Nail Changes in Patients Receiving Systemic Isotretinoin Therapy

Nail Changes in Patients Receiving Systemic Isotretinoin Therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Nail Changes in Patients Receiving Systemic Isotretinoin Therapy Dilek Yigit, Nermin Karaosmanoglu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4319935/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In this study, we aimed to describe isotretinoin-induced nail changes and to increase patients' compliance with treatment. A total of 200 patients diagnosed with acne vulgaris were included in the study, including 100 patients who started systemic isotretinoin treatment and 100 control patients who received topical acne treatment. The patients age, gender, treatment duration, total doses per month, type of nail changes were recorded. Patients with persistent nail changes were followed at 3rd and 6th month after treatment. A total of 34 patients had nail changes in the isotretinoin group. These changes included onychoschizia (55.9%), leukonychia (11.8%), onychorexis (8.8%), median nail dystrophy (5.9%), pyogenic granulomas (5.9%), chronic paronychia and granulation tissue (5.9%), onycholysis (2.9%) and Beau's line (2.9%). The rate of nail changes in the isotretinoin group was significantly higher than the topical treatment group (34% vs 11%, p:0.001). There was no statistically significant difference in terms of treatment duration between the patients with and without nail changes in the isotretinoin group. The total cumulative dose was significantly higher in patients with nail changes in isotretinoin group (p:0.043). Also, the regression of nail changes was slower in patients receiving higher cumulative doses (p:0.049). Isotretinoin increases the risk of nail changes, the most common being onychoschizia. The risk of developing nail changes have no association with treatment duration; however, it is associated with the total cumulative dose. Nail findings inducedby isotretinoin are completely reversible. isotretinoin nail disorders onychoschizia cumulative dose Figures Figure 1 Figure 2 Figure 3 Introduction Isotretinoin is a derivative of vitamin A that is frequently used in acne vulgaris recalcitrant to conventional treatment, severe papulopustular and nodulocystic acne [19]. Since its introduction in 1982, the benefits and side effects of isotretinoin have been extensively discussed. Its most prevalent adverse effects include mucocutaneous manifestations, along with ophthalmologic, teratogenic, laboratory, neuromuscular and psychiatric [22]. Despite numerous studies on mucocutaneous side effects secondary to systemic isotretinoin use, publications focusing specifically on nail changes are predominantly limited to case reports. Reported instances of nail changes induced by oral isotretinoin treatment encompass brittle nails, median nail dystrophy (MND), elkonychis, onycholysis, paronychia, pyogenic granuloma (PG), excessive granulation tissue, and transverse leukonychia. While isotretinoin induces various findings in the nails, the precise mechanism by which the drug impacts the nail plate and bed remains incompletely understood [19, 22]. Alterations in the nails pose challenges to patients in terms of functionality, cosmetics, and psychology, thereby complicating adherence to the treatment process. This study aims to characterize nail changes in patients undergoing systemic isotretinoin therapy, provide appropriate interventions when necessary, and enhance treatment compliance by informing patients about these risks at the initiation of therapy. Materials and Methods A total of 200 patients diagnosed as acne vulgaris who were admitted to the Department of Dermatology of Ankara Training and Research Hospital between January 2020- December 2022 were included in the study. The local ethic committee approved the study (Ethics Committee of Ankara Training and Research Hospital, Decision number 1165; 26.01.2023). All participants were informed about the study and a written consent form was obtained. The study was performed in accordance with the latest version of the ‘Helsinki Decleration’ and ‘Guidelines for Good Clinical Practice’. The patients were divided into two groups each including 100 individuals aged between 18–65 years. The first group contained 100 acne vulgaris patients who were started systemic isotretinoin therapy, while the other group was consisted of 100 patients receiving topical acne therapy (benzoyl peroxide (BPO), clindamycin and BPO combination, erythromycin and BPO combination, azelaic acid, sodium sulfacetamide). A daily dose of 0.25-1 mg/kg isotretinoin was initiated in the systemic isotretinoin group. In the topical therapy group, the patients were asked to apply the topical agent as a thin layer to the entire face at night and wash through in the morning. Patients with systemic diseases, and with a documented history of systemic drug use within the past year or currently using systemic medications, patients having skin conditions other than acne vulgaris and those with pre-existing nail disorders at the beginning of the study were not included. Individuals with professions, hobbies, or habits that could affect the nails; those diagnosed with onychotillomania, and those with a history of trauma to the nails were also excluded. Pregnant or lactating women were not included. The age, gender, and total treatment duration of all participants were recorded. In systemic isotretinoin patients, the monthly total dose, total cumulative dose (TCD), presence of nail changes, type of nail change, the consistent time of initiation of nail findings, and duration of nail changes were documented. For those with persistent nail changes at the end of treatment, the improvement status was assessed at the 3rd and 6th months post-treatment. In the topical therapy group, the type of topical treatment used, presence of nail changes, and type of nail findings were recorded and compared. Nail findings were evaluated through clinical and onychoscopic examination. Data Analysis In the evaluation of the findings obtained in the study, IBM SPSS Statistics 22 software was employed for statistical analyses. The conformity of parameters to a normal distribution was assessed using the Kolmogorov-Smirnov test. Descriptive statistical methods (Mean, Standard Deviation, Frequency) were utilized in the assessment of study data. For comparing non-normally distributed quantitative data among groups, the Kruskal-Wallis test was applied. For between-group comparisons of parameters exhibiting normal distribution, the