756 Research Letters
J AM ACAD DERMATOL
OCTOBER 2017
Supported by an Investigator Grant from Abbott/ AbbVie. Abbott/AbbVie approved the design of the study and provided funding.
4. Kopylov U, Watts C, Starr M, et al. Uncovering Crohn’s disease in patients with spondyloarthropathies using videocapsule endoscopy [abstract]. Arthritis Rheumatol. 2015;67(suppl 10).
Dr Bissonnette has received grants and research support, served as a consultant or received honoria from AbbVie, Amgen, Apopharma, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GSK-Stiefel, Merck, Incyte, Janssen, Kineta, Leo Pharma, Merck, Novartis, Pfizer, Tribute, and Xenoport. Dr Bolduc has served as a consultant or received Honoria from AbbVie, Amgen, Celgene, Eli Lilly, Galderma, GSK-Stiefel, Janssen, Leo Pharma, Merck, Novartis, Tribute, Pfizer, Incyte, and Xenoport. Dr Maari has received grants and research support or received Honoria from AbbVie, Amgen, Apopharma, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, Merck, Incyte, Janssen, Kineta, Leo Pharma, Novartis, Valeant, Pfizer, and Tribute. Dr Nigen has served as a consultant or received Honoria from AbbVie, Amgen, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, and Tribute. Dr Delorme served as speaker, advisory board or principal investigator and received Honoria from AbbVie, Actellion, Amgen, Celgene, Dermira, Dignity Science, Eli Lilly, Innovaderm Research, Galderma, Janssen, Kineta, Leo Pharma, Novartis, Regeneron, Vitae, Moberg Pharma, and Cutanea. Dr Lynde served as consultant, speaker, advisory board and principal investigator and received Honoria from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, and Eli Lilly. Dr Tamaz and Ms Robillard have no conflicts of interest to declare.
http://dx.doi.org/10.1016/j.jaad.2017.02.051
Approved by a research ethics board (IRB services, Aurora, Ontario, Canada) on February 23, 2012. Registered on ClinicalTrials.Gov on March 15, 2012 before the first subject enrollment (NCT01556672). Correspondence to: Robert Bissonnette, MD, MSc, FRCPC, Innovaderm Research, 1851 Sherbrooke E, Ste 502, Montreal, Quebec H2K 4L5, Canada. E-mail: [email protected]
REFERENCES 1. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease [e-pub ahead of print] Lancet. 2016. http: //dx.doi.org/10.1016/S0140-6736(16)31711-1. Accessed March 15, 2017. 2. Li WQ, Han JL, Chan AT, et al. Psoriasis, psoriatic arthritis and increased risk of incident Crohn’s disease in US women. Ann Rheum Dis. 2013;72:1200-1205. 3. Wu JJ, Nguyen TU, Poon KY, et al. The association of psoriasis with autoimmune diseases. J Am Acad Dermatol. 2012;67:924-930.
