Dermatological Indications for the Use of Isotretinoin Beyond Acne

Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20

Dermatological indications for the use of isotretinoin beyond acne

Emily Forbat, Faisal R. Ali & Firas Al-Niaimi

To cite this article: Emily Forbat, Faisal R. Ali & Firas Al-Niaimi (2018) Dermatological indications for the use of isotretinoin beyond acne, Journal of Dermatological Treatment, 29:7, 698-705, DOI: 10.1080/09546634.2018.1445194 To link to this article: https://doi.org/10.1080/09546634.2018.1445194

Accepted author version posted online: 26 Feb 2018. Published online: 14 Mar 2018.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ijdt20 JOURNAL OF DERMATOLOGICAL TREATMENT 2018, VOL. 29, NO. 7, 698–705 https://doi.org/10.1080/09546634.2018.1445194

REVIEW ARTICLE Dermatological indications for the use of isotretinoin beyond acne

Emily Forbata, Faisal R. Alib and Firas Al-Niaimib aChelsea and Westminster Hospital, London, UK; bDermatological Surgery & Laser Unit, St John’s Institute of Dermatology, Guy’s Cancer Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

ABSTRACT ARTICLE HISTORY While the use of isotretinoin has revolutionized the treatment of acne vulgaris, isotretinoin is increasingly Received 3 February 2018 recognized as a useful therapeutic option for many other cutaneous conditions. We review the evidence Accepted 14 February 2018 underlying the use of isotretinoin for a variety of dermatological indications including hidradenitis suppu- KEYWORDS rativa, sebaceous gland pathology, rosacea, scarring alopecia, cosmetic dermatology, and non-melanoma skin cancer prophylaxis amongst other uses, and thus consider alternative uses within dermatology prac- Isotretinoin; retinoids; rosacea; cosmetic tice. The studies found benefit of isotretinoin, however most trials lacked statistical power and in many dermatology; hidradenitis cases the use was limited to case series. Isotretinoin, if used within the correct cohort with appropriate suppurativa pretreatment counseling regarding side-effects, is a well-tolerated medication with potential as either an adjunctive treatment or a second-line agent in those recalcitrant cases unresponsive to first-line therapy.

Introduction 33 case studies/case series (6,7,9–39), two retrospective reviews (8,40), six randomized control trials (RCTs) (41–46), two random- Isotretinoin, also known as 13-cis-retinoic acid, is a synthetic drug ized comparative trials (47,48), one open-label non-randomized best known for its treatment of acne (1). The mechanism of action prospective pilot study (49), one retrospective comparison study results from isotretinoin-induced expression of apoptotic protein (50), one single-blind randomized study (51), two case-controlled necrosis factor, and a recent review suggests that apoptosis is the randomized clinical studies (52,53), and one cohort study (54). culprit for the multitude of well-known side-effects of isotretinoin (2). Isotretinoin regulates cell proliferation by binding to nuclear Within these studies, 2996 patients were treated between 1985 retinoic acid receptors. Furthermore, it is said to decrease poly- and 2017 (Table 1). amine synthesis and keratinization which contributes to its anti- inflammatory and anti-prolific properties (3). Isotretinoin was first Hidradenitis suppurativa approved for the treatment of acne in 1982 (4). The UK license for isotretinoin was first established in 2001, and the European direct- A retrospective review has been carried out assessing the use of ive advises the treatment of acne to start at a dose of 0.5 mg/kg isotretinoin for the treatment of hidradenitis suppurativa (HS) (39). and be avoided in children under 12 years old, with strict preg- There have been a multitude of papers which refute the benefit nancy prevention strategies. Furthermore, liver function and lipid of isotretinoin in patients with concomitant HS and acne (56,57). monitoring are required to be checked prior to treatment, Treatment with isotretinoin in these cases of dual pathology often 1 month post-initiation of treatment, and 3 months thereafter (5). demonstrated a minimal response of HS, despite both HS and The longest duration of use of isotretinoin from our review was 7 acne both being associated with ductal abnormalities (58). Huang years, in which low-dose isotretinoin was used intermittently to and Kirchhof argue that isotretinoin should not be dismissed, as treat erythema dyschromicum perstans (6). The age range of careful literature evaluation in fact demonstrates that in the cor- patients reviewed in this article varied from just under 7 months rect cohort – i.e. those with mild/moderate HS, females, or con- of age to 64 years old (7,8). comitant acne – complete remission has been achieved (8). Further research is required, as the use of isotretinoin in HS is Method sparse.