Student t-test was employed, whereas the Mann-Whitney U test was utilized for parameters lacking normal distribution. Chi-square test, Fisher's Exact Chi-Square test, Fisher Freeman Halton Exact Chi-Square test, and Continuity (Yates) Correction were used for the comparison of qualitative data. Spearman's rho correlation analysis was employed to explore relationships between parameters lacking normal distribution. A P-value less than 0.05 was considered indicative of statistical significance. Results Of the 100 patients receiving systemic isotretinoin, 21 were male and 79 were female. The mean age was 23.21 ± 5.15 years (range: 18–44). Of the 100 patients receiving topical treatment, 23 were male and 77 were female. The mean age was 24.33 ± 5.74 years (range: 18–48). No statistically significant difference was found between the isotretinoin and topical treatment groups in terms of age and gender (p > 0.05). The average total treatment duration in the systemic isotretinoin group was 6.79 ± 1.14 months (range: 5–11), with a median duration of 7 months. The TCD ranged from 3600 to 10800 mg, with a mean of 7006 ± 1267.53 mg and a median of 6900 mg. Of the 100 patients in the isotretinoin group, 34 had nail findings. 19 onychoschizia (55.9%), 4 leukonychia (11.8%), 3 onychorexis (8.8%), 2 MND (5.9%), 2 PG (5.9%), 2 chronic paronychia and granulation tissue (5.9%), 1 onycholysis (2.9%), and 1 Beau’s line (2.9%) were developed in these 34 patients (Fig. 1 ). 20 patients in the isotretinoin group developed nail changes within 3rd month. Onychoschizia was observed in 12 cases (60%), leukonychia in 3 cases (15%), onychorrhexis in 2 cases (10%), chronic paronychia and granulation tissue in 2 cases (10%), and onycholysis in 1 case (5%). 31 patients in the isotretinoin group developed nail changes within 6th month. Onychoschizia was observed in 18 cases (58.1%), leukonychia in 3 cases (9.7%), onychorrhexis in 3 cases (9.7%), PG in 2 cases (6.5%), chronic paronychia and granulation tissue in 2 cases (6.5%), and MND, onycholysis, and Beau's lines in one case each (3.2% each). In the other group, the total treatment duration ranged from 3 to 9 months, with a mean of 3.8 ± 1.17 months and a median duration of 3 months. Of the 100 patients; 58 received BPO and clindamycin, 22 received BPO and erythromycin, 7 received sodium sulfacetamide, 6 received azelaic acid, 4 received BPO, 2 received BPO and clindamycin, and azelaic acid, and one individual received BPO and erythromycin and azelaic acid therapy. Nail changes were observed in only 11 people in the second group. These changes were leukonychia (6 patients, 54.5%), PG (2 patients, 27.3%), onycholysis (1 patient, 9.1%) and Beau's line (1 patient, 9.1%) 7 patients in the topical therapy group developed nail changes within 3rd month. 3 were leukonychia (42.9%), 2 were PG (28.6%), 1 was onycholysis (14.3%), and 1 was Beau's lines (14.3%). 7 patients in the topical therapy group developed nail changes within 6th month. Leukonychia was observed in 5 cases (71.4%), Beau's lines in 1 case (14.3%), and PG in 1 case (14.3%). There was statistically significant difference between the two groups in terms of development rate of nail changes (p: 0.001). Onychoschizia (Fig. 2 and Fig. 3 ) was the most frequent nail finding in the isotretinoin group with a rate of 55.9%. None of the patients in the topical treatment had onychoschizia (p: 0.001). Nail symptoms in the isotretinoin group first began to appear at the first month, and new findings continued to occur until the 8th month of treatment. Average time to onset of findings was 3.47 ± 1.52 and a median duration of 3 months. There was statistically significant difference between the two groups in terms of the rates of nail findings at the third month of therapy (p: 0.013). Statistically significant difference was also found between the two groups at the sixth month of therapy in terms of nail findings (p: 0.001). In the systemic isotretinoin group, no statistically significant difference was observed in terms of mean ages between cases with and without nail changes (p > 0.05). 33% of males and 34.2% of females seemed to have nail changes in the isotretinoin group. There was no statistically significant difference in terms of rates of nail changes between the two genders (p > 0.05). In the systemic isotretinoin group, there was no statistically significant difference in treatment durations between cases with and without nail changes (p > 0.05). However, the TCD in individuals with nail changes was found to be statistically significantly higher than in those without changes (p: 0.043) (Table 1 ). Table 1 Evaluation of treatment duration and total cumulative dose according to the occurrence of nail changes in the patient group Patient group Absent Nail Changes (n = 66) Present Nail Changes (n = 34) Mean ± SD (median) Mean ± SD (median) p-value Treatment duration 6,70 ± 1,01 (7) 6,97 ± 1,36 (6) 0,610 Total cumulative dose 6750,0 ± 1082,62 (6900) 7502,94 ± 1457,99 (7200) 0,043* Mann Whitney U test SD: Standard Deviation n: number of patient *p < 0.05 Since daily treatment doses affected the TCD, it was observed that as the dose increased, the rate of occurrence of nail findings were also found to be increased (p: 0.013). The patients who had received a higher TCD of isotretinoin seemed to have a longer period of improvement compared with the lower TCD (p: 0.049). The duration of nail change continuation in the isotretinoin group ranged from 3 to 14 months, with a mean of 8.09 ± 2.69 and a median duration of 8 months. Of the 34 patients who developed nail findings during treatment; 2 patients had a spontaneous regression while continue treatment. The remaining 32 patients who did not show improvement during treatment were called for a follow-up appointment at the 3rd month after stopping the treatment. Of these 32 individuals, improvement was observed in 23 of them (71.9%) at the 3rd month after treatment. For the 9 individuals who did not show improvement at the 3rd month, the nail findings regressed in 8 of them (88.9%) at the 6th month after treatment. Only 1 patient (11.1%) who developed Beau's lines had a total improvement at the 8th month after treatment. Discussion İsotretinoin is a derivative of vitamin A and is naturally found in human serum. It is frequently preferred in various dermatological indications, although it is commonly used in severe nodulocystic acne resistant to conventional treatment and prone to scarring [19, 22]. Since isotretinoin is an analogue of vitamin A, its adverse effects