liao W. Diet and psoriasis, part I: impact of weight loss interventions. J Am Acad Dermatol 2014;71:133-40. 2. Naldi L, Conti A, Cazzaniga S, Patrizi A, Pazzaglia M, Lanzoni A, et al; the Psoriasis Emilia Romagna Study Group. Diet and physical exercise in psoriasis: a randomized controlled trial. Br J Dermatol 2014;170:634-42. 3. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782-7. http://dx.doi.org/10.1016/j.jaad.2014.05.072
The use of tumor necrosis factor inhibitors in pregnancy: What is the evidence? To the Editor: We commend Murase et al1 on their excellent review of the use of medications for dermatologic conditions in pregnant and lactating
J AM ACAD DERMATOL
830 Letters
women, which we believe will be of significant value for all dermatologists. We are concerned, however, about the lack of evidence supporting the statement in the CME article that there is an increased rate of spontaneous abortion if etanercept is used during the first trimester. This was based solely on a small study of 140 pregnant patients with rheumatoid arthritis from the British Society for Rheumatology Biologics Register.2 Patients were divided into 4 groups according to their medication status: patients receiving antietumor necrosis factor (TNF) therapy plus methotrexate or leflunomide at time of conception (n ¼ 21), patients on antieTNF therapy but no methotrexate or leflunomide at time of conception (n ¼ 50), patients who received antieTNF therapy before conception (n ¼ 59), and a control group of only 10 patients never exposed to antieTNF therapy. The rate of spontaneous abortions described in each of these groups was 33%, 24%, 17%, and 10%, respectively.2 The authors concluded that treatment with antieTNF-alfa therapy at the time of conception may be associated with an increased risk of spontaneous abortion, although the influence of disease severity was not assessed. There are significant data to suggest that severe rheumatoid arthritis may have unfavorable pregnancy outcomes that may well have played a role in the choice of therapeutic agent in these patients with rheumatoid arthritis. The rate of spontaneous abortions in the general population has been reported as up to 31%.3 The treatment of moderate to severe psoriasis in women of childbearing age is challenging for dermatologists as many oral medications commonly used to treat this disease are teratogenic, abortifacient, or both. Moreover, a case-control study comparing pregnancy outcomes of 145 pregnant patients with psoriasis with 860 nonpsoriatic women showed an increased risk of recurrent abortions in patients with psoriasis.4 Current antieTNF-alfa therapies are classified as pregnancy category B and studies have suggested a potential beneficial effect of etanercept in women with recurrent abortions by decreasing natural killer cell activity. More robust evidence from prospective studies that comprehensively record variables such as disease severity, comorbid conditions, and specific treatments are needed before conclusions can be made regarding the safety of TNF-alfa inhibitor use in patients with psoriasis during pregnancy. Thus, registry data from both patients with rheumatology and psoriasis, nationally and internationally, will provide larger numbers and more reliable data. In our large psoriasis clinic at Baylor University in Dallas, TX, we discuss regularly with our female patients considering pregnancy the
OCTOBER 2014
potential safety and risk of psoriasis therapies. According to a National Psoriasis Foundation report, TNF-alfa antagonists are considered third-line therapy of psoriasis in pregnancy, after topical treatments and phototherapy.5 As psoriasis improves spontaneously in up to 60% of pregnancies, we encourage our patients to discontinue their biologic agent during pregnancy, if possible, but to be extremely cautious in the immediate postpartum period when major flares of psoriasis are frequent. Dario Nicolas Kivelevitch, MD, Caitriona Ryan, MD, and Alan Menter, MD Baylor University Medical Center, Dallas, Texas Funding sources: None. Disclosure: Dr Menter has been on the advisory boards of AbbVie, Allergan, Amgen, Boehringer Ingelheim, Genentech, Janssen Biotech Inc, LEO Pharma, and Pfizer; been a consultant for AbbVie, Allergan, Amgen, Convoy Therapeutics Inc, Eli-Lilly, Janssen Biotech Inc, LEO Pharma, Novartis, Pfizer, Syntrix, Wyeth, and XenoPort; been an investigator for AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics Inc, Eli-Lilly, Genentech, Janssen Biotech Inc, LEO Pharma, Merck, Novartis, Pfizer, Symbio/Maruho, Syntrix, and Wyeth; been a speaker for AbbVie, Amgen, Janssen Biotech Inc, LEO Pharma, and Wyeth; received grants from AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics Inc, Genentech, Janssen Biotech Inc, LEO Pharma, Merck, Pfizer, Symbio/Maruho, and Syntrix; and received honoraria from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Convoy Therapeutics Inc, Eli-Lilly, Genentech, Janssen Biotech Inc, LEO Pharma, Novartis, Pfizer, Syntrix, Wyeth, and XenoPort. Dr Ryan has been on the advisory board and received honoraria from AbbVie and Pfizer. Dr Kivelevitch has been a speaker and received honoraria from AbbVie. Correspondence to: Alan Menter, MD, Baylor University Medical Center, 3900 Junius St, Suite 125, Dallas, TX 75246 E-mail: [email protected]
REFERENCES 1. Murase JE, Heller MM, Butler DC. Safety of dermatologic medications in pregnancy and lactation, part I: pregnancy. J Am Acad Dermatol 2014;70:401.e1-14, quiz 415. 2. 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
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.
