Isotretinoin and timing of procedural interventions: Clinical implications and practical points

For decades, the notion that elective surgeries and cutaneous procedures should be postponed for 6–12 months in patients on, or recently administered with isotretinoin, has been widely accepted. However, some recent studies showed the need for a change in this regard.


| INTRODUC TI ON
Isotretinoin or 13-cis-retinoic acid (13-CRA) is a retinoid commonly used for the treatment of severe nodulocystic acne vulgaris and some other dermatologic conditions. Despite its widely application in dermatology, there is concerns about its various side effects including alteration of wound healing process. [1][2][3] In mid-1980s, any elective surgical procedures such as those for acne scar repair were deferred for 6-24 months after systemic isotretinoin usage in order to lowering the risk of developing hypertrophic scar and potential keloid formation due to abnormal wound healing resulting from isotretinoin intake. 4,5 This recommendation was adopted based on the findings of some studies reported keloid formation and hypertrophic scarring in patients taking isotretinoin who underwent some ablative procedures such as dermabrasion or laser resurfacing for acne scar repair. 4,5 However, the association of isotretinoin with abnormal wound healing has not been shown in numerous newer studies, and it has now been assumed that hypertrophic scar or keloid formation in patients using isotretinoin might be an idiosyncratic phenomenon. [6][7][8] Due to these discrepancies in the literature, clinicians remain unsure if they can implement invasive procedures on patients using isotretinoin without any risk of atypical healing process.
Moreover, conflicting results of these studies has raised some issues about timing and protocol of receiving isotretinoin in patients undergoing various invasive procedures by plastic surgeons, ENT surgeons, dermatologists, and ophthalmologists. Here, we reviewed the existing data in this regard and tried to develop a guideline for this group of patients, especially Asian skins which have a higher potential of keloid formation and scarring.

| ME THODS
We searched on PubMed, Google Scholar, and Scopus in this regard, and all of the relevant papers, in English, published until October 2022, which we could access to their full-texts were included.
We focused on studies with experiences and recommendations made by clinicians in various fields including ENT, orthopedics, dentistry, ophthalmology, plastic surgery, and dermatology in this regard and tried to summarize them to provide a practical guide for clinicians.

