Indian Journal of Drugs in Dermatology

REVIEW ARTICLE
Year
: 2020  |  Volume : 6  |  Issue : 2  |  Page : 59--69

Isotretinoin: In acne and beyond – An overview


Aditya Kumar Bubna 
 Department of Dermatology, IQ City Medical College, Durgapur, West Bengal, India

Correspondence Address:
Aditya Kumar Bubna
Department of Dermatology, IQ City Medical College, Sovapur, Bijra Road, Jemua, Durgapur - 713 206, West Bengal
India

Abstract

Isotretinoin (ISO) has proven to be an extremely valuable drug for all dermatologists. Since its approval in 1982 by the US Food and Drug Administration for nodulocystic acne, it still remains the gold standard drug for the above indication till date, facing no competition from its contemporaries. Along with the treatment of nodulocystic acne, ISO has proved valuable in several other dermatoses as well. Further, even for treating acne, there have been a number of modifications as far as the prescription of ISO is concerned. This review will briefly highlight the various aspects of isotretinoin for acne and other cutaneous disorders.



How to cite this article:
Bubna AK. Isotretinoin: In acne and beyond – An overview.Indian J Drugs Dermatol 2020;6:59-69


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Bubna AK. Isotretinoin: In acne and beyond – An overview. Indian J Drugs Dermatol [serial online] 2020 [cited 2021 Jan 20 ];6:59-69
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Full Text



 Introduction



Isotretinoin (ISO) is a nonaromatic first-generation synthetic retinoid formed by changing the polyene side chain and polar groups of Vitamin A. It was first approved by the US Food and Drug Administration (FDA) in 1982 for treating nodulocystic acne. Till date, no other treatment for acne has superseded the clinical efficacy of ISO in acne, even after 37 years of its introduction for the same. Apart from acne, there are a number of indications in dermatology where ISO has been used, and will be subsequently discussed.

 Mechanism of Action



The mechanism of action of ISO is elaborated in [Figure 1].[1],[2],[3],[4],[5],[6],[7]{Figure 1}

At the molecular level, ISO has not demonstrated any clearly identified affinity for both retinoid receptors, i.e., retinoic acid receptors (RARs) and retinoid X receptors (RXRs). However, ISO may get converted to metabolites within the keratinocytes that can then act as agonists of RARs and RXRs. These complexes, in turn, bind to retinoic acid response element within the chromosomes, resulting in the expression of a number of proteins involved in growth and regulation.

 Pharmacokinetics



Given orally, ISO reaches peak levels within 3 h. Improved oral bioavailability is seen following food intake preferably rich in fat because gastrointestinal absorption of ISO is enhanced by its solubilization in dietary fat.[8] ISO is bound 99% to plasma albumin. Its t1/2 ranges from 10 to 20 h. Metabolism of ISO occurs in the liver. Elimination is via bile and urine.[9]

 Indications



Food and Drug Administration approved

Nodulocystic acne.

Off label

Hidradenitis suppurativa (HS)Acanthosis nigricans (AN)RosaceaPityriasis rubra pilaris (PRP)PsoriasisDarier's disease (DD)IchthyosisDisseminate and recurrent infundibulofolliculitis (DRIF)PhotoagingLupus erythematosusGranuloma annulare (GA)Lichen planus (LP)Nonmelanoma skin cancer prophylaxisCondyloma accuminata.

 Contraindications



Absolute

Pregnancy (category “X” drug).

Relative

Abnormal hepatic profileAbnormal lipid profileImpaired renal function.

 Clinical Uses



Acne

ISO remains the cornerstone for managing nodulocystic acne since its approval by the US FDA in 1982. Although ISO has been indicated primarily for severe nodular and inflammatory acne, it is now recognized that ISO constitutes a highly effective option, also in the following scenarios:

Refractory inflammatory acne, not exhibiting multiple nodules but having a high likelihood for acne scarringNonnodular acne, in cases where improvement demonstrated is <50% after 6 months of antibiotic treatment and there is significant acne scarring, or if there is associated psychological distress.