A cross-sectional study of psoriasis triggers among different ethno-racial groups To the Editor: Psoriasis is a common inflammatory skin condition that affects 1.5% to 3% of the US population.1 Although the prevalence and genetic risk factors of psoriasis differ by ethnicity,1,2 it is unknown how exacerbating factors of psoriasis compare across ethno-racial groups. The genetic risk factors specific to ethno-racial groups may predispose individuals to variations in skin responses when exposed to certain environmental insults. The aim of this study was to identify whether exacerbating factors for psoriasis vary between ethno-racial groups. We used cross-sectional survey data from 897 adult and pediatric patients with psoriasis seen from 2006 to 2016 at the University of CaliforniaeSan Francisco Department of Dermatology. Patients were classified into 4 ethno-racial groups (61% self-identified as white, 25% as Asian, 8% as Hispanic/Latino, and 5% as ‘‘other’’). To compare the distribution of 6 common patient-reported exacerbating factors (stress, infection, skin injury, strep throat, winter season, medications) between ethno-racial groups, we conducted multivariable logistic and analysis of covariance regression analyses in R, with the use of body mass index, age, age of onset, and sex as covariates. The Fisher’s exact test was used to compare the distribution of medication types. Analysis of baseline demographics revealed that Asians were significantly younger at the time of presentation than were whites. Hispanics/Latinos had higher body mass index values than did whites. Age of onset and sex distribution did not differ significantly between ethno-racial groups. Logistic regression models (Table I) revealed that Asians had more than twice the odds of reporting stress as an exacerbating factor compared with that reported by whites (odds ratio, 2.05 [95% CI, 1.18-3.70], P ¼ .0135). Similarly, there was a trend among Hispanics/Latinos toward high odds of reporting stress as an exacerbating factor compared with that reported by whites (odds ratio, 2.27; P ¼ .073). There was also a trend toward lower odds of medications as an exacerbating factor among Asians compared with that in whites (odds ratio, 0.137; P ¼ .056). Among the 47 respondents who listed medication as an exacerbating factor, the most commonly reported offenders were topical/systemic corticosteroids (23.4%), beta-blockers/other anti-hypertensives
J AM ACAD DERMATOL
Research Letters 757
VOLUME 77, NUMBER 4
Table I. Demographic features and prevalence of common exacerbating factors of psoriasis in a multi-ethnic patient cohort compared by use of multivariable logistic regression Ethnicity and demographic characteristics
Age, years, mean (SD) Sex Body mass index (SD) Age at onset, years, mean (SD)
White (n = 549)
Asian (n = 227)
48.49 45.8% 26.28 28.25
44.23 42.7% 26.80 28.68
(16.62) (F) (6.04) (17.38)
Hispanic (n = 75)
(17.09) (F) (5.27) (17.36)
46.16 45.3% 29.42 32.73
(17.34) (F) (6.92) (19.52)
P value
e
.006z .773 .013y .414
e e e e ORadjx 95% Confidence interval
Exacerbating factors
Stress Y/total (%Y)
Infection
Skin injury
Strep throat
Winter season
Medications
368/549 (67%)
172/227 (76%)
55/75 (73%)
42/549 (7.7%)
8/227 (3.5%)
9/75 (12%)
155/549 (28.2%)
55/227 (24.2%)
14/75 (18.7%)
71/549 (12.9%)
17/227 (7.49%)
4/75 (5.33%)
304/549 (55.4%)
119/227 (52.4%)
31/75 (41.3%)
36/549 (6.55%)
8/227 (3.52%)
3/75 (4%)
A vs W: P = .014y H vs W: P = .073* A vs W: P = .118 H vs W: P = .625 A vs W: P = .536 H vs W: P = .131 A vs W: P = .721 H vs W: P = .405 A vs W: P = .540 H vs W: P = .625 A vs W: P = .057* H vs W: P = .531
2.05 (1.18-3.70) 2.27 (0.97-5.97) e
e
e
e
0.14 (0.01-0.69) e
A vs W ¼ P value for Asians (A) compared with whites (W). H vs W ¼ P value for Hispanics (H) compared with whites (W). SD, Standard deviation; Y, yes; F, female. *Trend toward significance (P \ .1). y Significant at P ¼ .05. z Significant at P ¼ .01. x Odds ratio from logistic regression model adjusted for age, age of onset, body mass index, and sex.