usually mimic those of hypervitaminosis A. Numerous adverse effects have been reported, predominantly involving the mucocutaneous system, followed by ocular, teratogenic, laboratory, psychiatric, and neuromuscular findings [22]. Many of these adverse effects are typically reversible and not life threatening. The most serious side effect is teratogenicity [12]. Although the mechanisms of isotretinoin in acne therapy are partially understood, its mechanism of action on the skin remains controversial. Retinoids have been shown to relatively reduce the thickness of the stratum corneum [11]. The effects of retinoid group drugs on nails have been known for years, but the exact mechanism of how isotretinoin affects the nail is still not fully understood. Potentially, isotretinoin may affect nails similarly to the skin [18]. The long-term use of retinoids has been observed to cause damage to the nail matrix and nail plate, resulting in nail thinning [20]. In the recent literatüre it is reported that tendency of having acne vulgaris in both males and females is equal [9]. However, in this study, the female ratio in the isotretinoin group was higher than the male ratio (79%). In previous literatüre evaluating the side effects of isotretinoin; an average of 6 months of treatment duration and an average of 120–150 mg/kg TCD were reported [24]. The mean duration of treatment and the TCD of the isotretinoin group were similar to the literatüre in this study. In the literature, there is limited data specifically regarding the effects of isotretinoin on nails. Isotretinoin-induced onychoschizia, onychorrhexis, transverse leukonychia, onycholysis, PG, median canaliform dystrophy, onychocryptosis, paronychia, and granulation tissue are the reported findings of the nails in the literatüre [1–4, 6, 13, 15, 17, 23]. The study conducted by Özçelik et al. is the only research in the literature similar to this study, evaluating the effect of isotretinoin on nails. A total of 70 patients were included, with nail findings observed in 9 patients (12.8%). Of the 9 patients; onychoschizia was detected in 4 patients, paronychia in 2 patients, onychorrhexis in 1 patient, leukonychia in 1 patient, and onycholysis in 1 patient [18]. Brzezinski et al. evaluated all side effects in 3525 patients treated with isotretinoin. Nail findings were trachyonychia in 368 individuals (10.43%) and paronychia in 14 individuals (0.39%) [8]. Blasiak et al. evaluated 116 patients treated with isotretinoin for acne vulgaris. They reported that 16 of them (13.8%) had nail changes. The most frequent finding was paronychia, and it was detected in 9 patients (7.8%) [5]. In their study observing the systemic side effects of isotretinoin in 150 patients with acne vulgaris, Brito et al. detected nail fragility in 38 (25.3%) and PG in 20 patients (13.3%) [7]. Rademaker evaluated side effects in 1743 patients receiving isotretinoin and a total of 37 patients (2.1%) with periungual granulomas were reported [21]. Demirseren et al. also evaluated of 300 patients with moderate to severe acne under isotretinoin treatment and, reported that ingrown toenails was the only side effect on nails detected in 13 patients (4.3%) [10]. There were 34 patients in the isotretinoin group with nail findings in this study (34%). However, the variety of nail findings was greater in our study compared to previously reported studies. The higher occurrence of nail side effects and variety in our study compared to the literature may be associated with failure to specifically examine nails and underreporting of nail side effects. Özçelik et al. reported that onychoschizia was the most frequent nail finding in the isotretinoin group in the present study. One of the most important finding of this study is that onychoschizia was not observed in the group receiving topical treatment. As a result, we can conclude that isotretinoin directly contributes to the formation of onychoschizia. It increases the rate of nail growth and causes thinning of the nails, which may result in the formation of onychoschizia. Özçelik et al. found that the beginning of nail changes in their patients was the third month of treatment. Them also revealed that isotretinoin statistically significantly affected the nail growth rate and thickness when compared with the control groups at the third month of treatment. difference in nail growth rate between the isotretinoin and control groups began in the third month of treatment and progressively increased [18]. In a study involving 300 isotretinoin patients, nail ingrown were detected in 13 patients, with a median onset of nail ingrowth at 12 weeks (range 3–20) [10]. Here, with this study, we have also shown that isotretinoin can cause nail changes starting from the third month of treatment. Dermatologists prescribing isotretinoin for a period of longer than 3 month should inform the patients that potential nail changes may occur in the nail plate. Different results regarding the dose-dependency of isotretinoin side effects have been reported in the literature. Rademaker evaluated 1743 patients treated with isotretinoin and observed that commonly reported side effects were clearly dose-dependent. In this study, 18.5% of the patients had no side effects, and the majority of these were patients receiving very low doses of isotretinoin (< 0.25 mg/day) [21]. In the randomized controlled trial by Legiawati et al., different doses of isotretinoin regimens were compared and evaluated. They reported that low-dose isotretinoin regimens resulted in fewer side effects and showed similar efficacy to conventional doses. Therefore, they recommended a continuous low-dose treatment regimen [16]. In the study by Özçelik et al. since all patients received the same dose of medication, it was not possible to evaluate whether the observed nail findings were dose-dependent or not [18]. Blasiak et al. divided patients receiving isotretinoin into two groups based on cumulative doses ( 220 mg/kg group) and found no statistically significant difference in nail findings between the two treatment groups [5]. Goulden et al. evaluated adverse effects in 720 isotretinoin patients and found no association between cumulative dose or duration and potential side effects [14]. In this study, we found no relationship between nail changes and treatment duration. On the other hand, the TCD seemed to have important role in nail plate changes. In addition to all this, not suprisingly, patients with nail changes who had higher cumulative doses needed a longer healing time compared with the lower