We conducted a literature search in October 2017, to review the Sebaceous gland pathology current uses of isotretinoin in dermatology beyond the treatment of acne. A PubMed, search was carried out, with the search criteria A randomized comparative trial comparing alternate daily use of ‘Isotretinoin’ & ‘Dermatology’. Only articles published in English 10 mg isotretinoin versus topical anti-seborrheic treatment in were included. Review articles were omitted, unless they specific- moderate to severe seborrhea and seborrheic dermatitis (N ¼ 45) ally analyzed studies within them. Articles on the use of isotreti- over 6 months, demonstrated a significantly greater reduction in noin and acne were also excluded. scalp sebum secretion (p ¼ .004) in the isotretinoin arm after 3 months (47). Patients were not followed-up beyond 3 months and Results the dosage was not weight-dependent. Tagliolatto et al. treated 20 patients with sebaceous hyperplasia with isotretinoin (1 mg/kg Our search identified 1125 studies, of which 49 met the criteria of per day) for 2 months; the average number of skin lesions assessing the use of isotretinoin beyond acne. In total, there were decreased from 24 to 2 per patient (p < .05) (59). Isotretinoin is

CONTACT Dr Emily Forbat [email protected] Chelsea and Westminster Hospital, 369 Fulham Rd, London SW10 9NH, UK ß 2018 Informa UK Limited, trading as Taylor & Francis Group Table 1. Studies on the use of isotretinoin beyond acne. Study Indication Aim Patient number Dose Findings Part 1: Inflammatory dermatoses and infectious disorders Inflammatory dermatoses Huang and Kirchhof (8) Hidradenitis A retrospective N ¼ 25 0.45 ± 0.20 mg/kg/day for 6.8 ± 4.3 32% no response, suppurativa chart review months 32% partial response, 36% complete response Rademaker (40) Papulopustular A retrospective N ¼ 52 20 mg isotretinoin/day 12% did not attend follow up. rosacea review reduced to 10–20 mg once to five Those that did attend, 91% (42/46): rosacea cleared or times a week in 67%, was excellent. or One patient stopped due to SE. increased in 15% (who all had add- 44% no SE. itional acne) to 30–40 mg/day The most common SE was cheilitis in 52%, which was mild in all but one patient Sbidian et al. (41) Papulopustular A RCT N ¼ 156 0.25 mg/kg/day Post 4-month treatment at least 90% reduction of pap- rosacea versus ules/papules in comparison to pre-treatment. placebo for 4 months Significantly higher skindex score in treated group versus placebo group. 58.3% of 51 patients who agreed to 4 month FU, demonstrated relapse Rallis and Korfitis (20) Granulomatous A case study N ¼ 1 0.7 mg/kg/day for 24 weeks. 3-month FU: satisfactory rosacea 5-month FU: total remission 6-month post-cessation of treatment: no recurrence. Uslu et al. (22) Rosacea A case series N ¼ 25 20 mg/day for 4 months, tapering the Papule and pustule, erythema index, sebum level, dose within the following 6 months. dermatologist’s and patient’s erythema scores, and dermatologist’s sebum scores: significantly lower, one- month post-therapy versus pre-therapy (p < .05). 45% relapse within median FU of 11 months Gollnick et al. (52) Rosacea Doxycycline- and placebo- N ¼ 573 One of three different dosages of iso- Isotretinoin 0.3 mg/kg most effective dose versus placebo. controlled, randomized tretinoin With IST: clinical study 0.1 mg Complete remission in 24% (14%) 0.3 mg Marked improvement 57% (55%) versus the bracketed fig- 0.5 mg ures for doxycycline (per kg body weight) SE: increase incidence of dermatitis facialis with 0.5 mg/kg þ doxycycline (100 mg daily for 14 days, then 50 mg daily)