(17.0%), and antibiotics/antifungals (10.6%). Interestingly, 7 of the 8 subjects who reported betablockers/anti-hypertensives as exacerbating factors were white, although the distribution was not significantly different from non-whites (P ¼ .1605). Supplemental analyses with the use of an analysis of covariance model showed similar results (Supplemental Table I; available at http://www. jaad.org). These findings suggest that environmental factors such as stress and medication may play different roles in exacerbating psoriasis in different ethno-racial groups. The higher frequency of stress
as an exacerbating factor in Asians could reflect biologic differences in response to stress3 or a higher perception of stress among Asians. Medication side effects may be ethnicity-dependent, as observed with differences caused by human leukocyte antigen alleles.4 Limitations of our study include the exclusion of the ‘‘other’’ ethnic group because of the small sample size. Pediatric and adult patients could not be directly compared because of the small number of pediatric patients in our cohort. The role of medication as an exacerbating factor versus the disease for which it was being used is difficult to determine. Despite these limitations, our findings
758 Research Letters
suggest that the impact of environmental factors may differ by ethno-racial group and that long-term monitoring of exacerbating factors and multidisciplinary stress management may enhance patient-centered care for psoriasis. Di Yan, BA, Ladan Afifi, BA, MS, Caleb Jeon, BA, Kelly M. Cordoro, MD, and Wilson Liao, MD Department of Dermatology, University of CaliforniaeSan Francisco, San Francisco, California This study was supported in part by grants to Wilson Liao (NIH R01-AR065174, NIH-U01 AI119125, and a National Psoriasis Foundation Translational Research Award). Di Yan acknowledges support from a National Psoriasis Foundation Fellowship. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Wilson Liao, MD, 2340 Sutter Street, San Francisco, CA 94115 E-mail: [email protected]
REFERENCES 1. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005; 64(Suppl 2):ii18-ii23. 2. Schon MP, Boehncke WH. Psoriasis. N Engl J Med. 2005;352(18): 1899-1912. 3. Way BM, Taylor SE. The serotonin transporter promoter polymorphism is associated with cortisol response to psychosocial stress. Biol Psych. 2010;67(5):487-492. 4. Elzagallaai AA, Garcia-Bournissen F, Finkelstein Y, Bend JR, Rieder MJ, Koren G. Severe bullous hypersensitivity reactions after exposure to carbamazepine in a Han-Chinese child with a positive HLA-B*1502 and negative in vitro toxicity assays: evidence for different pathophysiological mechanisms. J Popul Ther Clin Pharmacol. 2011;18(1):e1-e9. http://dx.doi.org/10.1016/j.jaad.2017.04.1109
Potential impact of biologics and emerging therapies for psoriasis and atopic dermatitis on future fertility: Reassurance to patients but more data are needed To the Editor: For young patients suffering from atopic dermatitis, plaque psoriasis, and alopecia areata, new targeted therapies offer significant promise. The majority of these conditions present in individuals of reproductive age.1 Thus, there is a need to understand how new systemic drugs affect future fertility. In oncology, adverse effect on fertility
J AM ACAD DERMATOL
OCTOBER 2017
is an important consideration for treatment selection. In dermatology, established systemic medications such as methotrexate and cyclosporine have known fertility risks, including impaired spermatogenesis and sperm motility in humans.1,2 We conducted a retrospective review of US, EU, and Canadian regulatory data and a literature search to assess the fertility risk of medications approved after 2004. Recent off-label drugs were also included. We classified medications by using a previously published A/B/C/D/X/N fertility risk scheme analogous to the US Food and Drug Administration’s former pregnancy risk system.3 For females, 25% of medications (3 of 12) showed fertility risk in animals (category C). In mice, apremilast caused prolonged estrous cycles and increased early postimplantation losses at 1.8 times the maximum recommended human dose (MRHD) (see Table I). Given the key role of cyclic adenosine monophosphate in egg maturation, the inhibition of phosphodiesterase 4, which degrades cyclic adenosine monophosphate, could adversely affect fertility.4 The janus kinase inhibitors (tofacitinib, ruxolitinib) resulted in increased postimplantation losses in mice. Higher doses of tofacitinib resulted in decreased pregnancy rate, corpora lutea, implantation sites, and viable fetuses. Mechanistically, janus kinase signaling plays a critical role in neuroendocrine control of female reproduction in mice.5 Animal studies in 58% of medications (7 of 12) did not show ovarian toxicity (category B) with testing done at 8 to 50 times the MRHD. Finally, 17% (2 of 12) had an unknown risk (category N). No human data for females were available for any of the medications. In males, all medications received a category B rating. Ten of the 12 systemic medications (83%) did not show sperm toxicity in animal studies conducted in mice, rats, or monkeys (Table I). Adalimumab and etanercept lacked animal data, but the limited available human data did not reveal gonadal toxicity (category B).2 The impact of new systemic medications for common dermatologic conditions on future fertility is largely unknown, but the available data suggest that most treatments have no adverse effects. Because biologics are designed as antibodies targeted toward human cytokines and receptors, the ability to conduct and interpret animal safety studies presents a challenge. A lack of adverse effects on animal fertility does not exclude an adverse impact on human gametes or reproduction.2,3 The wide variation in MRHD exposure suggests a need for greater regulatory harmony for preclinical fertility testing in animals, which remains the primary source of information on potential human fertility risk. Ultimately,
J AM ACAD DERMATOL
Research Letters 758.e1
VOLUME 77, NUMBER 4
Supplemental Table I. Demographic features and prevalence of common triggers in a multi-ethnic patient cohort compared by analysis of covariance analysis Ethnicity and demographic characteristics White (n = 549)
Age, years (SD) Sex Body mass index (SD) Age at onset, years (SD) Triggers Stress (Y/N) Infection (Y/N) Skin injury (Y/N) Strep throat (Y/N) Winter season Medications
Asian (n = 227)
48.49 (16.62)z 45.8% (F) 26.28 (6.04)z 28.25 (17.38) 368/549z 42/549 155/549 71/549 304/549 36/549z
(67%) (7.7%) (28.2%) (12.9%) (55.4%) (6.55%)
44.23 (17.09)z 42.7% (F) 26.80 (5.27)x 28.68 (17.36) 172/227z 8/227 55/227 17/227 119/227 8/227z
SD, Standard deviation; Y/N, yes/no; F, female. *Significant at P ¼ .05. y Significant at P ¼ .01. zx Pairwise differences that were significant or trend toward significance.
(76%) (3.5%) (24.2%) (7.49%) (52.4%) (3.52%)
Hispanic (n = 75)
P value
46.16 (17.34) 45.3% (F) 29.42 (6.92)zx 32.73 (19.52)
.006y .773 .013* .414
55/75 9/75 14/75 4/75 31/75 3/75
.012* .216 .185 .548 .774 .081
(73%) (12%) (18.7%) (5.33%) (41.3%) (4%)
J AM ACAD DERMATOL
OCTOBER 2017
Supported by an Investigator Grant from Abbott/ AbbVie. Abbott/AbbVie approved the design of the study and provided funding.
4. Kopylov U, Watts C, Starr M, et al. Uncovering Crohn’s disease in patients with spondyloarthropathies using videocapsule endoscopy [abstract]. Arthritis Rheumatol. 2015;67(suppl 10).
Dr Bissonnette has received grants and research support, served as a consultant or received honoria from AbbVie, Amgen, Apopharma, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GSK-Stiefel, Merck, Incyte, Janssen, Kineta, Leo Pharma, Merck, Novartis, Pfizer, Tribute, and Xenoport. Dr Bolduc has served as a consultant or received Honoria from AbbVie, Amgen, Celgene, Eli Lilly, Galderma, GSK-Stiefel, Janssen, Leo Pharma, Merck, Novartis, Tribute, Pfizer, Incyte, and Xenoport. Dr Maari has received grants and research support or received Honoria from AbbVie, Amgen, Apopharma, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, Merck, Incyte, Janssen, Kineta, Leo Pharma, Novartis, Valeant, Pfizer, and Tribute. Dr Nigen has served as a consultant or received Honoria from AbbVie, Amgen, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, and Tribute. Dr Delorme served as speaker, advisory board or principal investigator and received Honoria from AbbVie, Actellion, Amgen, Celgene, Dermira, Dignity Science, Eli Lilly, Innovaderm Research, Galderma, Janssen, Kineta, Leo Pharma, Novartis, Regeneron, Vitae, Moberg Pharma, and Cutanea. Dr Lynde served as consultant, speaker, advisory board and principal investigator and received Honoria from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, and Eli Lilly. Dr Tamaz and Ms Robillard have no conflicts of interest to declare.