cumulative doses. These findings suggest that nail plate changes associated with isotretinoin are dose-dependent. In patients experiencing nail changes associated with isotretinoin, it may be possible to reduce the severity of these side effects by reducing the drug dose. More studies are needed to determine the necessary dose adjustments based on the nail findings associated with isotretinoin. We could not find any data in previous literatüre revealing the average recovery time of isotretinoin-induced nail findings. In this study, the mean duration of complete recovery after the occurrence of nail finding was found to be 8 months. We did not need to have dose reduction in any patients with nail changes in the isotretinoin group since the recipients had no complaint. The reason for prolonged persistence of nail findings in patients may be the continue treatment without interruption. We can conclude that the main important factor in the regression of nail findings is the cessation of the isotretinoin treatment. Isotretinoin primarily induce to temporary nail findings mostly secondary to cumulative dose and drug exposure. In the topical treatment group, a total of 4 different nail findings such as leukonychia, PG, onycholysis and Beau's lines were detected only in 11 patients. Additionally, all of these findings were observed only in one single nail plate. None of the findings observed in the isotretinoin group, such as onychoschizia, onychorexis, MND, chronic paronychia and granulation tissue, were found in the topical treatment group. These results may suggests that the findings in the isotretinoin group could be specific nail findings secondary to isotretinoin. Large interventional clinical trials including larger patients and control groups are needed to confirm this theory. The limitations of the present study was that it included a small number of patients and included no patient age under 18. The nail findings associated with isotretinoin could have been observed by the re-exposure of the drug to effected individuals. Another limitation was that it was a single-center study. As a result, secondary nail changes due to isotretinoin are reversible, independent of the treatment duration but directly associated with cumulative dose. Dermatologists prescribing isotretinoin should be allert of the nail findings which can occur especially during the treatment regimens longer than three months. They should also be aware that the findings are reversible with dose reduction or discontinuation of the drug. Declarations Competing Interests Statement: All the other authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript. Author Contribution DY and NK have attended and contributed equally for the study. They are first and co-authors for this manuscript. Acknowledgements: The authors declare that there are no relationships that provided financial or editorial support for the study which may in potential cause competing interest for the submission. 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Dermatol Clin 25(2):215 – 21, vii 10.1016/j.det.2007.01.006 Rademaker M (2010) Adverse effects of isotretinoin: A retrospective review of 1743 patients started on isotretinoin. Australas J Dermatol 51(4):248–253. 10.1111/j.1440-0960.2010.00657.x Vallerand IA, Lewinson RT, Farris MS et al (2018) Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol 178(1):76–85. 10.1111/bjd.15668 Yung A, Johnson P, Goodfield MJ (2005) Isotretinoin-induced elkonyxis. Br J Dermatol 153(3):671–672. 10.1111/j.1365-2133.2005.06782.x Zaenglein AL, Pathy AL, Schlosser BJ et al (2016) Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol 74(5):945 – 73 e33 10.1016/j.jaad.2015.12.037 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4319935","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":295306683,"identity":"1ed8f15b-72ab-48d2-8d3b-b0675292419a","order_by":0,"name":"Dilek Yigit","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIie3RMUsDMRTA8TwKzyV0vsOhX8EuocKR+yAudwTq5OpUJOlBuhRnC34FBxfnk4BdpLcedPF2B90UHHx3bcdLV8H8p0fIj1xyjIVCfzE30KBZxJCBefv4SmgJTOknsCc4KMar5bQl2k/KjlB4Yk85ut2iTwzXYJqVncjbkSHCK/mwcHTKLLnoI7GDYvxoI2URivP7yVY9veZEXqZXuoecObBxQwQRTP3Ot0qUREA7H1l874mOOG6UqJqjxAJ9mCQyjzmWUtRHTmnvEt9togwxbx9ZZaKmUzLPXYaVe/5cXt+ko2Ld0K+UqaguaZglvaQLkOWHDbsh823v+mHpYUx9+0KhUOh/9gtSb2gflqXgCwAAAABJRU5ErkJggg==","orcid":"","institution":"Bağcılar Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Dilek","middleName":"","lastName":"Yigit","suffix":""},{"id":295306684,"identity":"91c43161-aad7-4c5c-89e8-3bd7ee45b2e4","order_by":1,"name":"Nermin Karaosmanoglu","email":"","orcid":"","institution":"Ankara Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nermin","middleName":"","lastName":"Karaosmanoglu","suffix":""}],"badges":[],"createdAt":"2024-04-24 18:23:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4319935/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4319935/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55760837,"identity":"3b3f65f3-91bc-4cdd-ad6a-c001827a8153","added_by":"auto","created_at":"2024-05-02 18:57:23","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":41537,"visible":true,"origin":"","legend":"\u003cp\u003eNail changes occurring in the isotretinoin group\u003c/p\u003e","description":"","filename":"Figure1.Nailchangesoccurringintheisotretinoingroup.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4319935/v1/e1f7a385a24e6edc45c14fe4.jpg"},{"id":55762100,"identity":"49df269c-3281-4702-ac4f-56c4b5806a16","added_by":"auto","created_at":"2024-05-02 19:05:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":158085,"visible":true,"origin":"","legend":"\u003cp\u003eOnychoschizia on the 2nd and 3rd fingers of the right hand\u003c/p\u003e","description":"","filename":"Figure2.Onychoschiziaonthe2ndand3rdfingersoftherighthand.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4319935/v1/f0c3569216692e5e9eae4e01.jpg"},{"id":55760835,"identity":"8076b07a-1ded-4267-ae20-562091937d84","added_by":"auto","created_at":"2024-05-02 18:57:23","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":44548,"visible":true,"origin":"","legend":"\u003cp\u003eOnychoscopic image of the patient\u003c/p\u003e","description":"","filename":"Figure3.Onychoscopicimageofthepatient.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4319935/v1/46addc0b9c18ffced5a9e813.jpg"},{"id":55762421,"identity":"30fc0f25-b73f-4eb9-b059-6c333a2ee7dd","added_by":"auto","created_at":"2024-05-02 19:13:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":440905,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4319935/v1/2cb213ac-8c8a-4248-b335-dfd7ff067cee.