or placebo TREATMENT DERMATOLOGICAL OF JOURNAL for 12 weeks. Mortazavi et al. (51) Psoriasis vulgaris A single blind N ¼ 37 Intervention group: narrow band ultra- Psoriasis Area Severity Index (PASI) scores demonstrated randomized violet B (NBUVB) þ isotretinoin no significant difference between efficacies of two clinical study (0.5 mg/kg/day) treatments Control group: narrow band ultraviolet But B (NBUVB) þ isotretinoin Isotretinoin þ NBUVB can reduce phototherapy sessions (0.5 mg/kg/day) and cumulative NBUVB dose required. Al-Shobaili and Al- Pustular psoriasis A case study N ¼ 1 Initially started on methotrexate No relapse after methotrexate stopped after the isotreti- Khenaizan (30) 15 mg/week for 6 weeks, (relapsed noin was commenced. when methotrexate was reduced.) Excellent control when isotretinoin continued at 40 mg/ Therefore, day in conjunction with topical steroids. 40 mg/day per oral (0.75 mg/kg/day) isotretinoin was added, and 3 weeks later methotrexate was stopped. Infectious disorders Al-Hamamy, Salman and Plane Warts A case series N ¼ 26 Mean of 0.5 mg/kg/day for 2 months. 73.07% complete response Abdulsattar (19) 26.92% no response at the end of treatment. 78.94% who had complete response, no recurrence at 4- month follow up 699 (continued) Table 1. Continued 700 Study Indication Aim Patient number Dose Findings Georgala et al (44) Condylomata acumi- A randomized Placebo- N ¼ 60 Randomly assignment to receive Group 1: nata of the cervix controlled trial Group 1: isotretinoin, 0.5 mg/kg daily 32.1% responded completely AL. ET FORBAT E. for 12 weeks 39.2% responded partially Group 2: placebo 28.5% did not respond Group 2: 0% responded completely 8% responded partially 92% did not respond Oral isotretinoin demonstrated significant difference in treatment outcome. Yildirim et al. (34) Condyloma A case study N ¼ 1 IFNalfa-2a (three million unit’s S/C, 3/ Clearance at 3 months, no recurrence at 1 year FU. acuminatum week) þ oral isotretinoin (0.5 mg/kg/ SE: mild chelitis day) for 2 months. IFNalfa stopped at 2 months and IST continued for a further month. Part 2: Cosmetic, sebaceous gland pathology and scarring alopecia Cosmetic Bagatin et al. (48) Photo-aging A randomized, N ¼ 24 12 people treated with 20 mg/day Qol scores reduced for all subjects. comparative study 12 treated with Retinoic acid cream for Histology: 6 months Corneal layer diminution Epidermal thickness increase Elastosis reduction. No significant difference between groups Bagatin et al. (42) Photo-aging A RCT N ¼ 32 Group A: 20 mg isotretinoin 3/week- Significant difference in p53 between groups, major þ moisturizer/sunscreen for 3 reduction in p53 in group A. months Authors felt this reduction reinforced retinoid chemopre- Group B: moisturizer/sunscreen only vention. Not thought to be effective in photo aging Rabello-Fonseca et al. (29) Photo-aging A case series N ¼ 33 Group 1: Statistically significant increase in collagen fibers with 10 mg isotretinoin both regimes Group 2: Mean, 37.8%, increasing to 44.4%; p ¼ .029 with the 10- 20 mg 3/week for 3 months mg dosage Mean, 36.6%, increasing to 41.9%; p ¼ .01 with the 20-mg dosage. Overall improvement in texture, wrinkle depth, and skin coloration. Limitation: no placebo control group