http://dx.doi.org/10.1016/j.jaad.2017.02.051
Approved by a research ethics board (IRB services, Aurora, Ontario, Canada) on February 23, 2012. Registered on ClinicalTrials.Gov on March 15, 2012 before the first subject enrollment (NCT01556672). Correspondence to: Robert Bissonnette, MD, MSc, FRCPC, Innovaderm Research, 1851 Sherbrooke E, Ste 502, Montreal, Quebec H2K 4L5, Canada. E-mail: [email protected]
REFERENCES 1. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease [e-pub ahead of print] Lancet. 2016. http: //dx.doi.org/10.1016/S0140-6736(16)31711-1. Accessed March 15, 2017. 2. Li WQ, Han JL, Chan AT, et al. Psoriasis, psoriatic arthritis and increased risk of incident Crohn’s disease in US women. Ann Rheum Dis. 2013;72:1200-1205. 3. Wu JJ, Nguyen TU, Poon KY, et al. The association of psoriasis with autoimmune diseases. J Am Acad Dermatol. 2012;67:924-930.
A cross-sectional study of psoriasis triggers among different ethno-racial groups To the Editor: Psoriasis is a common inflammatory skin condition that affects 1.5% to 3% of the US population.1 Although the prevalence and genetic risk factors of psoriasis differ by ethnicity,1,2 it is unknown how exacerbating factors of psoriasis compare across ethno-racial groups. The genetic risk factors specific to ethno-racial groups may predispose individuals to variations in skin responses when exposed to certain environmental insults. The aim of this study was to identify whether exacerbating factors for psoriasis vary between ethno-racial groups. We used cross-sectional survey data from 897 adult and pediatric patients with psoriasis seen from 2006 to 2016 at the University of CaliforniaeSan Francisco Department of Dermatology. Patients were classified into 4 ethno-racial groups (61% self-identified as white, 25% as Asian, 8% as Hispanic/Latino, and 5% as ‘‘other’’). To compare the distribution of 6 common patient-reported exacerbating factors (stress, infection, skin injury, strep throat, winter season, medications) between ethno-racial groups, we conducted multivariable logistic and analysis of covariance regression analyses in R, with the use of body mass index, age, age of onset, and sex as covariates. The Fisher’s exact test was used to compare the distribution of medication types. Analysis of baseline demographics revealed that Asians were significantly younger at the time of presentation than were whites. Hispanics/Latinos had higher body mass index values than did whites. Age of onset and sex distribution did not differ significantly between ethno-racial groups. Logistic regression models (Table I) revealed that Asians had more than twice the odds of reporting stress as an exacerbating factor compared with that reported by whites (odds ratio, 2.05 [95% CI, 1.18-3.70], P ¼ .0135). Similarly, there was a trend among Hispanics/Latinos toward high odds of reporting stress as an exacerbating factor compared with that reported by whites (odds ratio, 2.27; P ¼ .073). There was also a trend toward lower odds of medications as an exacerbating factor among Asians compared with that in whites (odds ratio, 0.137; P ¼ .056). Among the 47 respondents who listed medication as an exacerbating factor, the most commonly reported offenders were topical/systemic corticosteroids (23.4%), beta-blockers/other anti-hypertensives
J AM ACAD DERMATOL
Research Letters 757
VOLUME 77, NUMBER 4
Table I. Demographic features and prevalence of common exacerbating factors of psoriasis in a multi-ethnic patient cohort compared by use of multivariable logistic regression Ethnicity and demographic characteristics
Age, years, mean (SD) Sex Body mass index (SD) Age at onset, years, mean (SD)
White (n = 549)
Asian (n = 227)
48.49 45.8% 26.28 28.25
44.23 42.7% 26.80 28.68
(16.62) (F) (6.04) (17.38)
Hispanic (n = 75)
(17.09) (F) (5.27) (17.36)
46.16 45.3% 29.42 32.73
(17.34) (F) (6.92) (19.52)
P value
e
.006z .773 .013y .414
e e e e ORadjx 95% Confidence interval
Exacerbating factors
Stress Y/total (%Y)
Infection
Skin injury
Strep throat
Winter season
Medications
368/549 (67%)
172/227 (76%)
55/75 (73%)
42/549 (7.7%)
8/227 (3.5%)
9/75 (12%)
155/549 (28.2%)
55/227 (24.2%)
14/75 (18.7%)
71/549 (12.9%)
17/227 (7.49%)
4/75 (5.33%)
304/549 (55.4%)
119/227 (52.4%)
31/75 (41.3%)
36/549 (6.55%)
8/227 (3.52%)
3/75 (4%)
A vs W: P = .014y H vs W: P = .073* A vs W: P = .118 H vs W: P = .625 A vs W: P = .536 H vs W: P = .131 A vs W: P = .721 H vs W: P = .405 A vs W: P = .540 H vs W: P = .625 A vs W: P = .057* H vs W: P = .531
2.05 (1.18-3.70) 2.27 (0.97-5.97) e
e
e
e
0.14 (0.01-0.69) e
A vs W ¼ P value for Asians (A) compared with whites (W). H vs W ¼ P value for Hispanics (H) compared with whites (W). SD, Standard deviation; Y, yes; F, female. *Trend toward significance (P \ .1). y Significant at P ¼ .05. z Significant at P ¼ .01. x Odds ratio from logistic regression model adjusted for age, age of onset, body mass index, and sex.