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Nail Changes in Patients Receiving Systemic Isotretinoin Therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIsotretinoin is a derivative of vitamin A that is frequently used in acne vulgaris recalcitrant to conventional treatment, severe papulopustular and nodulocystic acne [19]. Since its introduction in 1982, the benefits and side effects of isotretinoin have been extensively discussed. Its most prevalent adverse effects include mucocutaneous manifestations, along with ophthalmologic, teratogenic, laboratory, neuromuscular and psychiatric [22].\u003c/p\u003e \u003cp\u003eDespite numerous studies on mucocutaneous side effects secondary to systemic isotretinoin use, publications focusing specifically on nail changes are predominantly limited to case reports. Reported instances of nail changes induced by oral isotretinoin treatment encompass brittle nails, median nail dystrophy (MND), elkonychis, onycholysis, paronychia, pyogenic granuloma (PG), excessive granulation tissue, and transverse leukonychia. While isotretinoin induces various findings in the nails, the precise mechanism by which the drug impacts the nail plate and bed remains incompletely understood [19, 22].\u003c/p\u003e \u003cp\u003eAlterations in the nails pose challenges to patients in terms of functionality, cosmetics, and psychology, thereby complicating adherence to the treatment process. This study aims to characterize nail changes in patients undergoing systemic isotretinoin therapy, provide appropriate interventions when necessary, and enhance treatment compliance by informing patients about these risks at the initiation of therapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eA total of 200 patients diagnosed as acne vulgaris who were admitted to the Department of Dermatology of Ankara Training and Research Hospital between January 2020- December 2022 were included in the study. The local ethic committee approved the study (Ethics Committee of Ankara Training and Research Hospital, Decision number 1165; 26.01.2023). All participants were informed about the study and a written consent form was obtained. The study was performed in accordance with the latest version of the \u0026lsquo;Helsinki Decleration\u0026rsquo; and \u0026lsquo;Guidelines for Good Clinical Practice\u0026rsquo;.\u003c/p\u003e \u003cp\u003eThe patients were divided into two groups each including 100 individuals aged between 18\u0026ndash;65 years. The first group contained 100 acne vulgaris patients who were started systemic isotretinoin therapy, while the other group was consisted of 100 patients receiving topical acne therapy (benzoyl peroxide (BPO), clindamycin and BPO combination, erythromycin and BPO combination, azelaic acid, sodium sulfacetamide). A daily dose of 0.25-1 mg/kg isotretinoin was initiated in the systemic isotretinoin group. In the topical therapy group, the patients were asked to apply the topical agent as a thin layer to the entire face at night and wash through in the morning.\u003c/p\u003e \u003cp\u003ePatients with systemic diseases, and with a documented history of systemic drug use within the past year or currently using systemic medications, patients having skin conditions other than acne vulgaris and those with pre-existing nail disorders at the beginning of the study were not included. Individuals with professions, hobbies, or habits that could affect the nails; those diagnosed with onychotillomania, and those with a history of trauma to the nails were also excluded. Pregnant or lactating women were not included.\u003c/p\u003e \u003cp\u003eThe age, gender, and total treatment duration of all participants were recorded. In systemic isotretinoin patients, the monthly total dose, total cumulative dose (TCD), presence of nail changes, type of nail change, the consistent time of initiation of nail findings, and duration of nail changes were documented. For those with persistent nail changes at the end of treatment, the improvement status was assessed at the 3rd and 6th months post-treatment. In the topical therapy group, the type of topical treatment used, presence of nail changes, and type of nail findings were recorded and compared. Nail findings were evaluated through clinical and onychoscopic examination.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003eIn the evaluation of the findings obtained in the study, IBM SPSS Statistics 22 software was employed for statistical analyses. The conformity of parameters to a normal distribution was assessed using the Kolmogorov-Smirnov test. Descriptive statistical methods (Mean, Standard Deviation, Frequency) were utilized in the assessment of study data. For comparing non-normally distributed quantitative data among groups, the Kruskal-Wallis test was applied. For between-group comparisons of parameters exhibiting normal distribution, the Student t-test was employed, whereas the Mann-Whitney U test was utilized for parameters lacking normal distribution. Chi-square test, Fisher's Exact Chi-Square test, Fisher Freeman Halton Exact Chi-Square test, and Continuity (Yates) Correction were used for the comparison of qualitative data. Spearman's rho correlation analysis was employed to explore relationships between parameters lacking normal distribution. A P-value less than 0.05 was considered indicative of statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 100 patients receiving systemic isotretinoin, 21 were male and 79 were female. The mean age was 23.21\u0026thinsp;\u0026plusmn;\u0026thinsp;5.15 years (range: 18\u0026ndash;44). Of the 100 patients receiving topical treatment, 23 were male and 77 were female. The mean age was 24.33\u0026thinsp;\u0026plusmn;\u0026thinsp;5.74 years (range: 18\u0026ndash;48). No statistically significant difference was found between the isotretinoin and topical treatment groups in terms of age and gender (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eThe average total treatment duration in the systemic isotretinoin group was 6.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14 months (range: 5\u0026ndash;11), with a median duration of 7 months. The TCD ranged from 3600 to 10800 mg, with a mean of 7006\u0026thinsp;\u0026plusmn;\u0026thinsp;1267.53 mg and a median of 6900 mg.\u003c/p\u003e \u003cp\u003eOf the 100 patients in the isotretinoin group, 34 had nail findings. 