It has been acknowledged that there is sufficient evidence for using ISO in severe forms of acne, particularly, but not limited to severe recalcitrant nodular acne which has proven refractory to other forms of therapy, along with the physical and psychological impact of acne on patient life quality.

Guidelines for recommending ISO in acne are summarized in [Table 1].{Table 1}

Dosing for isotretinoin

The conventional recommended dose of ISO is 0.5–1 mg/kg/day for a period of 16–32 weeks with a maximum cumulative dose of 120–150 mg/kg.[15],[16],[17] However, there are other dosing schedules for ISO, also followed by dermatologists and will be subsequently discussed.

Conventional dosing

The optimal recommended starting dose of ISO is 0.5 mg/kg/day which is continued for 4 weeks, following which the dose is escalated to 1 mg/kg/day which is maintained over the ensuing treatment course unless laboratory values and adverse clinical effects warrant dose adjustments.[1],[2],[18] Treatment with ISO is continued till the cumulative dose of 120–150 mg/kg is attained. The FDA-approved dosing frequency is twice daily. There have been no pharmacokinetic studies that have changed this recommendation with regard to efficacy and safety.[19],[20] It has been also seen that twice-daily dosing with ISO helps in sustaining stable steady serum levels of the drug.[21],[22] However, many clinicians prefer once-daily dosing of ISO owing to the concern regarding missing of the second dose on many occasions.[23]

Within 6–8 weeks of initiation of therapy with ISO, rapid improvement is noticeable. However, if dosing is initiated with ≥1 mg/kg/day, anecdotal reports have demonstrated initial flaring up of acne clinically, presenting as multiple deep inflammatory papules and nodules. Although these can be managed without interfering with the completion of ISO therapy, the reduced starting dose of ISO at 0.5 mg/kg/day has been suggested to avert these initial inflammatory flares and has been shown to be highly successful.

On attaining the target cumulative dose of ISO, the likelihood of obtaining a long-term remission is maximized. In patients who experience nuisance side effects with ISO such as xerosis, muscle aches, cheilitis, and dry eyes, a lower dosing schedule with ISO can be adopted with the aim of obtaining the cumulative dose of 120–150 mg/kg, which in this setting may take a longer time to be achieved. However, it would be optimum to administer the complete course of therapy within 20 weeks if possible, without sacrificing the target cumulative dose.

 Alternative Dosing Schedules with Isotretinoin



High-dose schedule with isotretinoin in acne

It has been suggested that using higher daily doses of ISO (>1 mg/kg/day), and obtaining a higher total cumulative dose of ISO than what is recommended, produces a lower risk of acne relapse. Moreover, even when higher dosing of ISO (mean daily dosing of 1.6 mg/kg/day) is utilized, the duration of therapy is not compressed when the standard cumulative dose is achieved but is continued for 5–6 months, obtaining a total cumulative dose of 290 mg/kg at the end of therapy.[24] At this cumulative dose, ISO therapy has been reported to be well tolerated with none of the patients discontinuing treatment.

Blasiak et al.[25] in their study also demonstrated that a cumulative dose of ISO >220 mg/kg was significantly superior to a cumulative dose of ISO <220 mg/kg in terms of relapse. Further, even chances of major adverse effects with ISO were not considered substantial in this setting, thereby providing an added advantage.

Retinoid dermatitis was commonly observed in patients whose cumulative dose was >220 mg/kg. Other effects such as xerosis and cheilitis were also observed. However, none of them warranted the discontinuation of ISO therapy.

Low-dose isotretinoin therapy

Various authors have utilized ISO at a dose lower than the conventional dose for acne vulgaris. Dosages have ranged from 0.14 mg/kg/day to 0.75 mg/kg/day and dispensed either as a daily dose,[26],[27] intermittent schedule,[28],[29],[30] alternate day therapy[31] or gradually increasing the dose.[32]

However, though after an initial course of remission of lesions, in most instances, there occurs a recurrence of acne, with retreatment becoming mandatory. It therefore becomes important to compensate for the lower dose of ISO by extending the course of therapy to optimize the cumulative exposure to ISO over the treatment course.[33]

White et al.[34] have observed that the risk of acne recurrence is eightfold greater in patients treated with a cumulative dose of ISO <100 mg/kg as compared to those receiving a cumulative dose >100 mg/kg. In fact, acne recurrence was documented in 92% of patients treated with a cumulative total ISO dose of <90 mg/kg and in 40%–50% of patients receiving a cumulative dose of ISO ≥110 mg/kg. Further, in their analysis, they also found that of 61% of patients received retreatment for acne, 22.9% required at least one additional course of ISO.