(17.0%), and antibiotics/antifungals (10.6%). Interestingly, 7 of the 8 subjects who reported betablockers/anti-hypertensives as exacerbating factors were white, although the distribution was not significantly different from non-whites (P ¼ .1605). Supplemental analyses with the use of an analysis of covariance model showed similar results (Supplemental Table I; available at http://www. jaad.org). These findings suggest that environmental factors such as stress and medication may play different roles in exacerbating psoriasis in different ethno-racial groups. The higher frequency of stress
as an exacerbating factor in Asians could reflect biologic differences in response to stress3 or a higher perception of stress among Asians. Medication side effects may be ethnicity-dependent, as observed with differences caused by human leukocyte antigen alleles.4 Limitations of our study include the exclusion of the ‘‘other’’ ethnic group because of the small sample size. Pediatric and adult patients could not be directly compared because of the small number of pediatric patients in our cohort. The role of medication as an exacerbating factor versus the disease for which it was being used is difficult to determine. Despite these limitations, our findings
758 Research Letters
suggest that the impact of environmental factors may differ by ethno-racial group and that long-term monitoring of exacerbating factors and multidisciplinary stress management may enhance patient-centered care for psoriasis. Di Yan, BA, Ladan Afifi, BA, MS, Caleb Jeon, BA, Kelly M. Cordoro, MD, and Wilson Liao, MD Department of Dermatology, University of CaliforniaeSan Francisco, San Francisco, California This study was supported in part by grants to Wilson Liao (NIH R01-AR065174, NIH-U01 AI119125, and a National Psoriasis Foundation Translational Research Award). Di Yan acknowledges support from a National Psoriasis Foundation Fellowship. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Wilson Liao, MD, 2340 Sutter Street, San Francisco, CA 94115 E-mail: [email protected]
REFERENCES 1. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005; 64(Suppl 2):ii18-ii23. 2. Schon MP, Boehncke WH. Psoriasis. N Engl J Med. 2005;352(18): 1899-1912. 3. Way BM, Taylor SE. The serotonin transporter promoter polymorphism is associated with cortisol response to psychosocial stress. Biol Psych. 2010;67(5):487-492. 4. Elzagallaai AA, Garcia-Bournissen F, Finkelstein Y, Bend JR, Rieder MJ, Koren G. Severe bullous hypersensitivity reactions after exposure to carbamazepine in a Han-Chinese child with a positive HLA-B*1502 and negative in vitro toxicity assays: evidence for different pathophysiological mechanisms. J Popul Ther Clin Pharmacol. 2011;18(1):e1-e9. http://dx.doi.org/10.1016/j.jaad.2017.04.1109
Potential impact of biologics and emerging therapies for psoriasis and atopic dermatitis on future fertility: Reassurance to patients but more data are needed To the Editor: For young patients suffering from atopic dermatitis, plaque psoriasis, and alopecia areata, new targeted therapies offer significant promise. The majority of these conditions present in individuals of reproductive age.1 Thus, there is a need to understand how new systemic drugs affect future fertility. In oncology, adverse effect on fertility
J AM ACAD DERMATOL
OCTOBER 2017