| RE SULTS AND D ISCUSS I ON
As mentioned above, recent studies have not report a significant risk of abnormal healing process following isotretinoin intake. [6][7][8] Ungarelli et al have evaluated 47 studies about important aspects of Isotretinoin use in patients with surgical procedures and finally concluded that isotretinoin does not promote skin healing issues in patients. They also recommended that a shorter time interval as about 4 weeks between discontinuation of isotretinoin and surgery would be enough, based on drug pharmacokinetics. 9 Though a few conservative recommendations regarding the necessitate of postponing surgeries for at least 6-12 months following termination of the drug, 10 some ENT surgeons noticed even positive effects of this drug in a group of patients underwent rhinoplasty during isotretinoin use. 6,11,12 They reported that reduced nose size, reduced skin thickness and oil, and recovery from acne during postoperative period of rhinoplasty were more likely to happen in cases with a history of isotretinoin use, compared to other patients. 6 However, since patients under rhinoplasty experienced limited cutaneous incisions, this possible positive effect of isotretinoin should not be generalized to all skin surgeries.
Cutaneous abnormal healing is not the only issue regarding isotretinoin use. Some studies reported an impairment in the healing process of bones and even developing of bone thinning and osteoporosis in cases experienced a fracture of long bones. 13 Contrarily, isotretinoin might facilitate the bone healing process at the skull although with a risk of bone overgrowth. Hence, suggestion of stopping isotretinoin use or at least reducing its dosing to only 0.5 mg/ kg daily as well as correction of vitamin D and calcium status seems to be the most reasonable strategy in this regard. 8 However, this is not necessary to take such caution regarding dental interventions. 14 Isotretinoin has been shown to decrease skin fibroblasts' metabolism in cultures and could lead to decrease collagen formation. 15 This observation is the base of suggesting topical retinoid as a potential treatment for keloid. Moreover, it has been shown that retinoic acid could decrease pro-inflammatory cytokines production and increase anti-inflammatory cytokines secretion 16 as well as elevate Arg1 level due to enhancement of Arg1 gene activation in IL4-stimulated M2, anti-inflammatory macrophages 17 that is critical to wound healing. 18,19 On the contrary, a decrease in epidermal cell growth and resultant delayed epithelization as well as its effect on sebaceous glands have been also reported as potential mechanisms for delayed wound healing and subsequent scar hypertrophy. 20 It seems that a balance between these two opposite impact on tissue repair along with other unknown mechanisms could explain the controversy in reported outcomes in patients who underwent surgical procedures while on, or having recently completed isotretinoin therapy.
It seems that some factors such as duration and dosage of isotretinoin treatment, procedure type and patient's characteristics are associated with potential outcome of wound healing.
People with darker skin and those with ages between 20 and 40 years are more vulnerable to keloid formation. 21 While gender is not related to abnormal healing, 21 the wound anatomic location seems to be a matter: The central face and the lower cheek regions are more prone to develop abnormal scarring in patients on, or recently administered with isotretinoin. 22 Low-dose isotretinoin (10 mg/day) has been reported to be safe with nonablative infrared fractional laser, rhinoplasty, superficial peelings, laser hair removal, and LASIK eye surgery. [23][24][25][26] It is worthy to note that most of the previous studies used a dosage ranging between 10 and 80 mg. Hence, it is wise to suggest the dosage less than 0.5 mg/kg body weight in patients.
There is controversy regarding some procedures such as fractional CO 2 resurfacing, elective surgeries, manual dermabrasion, and fractionated radiofrequency: Some clinicians prefer to delay these procedures until more than 6 months 27 and others wait only 3 weeks, based on drug half-life, after stopping the oral isotretinoin. 28 However, mechanical dermabrasion, deep dermatological excisions or peels, muscle flap, and fully ablative laser were not recommended for patients currently or recently (6-12 months) exposed to isotretinoin. 29 Despite a recent study reported two cases of normal wound healing following bilateral reduction mammoplasty in young female patients taking therapeutic doses of Isotretinoin, 30 there was some evidence of skeletal muscle necrosis which make it risky to be done in patients on isotretinoin.
As mentioned above, some recently published guidelines recommended against the delay in superficial cosmetic procedures, biopsies, and dermatological surgeries without involvement of muscle planes. 31 Recent studies reported that using oral isotretinoin among acne patients not only did not prone them to abnormal scarring, but also might lead to a better clinical outcome in the case of using laser for scars, if started in the last month of treatment with isotretinoin. [32][33][34] However, Alwabili et al. reported a possible association between isotretinoin use and cartilage graft thinning or prosthesis extrusion complications following cartilage tympanoplasty. 20 Other contributing factors would be the physician's experience in performing a procedure, avoidance of inappropriate too invasive setting and having a good postoperative wound care.
Taking these factors into consideration, physicians may discuss with patients regarding the known risk of abnormal wound healing in the setting of systemic isotretinoin treatment and suggest that, when possible, surgical procedures be postponed until the activity of the retinoids has time to subside. It is even more important regarding patients with darker skins to follow an even more strict guideline. 34 In conclusion, hair removal by both laser (of different types) and intense pulsed light, fractional nonablative lasers, q-switched lasers, superficial and medium-depth peels, microneedling, microdermabrasion, and superficial excision by radio-frequency devices seem to be safe in patients recently used isotretinoin. 34 However, our current practice is to wait for around 2 months after stopping isotretinoin before starting such procedures.
Since skin biopsy needs to be performed for diagnosing serious disorders, its restriction because of isotretinoin usage is not recommended.
Aggressive procedures such as dermabrasion, full-face ablative laser resurfacing, and deep peels would be safer to be postponed for the window period of 6 months after stopping the drug.

ACK N OWLED G M ENTS
The authors would like to thank Razi Hospital Clinical Research

Development Center and Autoimmune Bullous Diseases Research
Center for their technical and editorial assistance.

FU N D I N G I N FO R M ATI O N
The authors received no funding for this research.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that they have no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author, upon reasonable request.

E TH I C S S TATEM ENT
Ethical approval from the Medical Ethics Committee of Tehran University of Medical Sciences was provided.