Sebaceous gland pathology De Souza Leao Kamamoto, Seborrhea and seb- A Randomized N ¼ 45 Group Isotretinoin (ISO): Rate of sebum production significantly decreased in et al. (47) orrheic dermatitis comparative trial Isotretinoin 10 mg alternate days Group ISO. Patient opinion, investigator, and QoL Group X: Topical anti-seborrheic topical assessments improved in both groups. treatment Gupta et al. (7) Sebaceous hyperpla- A case study N ¼ 1 Low dose isotretinoin-dose not 3 month FU: sia and sebaceous specified substantial improvement clinically and histologically adenomas Liu et al. (14) Familial sebaceous A case study N ¼ 2 0.2 mg/kg per day, a cumulative dose Case 1: no recurrence at 2 year FU hyperplasia of 41 mg/kg (case 1) and 64 mg/kg Case 2: 1-month Rx with 0.3 mg/kg reduced to 0.5 mg/kg (case 2), respectively for 9 months: Outcome: No recurrence for 19 months Jung et al. (15) Cyclosporine-induced A case study N ¼ 1 (1) Daily oral isotretinoin 20 mg for 2 (1) Near-complete remission, No SE. sebaceous months: Two months after discontinuing, a few new lesions started hyperplasia which resulted in to develop (2) Oral isotretinoin 20 mg was (2) The lesions cleared without recurrence for 9 months. restarted for 2 months. (continued) Table 1. Continued Study Indication Aim Patient number Dose Findings McDonald et al. 2011 (23) Cyclosporine-induced A case series N ¼ 2 Patient one: Patient one: almost complete clearance at 3 months sebaceous (0.14 mg/kg) daily for 3 months, then SE: minor chelitis hyperplasia maintained on this dose daily Patient two: almost complete clearance within 1 week, Patient two: 0.29 mg/kg/day, then almost complete resolution at 4 months maintained on this dose daily SE: nil No change in graft function in either patient Scarring alopecia Marquis et al. (11) Dissecting Cellulitis A case study N ¼ 1 Isotretinoin 20 mg/day (0.27 mg/ 4-month FU: near complete remission of scalp kg/day). 7-month phone follow up consultation: no further recurrence Tietze et al. (50) Folliculitis decalvans A retrospective N ¼ 28 Comparison of outcome between clin- Under treatment with isotretinoin, 90% of patients cured. comparison study damycin and rifampicin, clarithromy- 10% did not improve significantly under therapy but went cin, dapsone, and isotretinoin was into remission after the treatment was stopped. analyzed. 48% treated with IST. 5% monotherapy 50% in combination-mainly dapsone. 0.2–0.5 mg/kg daily for 5–7 months. After a stable emission, reduced by 10 mg 2 or 3 times a week for sev- eral months before treatment stopped. Part 3: Non-melanoma skin cancer prophylaxis, keratinization disorders, and miscellaneous Non-melanoma skin cancer prophylaxis Gahalut et al. (53) Chronic plaque-type A randomized hospital- N ¼ 35 Control group: PUVA sol only Combination of IST with PUVAsol statistically more effect- psoriasis vulgaris based study. Intervention group: ive than control group. PUVAsol þ isotretinoin (0.5 mg/ kg/day) Skroza et al. (17) SCC arising on an A case study N ¼ 1 Isotretinoin 0.5 mg/kg/day for 5 months 70% reduction in size with no other relapses was epidermoid observed during a 1-year follow-up. cyst (15) Tauber et al. (18) Unresectable A case study N ¼ 1 Interferon (IFN)-a2a (3MUI subcutane- Clinical and radiological reassessment at 4 weeks of ther- Perineal ously once a day) and isotretinoin apy showed a 50% tumor collapse Cuniculatum (1 mg/kg per day) and Cidofovir Carcinoma (5 mg/kg intravenously on weeks 0, 1, 3, and 5) however stopped due to TREATMENT DERMATOLOGICAL OF JOURNAL renal failure Nijsten and Stern (54) Cutaneous squa- A cohort study N ¼ 135 Comparison of SCC and BCC incidence Retinoid use: mous cell carcin- during years of substantial oral retin- 30% reduction in SCC incidence (P ¼ .002). oma risk in oid use versus other years Post-adjustment for other factors associated with SCC risk, patients with incidence of SCC: significantly decreased during years psoriasis treated of substantial retinoid use. with psor- Oral retinoid use and BCC incidence were not significantly alen-UVA associated.

Levine et al. (45) Skin cancer A randomized, double-blind, N ¼ 525 Group 1: oral retinol (25,000 units) Outcome measure: prevention controlled trial. Group 2: isotretinoin (5–10 mg) Time to first new occurrence of BCC or cutaneous SCC. Group 3: placebo supplementation No difference between groups. daily for 3 years Moon et al. (63) Retinoids to prevent A RCT (1985–1990) N ¼ 719 25,000 IU retinol or 5–10 mg isotreti- No preventative effect of oral isotretinoin in the high risk skin cancer noin versus placebo daily for 3 years candidates in high risk candidates (continued) 701 702 E. FORBAT ET AL.

beneficial in sebaceous hyperplasia and sebaceous adenoma (7), cyclosporine-induced sebaceous hyperplasia in renal transplant (15,23), and diffuse familial sebaceous hyperplasia (14).