In the study by Stainforth et al.,[35] 69% of patients treated with ISO (0.1 mg/kg/day), over a duration of 16 weeks, had a recurrence of acne. Moreover, in these patients, more than two courses of ISO were required in 88% of the cases when compared to 9.5% in the group receiving 1 mg/kg/day of ISO.

Therefore, it would be prudent to point out that dose adjustments of ISO should only be considered if adverse effects demonstrated by ISO become intolerable. Further, if the dose of ISO is reduced, then the duration of therapy is also prolonged to achieve the cumulative dose, thereby exposing the patient to a more prolonged period in which idiosyncratic adverse reactions may emerge, and in women with childbearing potential, the prolonged duration of therapy could prove disadvantageous as it becomes mandatory to avoid conception for a prolonged time period.

Although low-dose therapy with ISO has been found to control the initial flare of acne, there is an extremely high chance of relapse after cessation of therapy if the cumulative dose is not attained. Therefore, if the short-term gains were to be weighed with long-term control, it becomes very clear that the dosing of 1 mg/kg/day of ISO is definitely more valuable for a long-term success. Another feature of ISO retreatment is that repeated courses are equally effective for a therapeutic response in these acne patients.[36],[37]

Certain conditions where it would be mandatory to give doses of ISO 1 mg/kg/day or even higher based on the high dose protocol to achieve better therapeutic outcomes include:[38]

Family history of acneEarly-onset acneHyperseborrheaTruncal acneAcne scarring tendencyPsychological difficultiesPersistent or late-onset acneMales with acneSinus tractsMacrocomedonesAndrogen excess (e.g., polycystic ovarian syndrome [PCOS]).

Responses to isotretinoin

In general, by 1–2 months, ISO begins to demonstrate its beneficial effects. However, in certain cases, the response may be slow. In these cases, generally, macrocomedones are identified in 70% of cases, although hyperandrogenism may also play an important role with regard to resistance in ISO therapy.[39] In 25% of cases, poor responses to ISO are related to differences in receptor sensitivity, colonization with Staphylococcus aureus, and unusual variants of acne. In the remaining 5% of cases, the cause of poor response to ISO is unknown.[39]

Therefore, it would be imperative for the treating dermatologist to identify macrocomedones prior to starting ISO therapy. In most cases, these macrocomedones are subtle and need to be identified after stretching the skin under suitable light. Their identification is important because if not identified and treated, an acute flare of acne could be precipitated following administration of ISO. These macrocomedones can be treated with light cautery or hyfrecation.[40] The procedure should be initially performed on a test area of 10 cm2 and if no scarring or dyspigmentation occurs, then the procedure can be performed for all lesions.[40]

In cases where an acute flare of acne occurs after ISO therapy due to some other cause, an antibiotic like azithromycin 1 g daily or trimethoprim 200–300 mg Q12H can be used accordingly.[41] If the acne is extremely inflammatory, then a short course of oral corticosteroids may benefit the patient along with oral ISO.

In some patients, the metabolism of ISO may not be as good as others and therefore may require a higher dosing of the drug. Mucocutaneous side effects, particularly cheilitis, usually portray good absorption of the drug. In unusual variants of acne, especially in female patients with PCOS, apart from ISO, additional treatment with hormonal preparations such as cyproterone acetate, ethinylestradiol, and drosiperone may be required.

In cases of relapse, a further course of ISO immensely benefits the patient without the occurrence of tachyphylaxis.

