Enanthem in Patients with COVID-19 and Skin Rash Unrelated, and the Other 3 Were from 1 Family

Letters

(Figure 1). Their HAP scores gradually increased, and the hy- Additional Contributions: We thank the patients and/or the patients’ family potrichosis in the patient with TRPS1 did not improve members for granting permission to publish this information. (Figure 2A). Hair shaft diameters were increased in every par- 1. Tanahashi K, Sugiura K, Akiyama M. Topical minoxidil improves congenital hypotrichosis caused by LIPH mutations. Br J Dermatol. 2015;173(3):865-866. ticipant with LIPH pathogenic variants (Figure 2B and C). There doi:10.1111/bjd.13790 were no serious adverse events, but some mild adverse events 2. Tanahashi K, Sugiura K, Takeichi T, et al. Prevalent founder mutation were reported (dry skin on the scalp, trichiasis, and mild hy- c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to pertrichosis on the entire body). variable severity of hypotrichosis in adulthood. J Eur Acad Dermatol Venereol. 2013;27(9):1182-1184. doi:10.1111/j.1468-3083.2012.04526.x Discussion | Lysophosphatidic acids bind the P2Y5 receptor in 3. Kinoshita-Ise M, Kubo A, Sasaki T, Umegaki-Arao N, Amagai M, Ohyama M. Identification of factors contributing to phenotypic divergence via quantitative the hair follicle epithelium and activate hair growth.5 In ARWH image analyses of autosomal recessive woolly hair/hypotrichosis with due to LIPH pathogenic variants, loss-of-function variants in homozygous c.736T>A LIPH mutation. Br J Dermatol. 2017;176(1):138-144. LIPH lead to a deficiency of lysophosphatidic acids and insuf- doi:10.1111/bjd.14836 ficient activation of P2Y5. The present prospective interven- 4. Shibata A, Tanahashi K, Sugiura K, Akiyama M. TRPS1 haploinsufficiency tional study suggests that minoxidil could be associated with results in increased STAT3 and SOX9 mRNA expression in hair follicles in trichorhinophalangeal syndrome. Acta Derm Venereol. 2015;95(5):620-621. improvements in hypotrichosis in ARWH owing to LIPH patho- doi:10.2340/00015555-1948 genic variants. There appears to be a binary response to min- 5. Shinkuma S, Akiyama M, Inoue A, et al. Prevalent LIPH founder mutations oxidil, with one group responding better than the other. The lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive data on causative pathogenic variants suggest that it is unre- hypotrichosis. Hum Mutat. 2010;31(5):602-610. doi:10.1002/humu.21235 lated to the LIPH pathogenic variants. Among the 8 patients with ARWH due to LIPH pathogenic variants, 5 patients were Enanthem in Patients With COVID-19 and Skin Rash unrelated, and the other 3 were from 1 family. All 3 members Recalcati1 recently reported skin manifestations in 18 pa- of the family were in the group responding better. Thus, we tients in Italy with severe acute respiratory syndrome coro- cannot exclude the possibility that the family had an un- navirus 2 (SARS-CoV-2) infection, or coronavirus disease 2019 known genetic modifying factor affecting the efficacy of mi- (COVID-19), describing “erythematous rash,”“widespread ur- noxidil. We need to know more about the follicular pathology ticaria,”and “chickenpox-like vesicles.”Additional reports have to understand the pharmacologic response to minoxidil. described other rashes, including petechial and purpuric changes,2 transient livedo reticularis,3 and acro-ischemic 4 Tomoki Taki, MD, PhD lesions. Whether these manifestations are directly related to Kana Tanahashi, MD, PhD COVID-19 remains unclear, since both viral infections and ad- Takuya Takeichi, MD, PhD verse drug reactions are frequent causes of exanthems. An im- Takenori Yoshikawa, MD portant clue to distinguish between both entities is the pres- 5 Yuya Murase, MD ence of enanthem (oral cavity lesions). However, owing to Kazumitsu Sugiura, MD, PhD safety concerns, many patients with suspected or confirmed Masashi Akiyama, MD, PhD COVID-19 do not have their oral cavity examined. Herein we describe variants of enanthem in a series of patients with Author Affiliations: Department of Dermatology, Nagoya University Graduate COVID-19. School of Medicine, Nagoya, Aichi, Japan (Taki, Tanahashi, Takeichi, Yoshikawa, Murase, Akiyama); Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan (Sugiura). Methods | We included 21 consecutive patients from a tertiary care hospital who had skin rash and COVID-19, confirmed by Accepted for Publication: May6,2020. real-time reverse transcriptase–polymerase chain reaction from Corresponding Author: Masashi Akiyama, MD, PhD, Department of Dermatology, Nagoya University Graduate School of Medicine, 65 a nasopharyngeal swab, and who required dermatology con- Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan (makiyama@med. sultation from March 30 to April 8, 2020. The oral cavities of nagoya-u.ac.jp). patients presenting with skin rash were systematically exam- Published Online: July 15, 2020. doi:10.1001/jamadermatol.2020.2195 ined. Enanthems were classified into 4 categories: petechial, 5 Author Contributions: Drs Taki and Akiyama had full access to all of the data in macular, macular with petechiae, or erythematovesicular. This the study and take responsibility for the integrity of the data and the accuracy study was approved by the institutional review board of Ra- of the data analysis. mon y Cajal University Hospital in Madrid. Accordingly, in- Study concept and design: Taki, Sugiura, Akiyama. Acquisition, analysis, or interpretation of data: All authors. formed consent was obtained verbally from all patients be- Drafting of the manuscript: Taki, Akiyama. fore examination, and they have been deidentified through Critical revision of the manuscript for important intellectual content: Tanahashi, omission of individual age and sex. Takeichi, Yoshikawa, Murase, Sugiura, Akiyama. Statistical analysis: Taki. Obtained funding: Takeichi. Results | Of 21 patients with COVID-19 and skin rash, 6 patients Administrative, technical, or material support: Takeichi, Yoshikawa, Murase. (29%) had enanthem. The age range of these patients was be- Study supervision: Sugiura, Akiyama. tween 40 and 69 years, and 4 of the 6 (66%) were women. The Conflict of Interest Disclosures: Dr Taki reported receiving nonfinancial morphology of the skin rash was papulovesicular, purpuric support (the 1% minoxidil solution used in the present study) from Taisho periflexural, and erythema multiforme–like in 1, 2, and 3 pa- Pharmaceutical Co., Ltd. (Tokyo, Japan) during the conduct of the study and the 2018 Nagoya University Medical Association Research Encouragement Prize tients, respectively. The clinical and histologic findings of the outside the submitted work. No other disclosures were reported. erythema multiforme–like exanthem have been reported