Rosacea ), generalized erup- 27 ), sub-acute cutaneous ), steatocystoma multi- Five studies reviewing the use of isotretinoin in rosacea have 6

36 shown promising results (20,22,40,41,52). Sbidian et al. carried out an RCT among 156 patients with difficult to treat papulopustular rosacea, comparing 0.25 mg/kg/day isotretinoin versus placebo, with review at 4 months. Overall, the isotretinoin group demonstrated higher absolute and relative reductions in the number of lesions, as well as Skindex scores in comparison to the placebo arm, suggesting quality of life (QoL) as well as clinical outcome ), granuloma annulare ( were better in the isotretinoin group (41). 58.3% of patients who 35 did attend follow-up had a relapse in their symptoms (41), similar striction, reduced pain. partial improvement, no recurrence of pseudoainhum to Uslu et al. who found a 45% relapse at 11-month follow-up 1 month (FU): improvement of ischemia, softening8 of month con- FU: keratoderma and ichthyosis lesions showed

), erythema dyschromicum perstans ( (22). Rademaker demonstrated a 91% clearance of papulopustular

16 rosacea in patients treated with very low dose isotretinoin from 10 to 20 mg daily (40), and Gollnick et al. carried out a study reviewing the use of various doses of isotretinoin (from 0.1 to 05 mg/kg of body weight) in conjunction with either doxycycline or placebo; 0.3 mg/kg of isotretinoin to have the most effective outcome in the treatment of rosacea (52). ), synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (

26 Scarring alopecia

), annular elastolytic giant cell granuloma ( A recent case study demonstrated an excellent outcome of isotre- 33 ), lymphangioma circumscriptum ( tinoin 0.27 mg/kg/day in an 18-year-old male with dissecting cellu- 49

increased at 1 monthbody to weight 0.35 mg/kg litis recalcitrant to multiple antibiotics, clotrimazole, and betamethasone. At 4 months follow-up, there was near complete remission, and via phone consultation (post-discontinuation of treatment) the patient did not report recurrence (11). In this case, the authors postulated that isotretinoin reduced the overzealous

), follicular mucinosis ( immune response and thus normalized the skin and follicular 1 Daily dose of 0.35 mg/kg body weight, 32 ), atrophoderma vermiculatum ( apparatus. ¼ 25 N A retrospective study of 28 patients with folliculitis decalvans, ).

39 reviewed which treatment modalities had the best outcome using ), lichen planus pigmentosus (

13 either clindamycin and rifampicin, clarithromycin, dapsone or isotretinoin. Isotretionin treatment was the most successful with 90% of patients remaining in remission 2 years post-treatment cessation (50).

Viral warts

), vesiculous prurigo pigmentosa ( Isotretinoin has a good clinical outcome in the treatment of warts ), erythrokeratoderma variablilis ( 43 A case study 24

), atrophoderma vermiculatum ( (19,44). Al-Hamamy et al. demonstrated that 73.07% of warts

38 treated for 2 months with 0.5 mg/kg/day of oral isotretinoin

), generalized lichen amyloidosis ( resolved, with 78.94% of the cohort found to have no recurrence 12 at 4 months (19). Another case study using isotretinoin in con- ), melanoma ( junction with interferon had complete clearance at 3 months and 31 no recurrence at 1 year (34). with ichthyosis Cosmetic Outcomes of photo-aging following treatment with systemic iso- ), eruptive syringomas ( 9 ), chronic granulomatous disease (