19 onychoschizia (55.9%), 4 leukonychia (11.8%), 3 onychorexis (8.8%), 2 MND (5.9%), 2 PG (5.9%), 2 chronic paronychia and granulation tissue (5.9%), 1 onycholysis (2.9%), and 1 Beau\u0026rsquo;s line (2.9%) were developed in these 34 patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e20 patients in the isotretinoin group developed nail changes within 3rd month. Onychoschizia was observed in 12 cases (60%), leukonychia in 3 cases (15%), onychorrhexis in 2 cases (10%), chronic paronychia and granulation tissue in 2 cases (10%), and onycholysis in 1 case (5%).\u003c/p\u003e \u003cp\u003e31 patients in the isotretinoin group developed nail changes within 6th month. Onychoschizia was observed in 18 cases (58.1%), leukonychia in 3 cases (9.7%), onychorrhexis in 3 cases (9.7%), PG in 2 cases (6.5%), chronic paronychia and granulation tissue in 2 cases (6.5%), and MND, onycholysis, and Beau's lines in one case each (3.2% each).\u003c/p\u003e \u003cp\u003eIn the other group, the total treatment duration ranged from 3 to 9 months, with a mean of 3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.17 months and a median duration of 3 months. Of the 100 patients; 58 received BPO and clindamycin, 22 received BPO and erythromycin, 7 received sodium sulfacetamide, 6 received azelaic acid, 4 received BPO, 2 received BPO and clindamycin, and azelaic acid, and one individual received BPO and erythromycin and azelaic acid therapy.\u003c/p\u003e \u003cp\u003eNail changes were observed in only 11 people in the second group. These changes were leukonychia (6 patients, 54.5%), PG (2 patients, 27.3%), onycholysis (1 patient, 9.1%) and Beau's line (1 patient, 9.1%)\u003c/p\u003e \u003cp\u003e7 patients in the topical therapy group developed nail changes within 3rd month. 3 were leukonychia (42.9%), 2 were PG (28.6%), 1 was onycholysis (14.3%), and 1 was Beau's lines (14.3%). 7 patients in the topical therapy group developed nail changes within 6th month. Leukonychia was observed in 5 cases (71.4%), Beau's lines in 1 case (14.3%), and PG in 1 case (14.3%).\u003c/p\u003e \u003cp\u003eThere was statistically significant difference between the two groups in terms of development rate of nail changes (p: 0.001). Onychoschizia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) was the most frequent nail finding in the isotretinoin group with a rate of 55.9%. None of the patients in the topical treatment had onychoschizia (p: 0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNail symptoms in the isotretinoin group first began to appear at the first month, and new findings continued to occur until the 8th month of treatment. Average time to onset of findings was 3.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52 and a median duration of 3 months.\u003c/p\u003e \u003cp\u003eThere was statistically significant difference between the two groups in terms of the rates of nail findings at the third month of therapy (p: 0.013). Statistically significant difference was also found between the two groups at the sixth month of therapy in terms of nail findings (p: 0.001).\u003c/p\u003e \u003cp\u003eIn the systemic isotretinoin group, no statistically significant difference was observed in terms of mean ages between cases with and without nail changes (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). 33% of males and 34.2% of females seemed to have nail changes in the isotretinoin group. There was no statistically significant difference in terms of rates of nail changes between the two genders (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eIn the systemic isotretinoin group, there was no statistically significant difference in treatment durations between cases with and without nail changes (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, the TCD in individuals with nail changes was found to be statistically significantly higher than in those without changes (p: 0.043) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEvaluation of treatment duration and total cumulative dose according to the occurrence of nail changes in the patient group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsent Nail Changes (n\u0026thinsp;=\u0026thinsp;66)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePresent Nail Changes (n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (median)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (median)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e6,70\u0026thinsp;\u0026plusmn;\u0026thinsp;1,01 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e6,97\u0026thinsp;\u0026plusmn;\u0026thinsp;1,36 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,610\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cumulative dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e6750,0\u0026thinsp;\u0026plusmn;\u0026thinsp;1082,62 (6900)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e7502,94\u0026thinsp;\u0026plusmn;\u0026thinsp;1457,99 (7200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,043*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eMann Whitney U test SD: Standard Deviation n: number of patient *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSince daily treatment doses affected the TCD, it was observed that as the dose increased, the rate of occurrence of nail findings were also found to be increased (p: 0.013).\u003c/p\u003e \u003cp\u003eThe patients who had received a higher TCD of isotretinoin seemed to have a longer period of improvement compared with the lower TCD (p: 0.049).\u003c/p\u003e \u003cp\u003eThe duration of nail change continuation in the isotretinoin group ranged from 3 to 14 months, with a mean of 8.09\u0026thinsp;\u0026plusmn;\u0026thinsp;2.69 and a median duration of 8 months. Of the 34 patients who developed nail findings during treatment; 2 patients had a spontaneous regression while continue treatment. The remaining 32 patients who did not show improvement during treatment were called for a follow-up appointment at the 3rd month after stopping the treatment. Of these 32 individuals, improvement was observed in 23 of them (71.9%) at the 3rd month after treatment. For the 9 individuals who did not show improvement at the 3rd month, the nail findings regressed in 8 of them (88.9%) at the 6th month after treatment. Only 1 patient (11.1%) who developed Beau's lines had a total improvement at the 8th month after treatment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eİsotretinoin is a derivative of vitamin A and is naturally found in human serum. It is frequently preferred in various dermatological indications, although it is commonly used in severe nodulocystic acne resistant to conventional treatment and prone to scarring [19, 22].