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Figure. Clinical Presentation of Exanthem and Enanthem in a Patient With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

A Lateral view of the exanthem B Enanthem

This patient presented with coalescing purpuric macules distributed in a periflexural pattern, mainly around the buttocks and inguinal area (A), and enanthem on hard and soft palate consisting of millimetric petechiae without erythema (B).

Table. Clinical and Laboratory Findings of 6 Patients With COVID-19 and Enanthem

Patient, No. Age, y Exanthem type Enanthem type Time latency, da Drug intake Platelet count D-dimer level 1 40s Purpuric M 12 LP, H, Low High 2 60s Papulovesicular P −2 LP, H, A Normal High 3 60s EM-like MP 19 LP, H, A Normal High 4 50s EM-like MP 24 LP, H, A, T, C Normal High 5 40s Purpuric P 2 LP, H, A, T, C Low High 6 60s EM-like MP 19 LP, H, A, Normal Normal Abbreviations: A, azithromycin; C, corticosteroids; EM, erythema multiforme; (COVID-19) symptoms to the appearance of mucocutaneous lesions. H, hydroxychloroquine; LP, lopinavir/ritonavir; M, macular; MP, macular with According to our center reference values, platelet count <140 × 103/μL was petechiae; P, petechial; T, tocilizumab. considered low, D-dimer level >0.5 μg/mL was considered high. a Time latency is defined as days from the onset of coronavirus disease 2019