Patient adherence to treatment

As ISO therapy for acne is a chronic one, patient adherence to therapy is mandatory. At times, patients may demonstrate suboptimal adherence like not being able to take ISO with a high-fat (HF)/high-calorie (HC) meal. This comes to a very practical consideration about how feasible would it be to ingest an HF/HC meal with ISO throughout the treatment course as many clinicians feel that the diet advocated is not a very healthy one for such a prolonged duration.[8] Further, if ISO is consumed on an empty stomach, there is a marked reduction in the drug's bioavailability. Moreover, the bioavailability of ISO after consuming meals with low content of fat and calories is not specifically known. Hence, we now come to a question as to what should be the optimum fat and calorie consumption to obtain adequate blood levels of ISO. Well, the answer to this question still remains unanswered. However, it must be stated that if ISO is taken on an empty stomach, there is a substantial reduction in its bioavailability by approximately 60%.[8]

It has been seen that the amount of calories and fat in most diets consumed is markedly lower than the required amount when analyzed with pharmacokinetic study protocols with ISO. Therefore, practically, it may not be possible to be adherent to these specific dietary recommendations elaborated with regard to ISO ingestion. The best possible approach thus would be to consume ISO after meals that are balanced with regard to both macronutrients and micronutrients.

iPLEDGE program

This program was introduced in 2006 and is an FDA-mandated computer-based risk management program providing documented trackable links to prescribers, pharmacists, patients, and manufacturers.[42] All patients who are prescribed ISO are supposed to participate in this program including men, and women who are not of childbearing potential. Women in the childbearing age group are required to obtain a negative pregnancy test before and during ISO therapy at regular intervals, only then they can get access to ISO. The iPLEDGE program requires one negative pregnancy test 30 days before commencing prescription of ISO and another negative pregnancy test during a 7-day window during which time the drug is dispensed to the patient. Thus, two negative pregnancy tests are needed to initiate treatment with ISO. If the drug is not administered in the 7-day window, the patient is locked out and must wait another 12 days to submit a new negative pregnancy test and open a new 7-day window period.

This aspect of the program has been criticized, though, as being an additional burden for the health-care system and disruptive for patient therapy. However, there remains a responsibility on the patient to be adherent to this program.[43]

In addition to requiring pregnancy tests and monitoring prescriptions, iPLEDGE also provides monthly education to the patient regarding:

Not sharing medicationsNot donating bloodVarious forms of birth control

Women with childbearing potential are required to use two forms of contraception recognized on the list provided in the iPLEDGE birth control workbook.[44]

Rosacea

Oral ISO has shown to be effective, particularly in treating papulopustular rosacea, although beneficial properties of ISO have also been seen in erythematotelangiectatic rosacea and phymatous rosacea.[45],[46] In rosacea, ISO reduces cutaneous blood flow and also diminishes the size and number of sebaceous glands in the prefibrotic stage.[47] Apart from facial rosacea, ISO has also been employed in the treatment of extrafacial rosacea (EFR) (excluding ocular rosacea).[48] The most effective dosing for rosacea is 20 mg/day or 0.3 mg/kg/day.

In the study by Uslu et al.,[49] 20 mg of ISO was administered to rosacea patients for 4 months and then gradually tapered over the next 6 months till an end dose of 20 mg/week was obtained. This dosing schedule demonstrated significant improvements within the first month of treatment for both papulopustular lesions and the erythematous component of rosacea.

Similarly, Gollnick et al.[50] also demonstrated favorable effects with 0.3 mg/kg/day of ISO in rosacea over a 12 week period, which was equally effective as doxycycline.

There has also been another dosing schedule for rosacea, using a continuous microdose of ISO (mean of 34.2 mg/week for 33 months) and it has been effective in controlling flare-ups, which can be implemented once the adequate resolution of rosacea has been obtained.[51]

Higher doses of ISO in rosacea (≥0.5 mg/kg/day) usually are associated with dermatitis facialis and therefore should be avoided.