) Vohwinkel syndrome tretinoin remain mixed. Two studies have demonstrated that ), bilateral nipple hyperkeratosis ( 21 10 ), prurigo pigmentosa ( 20 mg of isotretinoin daily, does not improve outcome in compari- 37 28 son to either topical retinoic acid or topical sunscreen, as assessed by histology and quality of life (QoL) scores (42,48). Whereas one case series demonstrated a statistically significant increase in colla- Continued gen fibers, post-treatment with either 10 or 20 mg isotretinoin three times per week for 3 months, with overall skin improvement plex suppurativum ( lupus erythematosus ( tive histiocytoma ( Miscellaneous Macular hypomelanosis ( Table 1. StudyKeratinization disorders Nico and Fernandes ( Indication Aim Patient numberas a result (29 Dose). Interestingly, the use of isotretinoin Findings has JOURNAL OF DERMATOLOGICAL TREATMENT 703 dichotomous outcomes in Fordyce spots in patients with associ- action in those conditions. Those that did, felt isotretinoin’s mech- ated acne, with some showing improvement in Fordyce spots, anism of action were: anti-inflammatory (49), anti-angiogenic (16), and others not (59). immunomodulatory (6), sebosuppressive (33), and anti-neoplas- tic (43). Non-melanoma skin cancer (NMSC) prophylaxis Refer Table 1 for an overview of these studies. Immunosuppressed patients, for example organ transplant recipients, are at higher risk of NMSC. Articles often state that retinoids Conclusion have chemoprotective effects, however robust literature is lacking. A Cochrane review of ten trials (N ¼ 7229) carried out in 2007 Isotretinoin, if used within the correct cohort, with appropriate found that two trials within this review demonstrated evidence pretreatment counseling regarding side-effects, is a well-tolerated that isotretinoin could either cause increased adverse effects, or medication with potential as either an adjunctive treatment or a increase the risk of squamous cell carcinoma (SCC) in comparison second line agent in those with disease recalcitrant to first line to placebo (60). However, they also stated that due to the small therapy. To date, there has been interest demonstrated in isotreti- number of trials and inconsistent results that they were unable to noin use beyond the treatment of acne, however the majority of declare that these results were reliable. studies presented are only case studies or small retrospective A randomized, double-blind, controlled trial compared the time reviews. Large RCTs are required to validate the possibility of iso- to first new occurrence of either a basal cell carcinoma (BCC) or tretinoin as an inexpensive drug to treat a multitude of other dis- cutaneous SCC in 525 patients treated with either oral retinol orders within dermatology, including most importantly, the use of (25,000 units), 5–10 mg of oral isotretinoin, or a placebo over the isotretinoin in NMSC which at present has contrasting outcomes. course of 3 years. They found no significant difference between the groups, and no overall skin cancer prevention (45). Skroza et al. reviewed the treatment of isotretinoin 0.5 mg/kg/ Disclosure statement day for 5 months to a SCC on top of an epidermoid cyst. They The authors report no conflicts of interest. found a 70% reduction in the size with no further relapses at 1 year post-treatment (17). Interestingly a cohort study of 135 patient comparing SCC and References BCC incidence during years of oral retinoid treatment compared with non-treatment years in patients with psoriasis treated with 1. IsotretinoinjDermNet New Zealand [Internet]. [cited 2017 PUVA, found there to be a significant (p ¼ .002) 30% reduction in Sep 9]. Available from: https://www.dermnetnz.org/topics/ SCC with retinoid use. However, retinoid use did not affect the isotretinoin/ incidence of BCC (54). Moon et al. carried out the SKICAP-AK trial 2. Melnik BC. Apoptosis may explain the pharmacological which randomized patients with at least ten actinic keratoses and mode of action and adverse effects of isotretinoin, including up to two previous skin cancers to either placebo or 25,000 IU of teratogenicity. Acta Derm Venerol. 2017;97:173–181. systemic retinol (precursor of retinoic acid) and found that retinol 3. Isotretinoin – DrugBank [Internet]. [cited 2017 Nov 9]. is beneficial in reducing the incidence of first SCC but had no Available from: https://www.drugbank.ca/drugs/DB00982 effect on BCCs. They then carried out the SKICAP-SCC/BCC trial for 4. Accutane was approved in May, 1982 with a pregnancy cat- high risk patients (who had had at least 4 skin cancers previously) egory X [Internet]. [cited 2018 Jan 17]. Available from: and randomized these patients to treatment with either retinol or https://www.fda.gov/ohrms/dockets/ac/04/briefing/4017B1- oral isotretinoin at a dose of 5–10 mg daily or placebo, found no 02%20%20AC%20Intro%20Review%20-Section%20A%20 benefit in this cohort (46,61). Interestingly, Clouser et al. re- Tab1.htm reviewed the statistics of the above studies in 2010, and declared 5. Layton AM, Dreno B, Gollnick HPM, et al. A review of the that in fact retinol could increase the risk of SCC in patients dur- European Directive for prescribing systemic isotretinoin for ing the first quartile or retinol dose. 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