\u003c/p\u003e \u003cp\u003eSince isotretinoin is an analogue of vitamin A, its adverse effects usually mimic those of hypervitaminosis A. Numerous adverse effects have been reported, predominantly involving the mucocutaneous system, followed by ocular, teratogenic, laboratory, psychiatric, and neuromuscular findings [22]. Many of these adverse effects are typically reversible and not life threatening. The most serious side effect is teratogenicity [12]. Although the mechanisms of isotretinoin in acne therapy are partially understood, its mechanism of action on the skin remains controversial. Retinoids have been shown to relatively reduce the thickness of the stratum corneum [11]. The effects of retinoid group drugs on nails have been known for years, but the exact mechanism of how isotretinoin affects the nail is still not fully understood. Potentially, isotretinoin may affect nails similarly to the skin [18]. The long-term use of retinoids has been observed to cause damage to the nail matrix and nail plate, resulting in nail thinning [20].\u003c/p\u003e \u003cp\u003eIn the recent literat\u0026uuml;re it is reported that tendency of having acne vulgaris in both males and females is equal [9]. However, in this study, the female ratio in the isotretinoin group was higher than the male ratio (79%). In previous literat\u0026uuml;re evaluating the side effects of isotretinoin; an average of 6 months of treatment duration and an average of 120\u0026ndash;150 mg/kg TCD were reported [24]. The mean duration of treatment and the TCD of the isotretinoin group were similar to the literat\u0026uuml;re in this study.\u003c/p\u003e \u003cp\u003eIn the literature, there is limited data specifically regarding the effects of isotretinoin on nails. Isotretinoin-induced onychoschizia, onychorrhexis, transverse leukonychia, onycholysis, PG, median canaliform dystrophy, onychocryptosis, paronychia, and granulation tissue are the reported findings of the nails in the literat\u0026uuml;re [1\u0026ndash;4, 6, 13, 15, 17, 23].\u003c/p\u003e \u003cp\u003eThe study conducted by \u0026Ouml;z\u0026ccedil;elik et al. is the only research in the literature similar to this study, evaluating the effect of isotretinoin on nails. A total of 70 patients were included, with nail findings observed in 9 patients (12.8%). Of the 9 patients; onychoschizia was detected in 4 patients, paronychia in 2 patients, onychorrhexis in 1 patient, leukonychia in 1 patient, and onycholysis in 1 patient [18]. Brzezinski et al. evaluated all side effects in 3525 patients treated with isotretinoin. Nail findings were trachyonychia in 368 individuals (10.43%) and paronychia in 14 individuals (0.39%) [8]. Blasiak et al. evaluated 116 patients treated with isotretinoin for acne vulgaris. They reported that 16 of them (13.8%) had nail changes. The most frequent finding was paronychia, and it was detected in 9 patients (7.8%) [5]. In their study observing the systemic side effects of isotretinoin in 150 patients with acne vulgaris, Brito et al. detected nail fragility in 38 (25.3%) and PG in 20 patients (13.3%) [7]. Rademaker evaluated side effects in 1743 patients receiving isotretinoin and a total of 37 patients (2.1%) with periungual granulomas were reported [21]. Demirseren et al. also evaluated of 300 patients with moderate to severe acne under isotretinoin treatment and, reported that ingrown toenails was the only side effect on nails detected in 13 patients (4.3%) [10]. There were 34 patients in the isotretinoin group with nail findings in this study (34%). However, the variety of nail findings was greater in our study compared to previously reported studies. The higher occurrence of nail side effects and variety in our study compared to the literature may be associated with failure to specifically examine nails and underreporting of nail side effects.\u003c/p\u003e \u003cp\u003e\u0026Ouml;z\u0026ccedil;elik et al. reported that onychoschizia was the most frequent nail finding in the isotretinoin group in the present study. One of the most important finding of this study is that onychoschizia was not observed in the group receiving topical treatment. As a result, we can conclude that isotretinoin directly contributes to the formation of onychoschizia. It increases the rate of nail growth and causes thinning of the nails, which may result in the formation of onychoschizia.\u003c/p\u003e \u003cp\u003e\u0026Ouml;z\u0026ccedil;elik et al. found that the beginning of nail changes in their patients was the third month of treatment. Them also revealed that isotretinoin statistically significantly affected the nail growth rate and thickness when compared with the control groups at the third month of treatment. difference in nail growth rate between the isotretinoin and control groups began in the third month of treatment and progressively increased [18]. In a study involving 300 isotretinoin patients, nail ingrown were detected in 13 patients, with a median onset of nail ingrowth at 12 weeks (range 3\u0026ndash;20) [10]. Here, with this study, we have also shown that isotretinoin can cause nail changes starting from the third month of treatment. Dermatologists prescribing isotretinoin for a period of longer than 3 month should inform the patients that potential nail changes may occur in the nail plate.\u003c/p\u003e \u003cp\u003eDifferent results regarding the dose-dependency of isotretinoin side effects have been reported in the literature. Rademaker evaluated 1743 patients treated with isotretinoin and observed that commonly reported side effects were clearly dose-dependent. In this study, 18.5% of the patients had no side effects, and the majority of these were patients receiving very low doses of isotretinoin (\u0026lt;\u0026thinsp;0.25 mg/day) [21]. In the randomized controlled trial by Legiawati et al., different doses of isotretinoin regimens were compared and evaluated. They reported that low-dose isotretinoin regimens resulted in fewer side effects and showed similar efficacy to conventional doses. Therefore, they recommended a continuous low-dose treatment regimen [16]. In the study by \u0026Ouml;z\u0026ccedil;elik et al. since all patients received the same dose of medication, it was not possible to evaluate whether the observed nail findings were dose-dependent or not [18]. Blasiak et al. divided patients receiving isotretinoin into two groups based on cumulative doses (\u0026lt;\u0026thinsp;220 mg/kg and \u0026gt;\u0026thinsp;220 mg/kg group) and found no statistically significant difference in nail findings between the two treatment groups [5]. Goulden et al. evaluated adverse effects in 720 isotretinoin patients and found no association between cumulative dose or duration and potential side effects [14]. In this study, we found no relationship between nail changes and treatment duration. On the other hand, the TCD seemed to have important role in nail plate changes. In addition to all this, not suprisingly, patients with nail changes who had higher cumulative doses needed a longer healing time compared with the lower cumulative doses. These findings suggest that nail plate changes associated with isotretinoin are dose-dependent. In patients experiencing nail changes associated with isotretinoin, it may be possible to reduce the severity of these side effects by reducing the drug dose. More studies are needed to determine the necessary dose adjustments based on the nail findings associated with isotretinoin.