In rare forms of rosacea like rosacea fulminans (pyoderma faciale), ISO forms the primary therapy. Rosen et al.[52] have demonstrated that ISO is the only treatment demonstrating consistent successful results in rosacea fulminans. In this setting prior to initiating therapy with ISO, systemic prednisolone 40–60 mg/day for 2 weeks with the gradual taper is given to the patient followed by the gradual introduction of ISO to the therapeutic regimen at 0.2–0.5 mg/kg/day with the dose gradually being increased to 0.5–1 mg/kg/day. Treatment with ISO is continued for 3–4 months or more till the cumulative dose of 150 mg/kg is attained or till the lesions resolve.[52],[53],[54],[55]

Extrafacial rosacea

Although EFR is difficult to diagnose, there have been multiple cases in the literature.[56],[57],[58] EFR predominantly affects men and involves the photo-exposed parts of the skin. ISO as monotherapy (10–20 mg/day) or in combination with oral glucocorticoids (deflazacort 30 mg for 3 weeks) and azithromycin 500 mg for 3 days/week for 4 weeks has been found to be effective.[48],[56]

Pityriasis rubra pilaris

There have been mixed reports with ISO in PRP. According to Dicken[59] and Allison et al.,[60] ISO can be employed as a first-line therapy for PRP with a higher level of efficacy compared to ultraviolet B (UVB) + tar, topical calcipotriol, keratolytics, azathioprine, methotrexate, and cyclosporine. The dosage employed ranged from 1 to 1.5 mg/kg/day in the study by Dicken,[59] with Allison et al.,[60] employing 20mg/day of ISO in children and 40 mg/day of ISO in adults. This dosing was considered effective. Another study utilizing 0.5 mg/kg/day of ISO in PRP demonstrated complete clearance in 25% of patients with 50% improvement in the remaining 75% of patients.[61] Treatment duration in PRP generally ranges from 16 to 24 weeks, with treatment responses being evident by 14–16 weeks.[62]

Other supportive care like adequate moisturizaton needs to be advocated along with ISO therapy. In erythrodermic PRP, prednisolone 40 mg/day and hospitalization may be required.[63]

Psoriasis

ISO in psoriasis can be considered a therapeutic option in women with childbearing potential who wish to avoid long-term use of contraceptives following acitretin for almost 2–3 years, in view of its shorter half-life. As ISO modulates inflammatory cells and keratinocyte hyperproliferation and differentiation, it has been shown to be of value in psoriasis.[64] ISO probably has been shown to be most effective in managing pustular psoriasis. In children, the dose usually administered is 40 mg/day and in adults, it is 1.5–2 mg/kg/day with an extremely good success rate.[65] Further, on combining ISO with NBUVB, the dose of ISO can be reduce to 0.5 mg/kg/day and has also been found to be equally effective.[66] In plaque-type psoriasis, ISO is generally not very effective.[64]

Hidradenitis suppurativa

In HS, painful deep-seated nodular abscesses develop in the axillary, inguinal, and anogenital regions causing major disability and negatively impacting patients' quality of life.[67] HS is thought to occur secondary to follicular occlusion and dysfunction of apocrine glands.[68] Although ISO has not been included in the treatment guideline of HS, there have been reports supporting the use and efficacy of ISO in HS.

The reasons why ISO can be used in HS include:[6],[7],[69],[70]

HS, like acne is associated with ductal hypercornification and occlusion and ISO reduces ductal obstruction and hypercornificationISO induces sebocyte apoptosisISO helps to moderate the rate of sebum excretionISO modulates apocrine functionISO has immunomodulatory and anti-inflammatory propertiesISO prevents infundibular plugging and reduces sebaceous and apocrine gland functions.

Moreover, there are certain patient characteristics that influence a good therapeutic response with ISO in HS. They include:[71]

Younger ageFemale genderLower body weightPersonal history of acneHurley Grade I and II HS.

Reports following the use of ISO in HS have been mixed. Boer and Van Gemert[72] have used ISO at 0.5–0.8 mg/kg/day for 4–6 months in HS and have reported a complete response in 24% of their patients, with 37% of the patients demonstrating lesser improvement.

