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 and > 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.