elsewhere.6 No enanthem was observed in patients with ur- them suggest an infectious etiology, especially viral.5 In a ticarial or typical maculopapular rashes. The enanthem was large series of patients with atypical exanthems,5 only 9% of macular in 1 patient, petechial in 2 patients, and macular with patients with enanthem had a drug reaction, whereas 88% petechiae in 3 patients, and was located in the palate in all pa- had an infectious etiology, most frequently viral. Enan- tients (Figure). No patient presented with an erythemato- thems may present with petechiae, macules, papules, or vesicular enanthem. The mean (range) time between the vesicles in the mouth. Erythemato-vesicular and petechial onset of COVID-19 symptoms and the appearance of mucocu- patterns were most commonly associated with viral infec- taneous lesions was 12.3 days (range, −2 to 24 days). Interest- tions, the latter being more frequent in adults.5 This is con- ingly, this latency was shorter in patients with petechial en- sistent with the present series, in which 5 patients (83%) anthem compared with those with a macular lesion with had petechiae as a main component of the enanthem. Fur- petechiae appearance. Drug intake and laboratory findings thermore, the 2 patients with a pure petechial enanthem were not associated with any enanthem type (Table). developed these lesions 2 days before and 2 days after the onset of COVID-19 symptoms, making association with the Discussion | The etiological diagnosis of exanthems can be drug intake unlikely. challenging for dermatologists. Some useful clues are the This work describes preliminary observations and is lim- rash morphology, the associated symptoms, and the pres- ited by the small number of cases and the absence of a control ence of enanthem.5 Pustular morphology and dusky lesions group. Despite the increasing reports of skin rashes in pa- are suggestive of drug etiology, while petechial or vesicular tients with COVID-19, establishing an etiological diagnosis is pattern, involvement of buttocks or acral sites, and enan- challenging. However, the presence of enanthem is a strong