Soria et al.[73] studied the effects of ISO in 88 patients of HS who were treated with ISO ranging from 20 to 140 mg/day for a mean treatment period of 7–8 months. Improvement was seen in only 16% of their patients with 77% demonstrating no improvement and in the remaining 7%, the disease rather worsened. Only those patients elucidating Hurley stage I disease of HS demonstrated improvement with ISO.

Generalized granuloma annulare

Generalized GA is characterized by widespread annular papules, plaques, and nodules which are particularly recalcitrant to various treatments. There have been many individual case reports demonstrating ISO to be beneficial in generalized GA.

The dose generally employed is 0.5 mg/kg/day and in those cases where the dermatosis is responsive to ISO, within 2–6 months, remission is noticeable and may persist for 6–12 months post therapy.[74],[75],[76],[77],[78]

It has also been seen in some cases that if an adequate response to ISO is not witnessed at a dose of 0.5 mg/kg/day, then escalating the dose to 1 mg/kg/day may be effective in some cases.[79],[80] In cases where relapses are common, posttreatment with ISO using a low maintenance dose for an additional 3 months to 1 year could be beneficial.[81],[82]

Darier's disease

DD is an autosomal dominant disease clinically affecting the body in a seborrheic distribution pattern. It usually manifests before 30 years of age.[83] In cases where symptoms are particularly severe, a trial of ISO is certainly justified. There have been several case reports demonstrating the promising effects of ISO in DD.[84],[85],[86],[87] Usually, a dose ranging from 0.5 to 1 mg/kg/day is employed. However, many authors advocate a lower initial dose of 0.2 mg/kg/day which can then be gradually escalated as treatment progresses to minimize the side effects associated with ISO. Within a fortnight to 1 month, responses to treatment with ISO become evident.

In some cases, a low maintenance dosing protocol can also be employed.[83]

Although a cumulative dose of 1075 mg/kg of ISO was not associated with skeletal abnormalities as demonstrated by Ling et al.,[88] caution needs to be exercised with regular monitoring when patients are on long-term therapy with ISO.

Cutaneous lupus erythematosus

It has been demonstrated that ISO and acitretin are effective treatment options in those cases of subacute cutaneous lupus erythematosus, discoid lupus erythematosus (DLE), and chronic cutaneous lupus erythematosus (CCLE) that have been unresponsive to conventional treatments.

Vena et al.[89] in a 16-week trial utilizing ISO (0.15 mg/kg/day and then increased to 0.5 mg/kg/day) for cutaneous lupus erythematosus (CLE) demonstrated both clinical improvement and histological improvement in 86.9% of the 24 patients with CLE.

Shornick et al.[90] in their case series of six patients with CCLE demonstrated a rapid response with 1 mg/kg/day of ISO. However, in these patients, the condition relapsed after discontinuation of ISO.

D'Erme et al.[91] in their case report of a 26-year-old woman with refractory CLE to other conventional therapies, a remarkable response was demonstrated using 40 mg/day of ISO.

However, one major drawback of ISO therapy for CLE is a rapid and more severe recurrence after cessation of therapy. This can be tackled by a low maintenance dose of ISO.[92] Other disadvantages of ISO include its expense and its contraindication in those cases of CLE with Sjogren's syndrome owing to the presence of keratoconjunctivitis sicca.

Nevertheless, retinoid therapy has shown to be of value is CLE. Dosages usually range from 0.2–1 mg/kg/day, with responses being evident by 2–6 weeks.

Condylomata accuminata

ISO has been employed in CA both as monotherapy and also in combination with interferon (IFN) α. ISO prompts regression of CA based on its immunomodulatory properties. Details of studies on ISO monotherapy and in combination with IFN-α for CA are depicted in [Table 2] and [Table 3], respectively.{Table 2}{Table 3}

It has been shown that IFN-α is best used as an adjunct to Other modalities of therapy including 5-Fluorouracil (5-FU), laser ablation and surgical excision, and its combined utility has led to lower recurrence rates.

Till date, there are very few studies demonstrating the efficacy of combining IFN-α and ISO for CA, following traditional destructive therapies. This could be a valuable zone of exploration in the near future.