is an important consideration for treatment selection. In dermatology, established systemic medications such as methotrexate and cyclosporine have known fertility risks, including impaired spermatogenesis and sperm motility in humans.1,2 We conducted a retrospective review of US, EU, and Canadian regulatory data and a literature search to assess the fertility risk of medications approved after 2004. Recent off-label drugs were also included. We classified medications by using a previously published A/B/C/D/X/N fertility risk scheme analogous to the US Food and Drug Administration’s former pregnancy risk system.3 For females, 25% of medications (3 of 12) showed fertility risk in animals (category C). In mice, apremilast caused prolonged estrous cycles and increased early postimplantation losses at 1.8 times the maximum recommended human dose (MRHD) (see Table I). Given the key role of cyclic adenosine monophosphate in egg maturation, the inhibition of phosphodiesterase 4, which degrades cyclic adenosine monophosphate, could adversely affect fertility.4 The janus kinase inhibitors (tofacitinib, ruxolitinib) resulted in increased postimplantation losses in mice. Higher doses of tofacitinib resulted in decreased pregnancy rate, corpora lutea, implantation sites, and viable fetuses. Mechanistically, janus kinase signaling plays a critical role in neuroendocrine control of female reproduction in mice.5 Animal studies in 58% of medications (7 of 12) did not show ovarian toxicity (category B) with testing done at 8 to 50 times the MRHD. Finally, 17% (2 of 12) had an unknown risk (category N). No human data for females were available for any of the medications. In males, all medications received a category B rating. Ten of the 12 systemic medications (83%) did not show sperm toxicity in animal studies conducted in mice, rats, or monkeys (Table I). Adalimumab and etanercept lacked animal data, but the limited available human data did not reveal gonadal toxicity (category B).2 The impact of new systemic medications for common dermatologic conditions on future fertility is largely unknown, but the available data suggest that most treatments have no adverse effects. Because biologics are designed as antibodies targeted toward human cytokines and receptors, the ability to conduct and interpret animal safety studies presents a challenge. A lack of adverse effects on animal fertility does not exclude an adverse impact on human gametes or reproduction.2,3 The wide variation in MRHD exposure suggests a need for greater regulatory harmony for preclinical fertility testing in animals, which remains the primary source of information on potential human fertility risk. Ultimately,
J AM ACAD DERMATOL
Research Letters 758.e1
VOLUME 77, NUMBER 4
Supplemental Table I. Demographic features and prevalence of common triggers in a multi-ethnic patient cohort compared by analysis of covariance analysis Ethnicity and demographic characteristics White (n = 549)
Age, years (SD) Sex Body mass index (SD) Age at onset, years (SD) Triggers Stress (Y/N) Infection (Y/N) Skin injury (Y/N) Strep throat (Y/N) Winter season Medications
Asian (n = 227)
48.49 (16.62)z 45.8% (F) 26.28 (6.04)z 28.25 (17.38) 368/549z 42/549 155/549 71/549 304/549 36/549z
(67%) (7.7%) (28.2%) (12.9%) (55.4%) (6.55%)
44.23 (17.09)z 42.7% (F) 26.80 (5.27)x 28.68 (17.36) 172/227z 8/227 55/227 17/227 119/227 8/227z
SD, Standard deviation; Y/N, yes/no; F, female. *Significant at P ¼ .05. y Significant at P ¼ .01. zx Pairwise differences that were significant or trend toward significance.
(76%) (3.5%) (24.2%) (7.49%) (52.4%) (3.52%)
Hispanic (n = 75)
P value
46.16 (17.34) 45.3% (F) 29.42 (6.92)zx 32.73 (19.52)
.006y .773 .013* .414
55/75 9/75 14/75 4/75 31/75 3/75
.012* .216 .185 .548 .774 .081
(73%) (12%) (18.7%) (5.33%) (41.3%) (4%)