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clue that suggests a viral etiology rather than a drug reaction, pharmaceutical companies provide discounts to payers (re- especially when a petechial pattern is observed. bates) and other offsets, such as copay assistance, which affect the net price of these drugs. We describe 2009 to Juan Jimenez-Cauhe, MD 2019 trends in list and net prices for self-administered pso- Daniel Ortega-Quijano, MD riasis therapies manufactured by companies publicly traded Dario de Perosanz-Lobo, MD in the United States. Patricia Burgos-Blasco, MD Sergio Vañó-Galván, MD, PhD Methods | We obtained 2007 to 2019 list and net price data from Montse Fernandez-Guarino, MD, PhD the investment firm SSR Health for self-administered psoria- Diego Fernandez-Nieto, MD sis therapies available in the United States by January 1, 2019 (Table).2 This study was not subject to institutional review Author Affiliations: Dermatology Department, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain. board review because no human data were used. Accepted for Publication: May 19, 2020. SSR Health estimates net prices for branded drugs Corresponding Author: Juan Jimenez-Cauhe, MD, Dermatology Department, manufactured by publicly traded companies using Hospital Universitario Ramon y Cajal, Carretera Colmenar Viejo km 9.100, company-reported sales and number of units sold each 28034 Madrid, Spain ([email protected]). quarter across the United States. Net prices account for all Published Online: July 15, 2020. doi:10.1001/jamadermatol.2020.2550 manufacturer discounts, including rebates to payers, cou- Author Contributions: Dr Jimenez-Cauhe had full access to all of the data in the pon cards, 340B discounts (discounted prices to organiza- study and takes responsibility for the integrity of the data and the accuracy of tions caring for low-income and vulnerable patients), and the data analysis. Concept and design: Jimenez-Cauhe, Ortega-Quijano, de Perosanz-Lobo, any other concession accounted for in the reporting of sales. Vañó-Galván, Fernandez-Guarino. The robustness of SSR Health data in estimating net prices Acquisition, analysis, or interpretation of data: Jimenez-Cauhe, Burgos-Blasco, for prescription drugs has been demonstrated in peer- Vañó-Galván, Fernandez-Nieto. reviewed research.3 Net pricing for tildrakizumab was not Drafting of the manuscript: Jimenez-Cauhe, Ortega-Quijano, de Perosanz-Lobo, Fernandez-Nieto. available as it is manufactured by a nonpublicly traded Critical revision of the manuscript for important intellectual content: de manufacturer. Perosanz-Lobo, Burgos-Blasco, Vañó-Galván, Fernandez-Guarino, For each drug and year, we calculated average list (whole- Fernandez-Nieto. sale acquisition) and net costs of psoriasis treatment for the Statistical analysis: Ortega-Quijano, Burgos-Blasco, Vañó-Galván. Administrative, technical, or material support: Jimenez-Cauhe, Burgos-Blasco. initial year of therapy for an 80-kg patient based on US Food Supervision: de Perosanz-Lobo, Vañó-Galván, Fernandez-Guarino. and Drug Administration–approved recommended dosing. We Conflict of Interest Disclosures: None reported. adjusted prices by inflation using the consumer price index. Additional Contributions: We thank the pictured patient for granting All prices are shown adjusted to the value of the US dollar in permission to publish this information. 2009. 1. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. Results | For all drugs studied, list prices increased substan- J Eur Acad Dermatol Venereol. 2020;34(5):e212-e213. doi:10.1111/jdv.16387 tially over time, with the greatest increase observed for tu- 2. Jimenez-Cauhe J, Ortega-Quijano D, Prieto-Barrios M, Moreno-Arrones OM, Fernandez-Nieto D. Reply to “COVID-19 can present with a rash and be mistaken mor necrosis factor inhibitors, which increased by approxi- for dengue”: petechial rash in a patient with COVID-19 infection. J Am Acad mately 200% from 2009 to 2019 (annual mean change for Dermatol. Published online April 10, 2020. doi:10.1016/j.jaad.2020.04.016 etanercept, 12%; adalimumab, 12%; and certolizumab, 10%). 3. Manalo IF, Smith MK, Cheeley J, Jacobs R. A dermatologic manifestation of Although net prices steadily increased until 2016, they began COVID-19: transient livedo reticularis. J Am Acad Dermatol. to decrease for ustekinumab in 2016, secukinumab and gusel- Published online April 10, 2020. kumab in 2017, and brodalumab, adalimumab, and certoli- 4. Zhang Y, Cao W, Xiao M, et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Article in zumab in 2018 (Figure). Chinese. Zhonghua Xue Ye Xue Za Zhi. 2020;41(0):E006. doi:10.3760/cma.j. As of 2019, there was a large (30%-59%) and widening gap issn.0253-2727.2020.0006 between list and net prices because of increasing discounts. 5. Drago F, Paolino S, Rebora A, et al. The challenge of diagnosing atypical The list price was highest for certolizumab ($94 379), fol- exanthems: a clinico-laboratory study. J Am Acad Dermatol. 2012;67(6):1282-1288. lowed by the interleukin (IL)-17A inhibitors secukinumab doi:10.1016/j.jaad.2012.04.014 ($77 883) and ixekizumab ($75 848), and lowest for the oral 6. Jimenez-Cauhe J, Ortega-Quijano D, Carretero-Barrio I, et al. Erythema multiforme-like eruption in patients with COVID-19 infection: clinical and phosphodiesterase-4 inhibitor apremilast ($34 545); net price histological findings. Clin Exp Dermatol. Published online May 9, 2020. was highest for the 3 tumor necrosis factor inhibitors (certoli- doi:10.1111/ced.14281 zumab, $48 193; etanercept, $43 910; and adalimumab, $39 751) and lowest for the IL-17–receptor inhibitor brodalumab Trends in List and Net Prices of Self-administered ($17 692) (Table). Systemic Psoriasis Therapies Manufactured by US-Based Pharmaceutical Companies Discussion | We identified substantial price increases from 2009 Systemic psoriasis therapies are among the costliest drugs to 2019 for self-administered psoriasis therapies. Even after prescribed by dermatologists, and list prices of many of accounting for inflation and discounts, the net price of some these drugs have increased over time.1 However, list price therapies more than doubled, highlighting the financial bur- alone gives an incomplete picture of true treatment costs, as den on payers and patients for these therapies.

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