Letters 829
VOLUME 71, NUMBER 4
surgical excision of dermatofibrosarcoma protuberans. J Dermatol Surg Oncol 1994;20:687-9. 6. Kelley LC, Starkus L. Immunohistochemical staining of lentigo maligna during Mohs micrographic surgery using MART-1. J Am Acad Dermatol 2002;46:78-84. 7. Cherpelis BS, Turner L, Ladd S, Glass LF, Fenske NA. Innovative 19-minute rapid cytokeratin immunostaining of nonmelanoma skin cancer in Mohs micrographic surgery. Dermatol Surg 2009; 35:1050-6. http://dx.doi.org/10.1016/j.jaad.2014.05.043
Comments on ‘‘Diet and psoriasis, part I: Impact of weight loss interventions’’ To the Editor: We read with great interest the review on weight loss in psoriasis recently published online in the Journal.1 The authors concluded that weight loss may be a useful preventive and adjunctive therapy for the treatment of psoriasis but ‘‘larger, prospective clinical studies are needed to further delineate the efficacy of diet and weight loss interventions in psoriasis improvement.’’ We have recently completed a randomized clinical trial on weight reduction in overweight or obese psoriatic patients.2 The study included patients with chronic plaque psoriasis, aged 18 to 80 years, with body mass index 25 or higher and a Psoriasis Area and Severity Index (PASI) score of 10 or higher, who had started a systemic therapy for psoriasis not achieving clearance after 4 weeks of continuous treatment. A total of 588 patients were initially screened and 303 were finally randomized. The impact of a dietetic plan associated with advice on physical exercise was compared with a simple informative counseling about the utility of weight loss during a 20-week period. The dietetic plan was based on the exchange system, in which foods are divided into groups, and, within each group, the maximum food allowance is defined based on the amount of calories involved. The main outcome was any reduction of PASI score from baseline at week 20. The target weight reduction was a loss equal to or greater than 5% of baseline weight at week 20. Outcome parameters were evaluated by an assessor, different from the treating physician, blind to the patient treatment allocation. Only 29 enrolled patients (6.9%) withdrew before the end of the study. Intention-to-treat analysis showed a median PASI score reduction of 48% in the dietary intervention arm and 25.5% in the information-only arm (P ¼ .02). The weight-loss target was reached by 29.8% of patients in the dietary intervention arm and 14.5% in the information-only arm (P ¼ .001). Interestingly, there was a clear correlation between the amount of weight loss and the improvement of psoriasis expressed as percent reduction of PASI
value, both in the intervention arm and in the information-only arm. All in all, our study documented that, in the short term, even limited weight loss could help reduce psoriasis severity in overweight or obese patients, increasing the efficacy of systemic treatment. Interestingly, similar to metabolic control in diabetes,3 we showed that even a small reduction in body weight may have a large clinical influence on disease activity. The long-term impact of a dietetic intervention on psoriasis remains to be documented, and we are exploring the possibility of promoting a larger international collaboration focusing on the impact of dietetic interventions in the long-term management of psoriasis and its comorbidities, possibly by nesting randomized trials within existing disease registries. Simone Cazzaniga, PhD,a Andrea Conti, MD,b Luigi Naldi, MD,a,c on behalf of the Psoriasis Emilia Romagna Study Group Centro Studi Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED), Bergamo, Italya; Department of Dermatology, Azienda Ospedaliero-Universitaria-Policlinico, Modena, Italyb; and Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italyc Supported by a research grant from the Emilia Romagna region (Programma di Ricerca Regione Universit a 2007-2009, AREA 2 Ricerca per il governo clinico). Conflicts of interest: None declared. Correspondence to: Luigi Naldi, MD, Centro Studi GISED, Via Garibaldi 13/15, 24122 Bergamo, Italy E-mail: [email protected] REFERENCES 1. Debbaneh M, Millsop JW, Bhatia BK, Koo J, Liao W. Diet and psoriasis, part I: impact of weight loss interventions. J Am Acad Dermatol 2014;71:133-40. 2. Naldi L, Conti A, Cazzaniga S, Patrizi A, Pazzaglia M, Lanzoni A, et al; the Psoriasis Emilia Romagna Study Group. Diet and physical exercise in psoriasis: a randomized controlled trial. Br J Dermatol 2014;170:634-42. 3. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782-7. http://dx.doi.org/10.1016/j.jaad.2014.05.072
The use of tumor necrosis factor inhibitors in pregnancy: What is the evidence? To the Editor: We commend Murase et al1 on their excellent review of the use of medications for dermatologic conditions in pregnant and lactating
J AM ACAD DERMATOL
830 Letters