\u003c/p\u003e \u003cp\u003eWe could not find any data in previous literat\u0026uuml;re revealing the average recovery time of isotretinoin-induced nail findings. In this study, the mean duration of complete recovery after the occurrence of nail finding was found to be 8 months. We did not need to have dose reduction in any patients with nail changes in the isotretinoin group since the recipients had no complaint. The reason for prolonged persistence of nail findings in patients may be the continue treatment without interruption. We can conclude that the main important factor in the regression of nail findings is the cessation of the isotretinoin treatment. Isotretinoin primarily induce to temporary nail findings mostly secondary to cumulative dose and drug exposure.\u003c/p\u003e \u003cp\u003eIn the topical treatment group, a total of 4 different nail findings such as leukonychia, PG, onycholysis and Beau's lines were detected only in 11 patients. Additionally, all of these findings were observed only in one single nail plate. None of the findings observed in the isotretinoin group, such as onychoschizia, onychorexis, MND, chronic paronychia and granulation tissue, were found in the topical treatment group. These results may suggests that the findings in the isotretinoin group could be specific nail findings secondary to isotretinoin. Large interventional clinical trials including larger patients and control groups are needed to confirm this theory.\u003c/p\u003e \u003cp\u003eThe limitations of the present study was that it included a small number of patients and included no patient age under 18. The nail findings associated with isotretinoin could have been observed by the re-exposure of the drug to effected individuals. Another limitation was that it was a single-center study.\u003c/p\u003e \u003cp\u003eAs a result, secondary nail changes due to isotretinoin are reversible, independent of the treatment duration but directly associated with cumulative dose. Dermatologists prescribing isotretinoin should be allert of the nail findings which can occur especially during the treatment regimens longer than three months. They should also be aware that the findings are reversible with dose reduction or discontinuation of the drug.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests Statement:\u003c/h2\u003e\u003cp\u003e All the other authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDY and NK have attended and contributed equally for the study. They are first and co-authors for this manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe authors declare that there are no relationships that provided financial or editorial support for the study which may in potential cause competing interest for the submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAllegue F, Gonzalez-Vilas D, Zulaica A (2017) Isotretinoin-Induced Elkonyxis. 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J Am Acad Dermatol 74(5):945\u0026thinsp;\u0026ndash;\u0026thinsp;73 e33 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaad.2015.12.037\u003c/span\u003e\u003cspan address=\"10.1016/j.jaad.2015.12.037\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"isotretinoin, nail disorders, onychoschizia, cumulative dose","lastPublishedDoi":"10.21203/rs.3.rs-4319935/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4319935/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn this study, we aimed to describe isotretinoin-induced nail changes and to increase patients' compliance with treatment. A total of 200 patients diagnosed with acne vulgaris were included in the study, including 100 patients who started systemic isotretinoin treatment and 100 control patients who received topical acne treatment. The patients age, gender, treatment duration, total doses per month, type of nail changes were recorded. Patients with persistent nail changes were followed at 3rd and 6th month after treatment. A total of 34 patients had nail changes in the isotretinoin group. These changes included onychoschizia (55.9%), leukonychia (11.8%), onychorexis (8.8%), median nail dystrophy (5.9%), pyogenic granulomas (5.9%), chronic paronychia and granulation tissue (5.9%), onycholysis (2.9%) and Beau's line (2.9%). The rate of nail changes in the isotretinoin group was significantly higher than the topical treatment group (34% vs 11%, p:0.001). There was no statistically significant difference in terms of treatment duration between the patients with and without nail changes in the isotretinoin group. The total cumulative dose was significantly higher in patients with nail changes in isotretinoin group (p:0.043). Also, the regression of nail changes was slower in patients receiving higher cumulative doses (p:0.049). Isotretinoin increases the risk of nail changes, the most common being onychoschizia. The risk of developing nail changes have no association with treatment duration; however, it is associated with the total cumulative dose. Nail findings inducedby isotretinoin are completely reversible.\u003c/p\u003e","manuscriptTitle":"Nail Changes in Patients Receiving Systemic Isotretinoin Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-02 18:57:19","doi":"10.21203/rs.3.rs-4319935/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"db80fcc6-11bb-4a54-a115-701ec4614646","owner":[],"postedDate":"May 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-02T18:57:21+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-02 18:57:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4319935","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4319935","identity":"rs-4319935","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}