women, which we believe will be of significant value for all dermatologists. We are concerned, however, about the lack of evidence supporting the statement in the CME article that there is an increased rate of spontaneous abortion if etanercept is used during the first trimester. This was based solely on a small study of 140 pregnant patients with rheumatoid arthritis from the British Society for Rheumatology Biologics Register.2 Patients were divided into 4 groups according to their medication status: patients receiving antietumor necrosis factor (TNF) therapy plus methotrexate or leflunomide at time of conception (n ¼ 21), patients on antieTNF therapy but no methotrexate or leflunomide at time of conception (n ¼ 50), patients who received antieTNF therapy before conception (n ¼ 59), and a control group of only 10 patients never exposed to antieTNF therapy. The rate of spontaneous abortions described in each of these groups was 33%, 24%, 17%, and 10%, respectively.2 The authors concluded that treatment with antieTNF-alfa therapy at the time of conception may be associated with an increased risk of spontaneous abortion, although the influence of disease severity was not assessed. There are significant data to suggest that severe rheumatoid arthritis may have unfavorable pregnancy outcomes that may well have played a role in the choice of therapeutic agent in these patients with rheumatoid arthritis. The rate of spontaneous abortions in the general population has been reported as up to 31%.3 The treatment of moderate to severe psoriasis in women of childbearing age is challenging for dermatologists as many oral medications commonly used to treat this disease are teratogenic, abortifacient, or both. Moreover, a case-control study comparing pregnancy outcomes of 145 pregnant patients with psoriasis with 860 nonpsoriatic women showed an increased risk of recurrent abortions in patients with psoriasis.4 Current antieTNF-alfa therapies are classified as pregnancy category B and studies have suggested a potential beneficial effect of etanercept in women with recurrent abortions by decreasing natural killer cell activity. More robust evidence from prospective studies that comprehensively record variables such as disease severity, comorbid conditions, and specific treatments are needed before conclusions can be made regarding the safety of TNF-alfa inhibitor use in patients with psoriasis during pregnancy. Thus, registry data from both patients with rheumatology and psoriasis, nationally and internationally, will provide larger numbers and more reliable data. In our large psoriasis clinic at Baylor University in Dallas, TX, we discuss regularly with our female patients considering pregnancy the
OCTOBER 2014
potential safety and risk of psoriasis therapies. According to a National Psoriasis Foundation report, TNF-alfa antagonists are considered third-line therapy of psoriasis in pregnancy, after topical treatments and phototherapy.5 As psoriasis improves spontaneously in up to 60% of pregnancies, we encourage our patients to discontinue their biologic agent during pregnancy, if possible, but to be extremely cautious in the immediate postpartum period when major flares of psoriasis are frequent. Dario Nicolas Kivelevitch, MD, Caitriona Ryan, MD, and Alan Menter, MD Baylor University Medical Center, Dallas, Texas Funding sources: None. Disclosure: Dr Menter has been on the advisory boards of AbbVie, Allergan, Amgen, Boehringer Ingelheim, Genentech, Janssen Biotech Inc, LEO Pharma, and Pfizer; been a consultant for AbbVie, Allergan, Amgen, Convoy Therapeutics Inc, Eli-Lilly, Janssen Biotech Inc, LEO Pharma, Novartis, Pfizer, Syntrix, Wyeth, and XenoPort; been an investigator for AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics Inc, Eli-Lilly, Genentech, Janssen Biotech Inc, LEO Pharma, Merck, Novartis, Pfizer, Symbio/Maruho, Syntrix, and Wyeth; been a speaker for AbbVie, Amgen, Janssen Biotech Inc, LEO Pharma, and Wyeth; received grants from AbbVie, Allergan, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Convoy Therapeutics Inc, Genentech, Janssen Biotech Inc, LEO Pharma, Merck, Pfizer, Symbio/Maruho, and Syntrix; and received honoraria from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Convoy Therapeutics Inc, Eli-Lilly, Genentech, Janssen Biotech Inc, LEO Pharma, Novartis, Pfizer, Syntrix, Wyeth, and XenoPort. Dr Ryan has been on the advisory board and received honoraria from AbbVie and Pfizer. Dr Kivelevitch has been a speaker and received honoraria from AbbVie. Correspondence to: Alan Menter, MD, Baylor University Medical Center, 3900 Junius St, Suite 125, Dallas, TX 75246 E-mail: [email protected]
REFERENCES 1. Murase JE, Heller MM, Butler DC. Safety of dermatologic medications in pregnancy and lactation, part I: pregnancy. J Am Acad Dermatol 2014;70:401.e1-14, quiz 415. 2. 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
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.