Disseminate and recurrent infundibulofolliculitis

It is a clinical condition characterized clinically by hundreds of skin-colored follicular papules resembling goose bumps. It may last for months to years and may be pruritic. ISO (0.5 mg/kg/day) for 16 weeks has been tried, but evidence for the efficacy of ISO is anecdotal.

Acanthosis nigricans

AN is a cutaneous finding that is usually associated with an underlying endocrinopathy or may even be idiopathic and is characterized by dark, coarse, thickened, and velvety skin. Katz[98] has reported ISO to be effective as monotherapy for AN. His patient was a 33-year-old woman who had AN over the groins, axilla, antecubital fossa, angles of the mouth, dorsa of the hands, and inferior segments of the mouth, dorsa of the hands, and inferior segments of the breast and neck. She was started with 0.5mg/kg/day of ISO, but as all lesions did not respond, weekly increments by 0.5 mg/kg/day were done till a maximum dose of 3 mg/kg/day was administered. This dose enabled the resolution of AN. However, owing to hypertriglyceridemia and mucocutaneous side effects of ISO, the dose was reduced to 2 mg/kg/day and after 16 weeks of therapy owing to complete resolution of lesions, the drug was discontinued. However, after 2 months of cessation of ISO, there was a relapse to the level of pretreatment severity. The patient was then started with a maintenance dosing of 2 mg/kg/day with a good clinical response and minimal side effects.

Walling et al.[99] have used ISO along with metformin for AN. In this way, the dose of ISO could be reduced, thereby obtaining the best aspects of both the drugs for treating AN and minimizing drug toxicities.

Lichen planus

Handler[100] has employed ISO for treating both oral and cutaneous LP. The dose given here was 0.25 mg/kg/day to begin with and did not exceed more than 20 mg/day. The duration of treatment lasted not more than 2 months. The results obtained were good to excellent without relapses.

Systemic ISO at a dose of 0.5 mg/kg/day has also been reported to be effective in severe LP involving the oral mucosa and skin, witnessed in two patients as reported by Woo.[101]

However, Camisa and Allen[102] did not witness promising effects with ISO in oral erosive LP. In their series of six patients with ISO doses at 10–60 mg daily for 8 weeks, the improvement witnessed was slight with a relapse to the pretreatment status after 2 months of treatment cessation. Further, owing to side effects experienced, patients declined re-treatment with ISO.

Photoaging

Although topical tretinoin is generally accepted as a cosmetically beneficial medication for photo-damaged skin, oral ISO is not.

However, Perez et al.[103] have demonstrated a significant cosmetic improvement with ISO administered at 10–20 mg 3 times a week over 2 months along with rejuvenation cosmetic procedures when compared to using both treatments individually. The parameters that demonstrated improvement included:

WrinklesSkin color and thicknessSkin elasticityPore sizeReduction of mottled pigmentation.

Similarly, the above findings were reiterated by Rabello-Fonseca et al.[104]

 Precancerous Cutaneous Conditions



Actinic keratosis

ISO 20 mg/day combined with topical 5-FU helps in drastically reducing the number of existing lesions of actinic keratosis and at the same time preventing new lesion development. Further, beneficial effects on the repair of photodamaged skin are also noticeable.[105]

This combination is particularly beneficial in patients where the level of actinic damage is severe and where 5-FU alone may not be sufficient. It has been further demonstrated that this combination enhances cell apoptosis and inhibits oral squamous cell carcinoma line proliferation significantly.[106]

Leukoplakia

Clinical improvement of leukoplakia has been reported with ISO (1–2 mg/kg/day) used for 3 months. However, after cessation of treatment, a high relapse rate has been reported by Hong et al.[107]

Another study demonstrated the advantage of ISO (first at 1.5 mg/kg/day for 3 months followed by a lower maintenance dose of 0.5 mg/kg/day for 9 months) with dose adjustments to achieve better relapse-free states in oral carcinogenesis.[108]

Topical ISO (0.18%) cream has also been utilized for leukoplakia with success.[109]

However, despite short-term effectiveness, retinoids do not prevent recurrences of lesions and there may not be a significant increase of cancer-free survival.

Cutaneous malignancies

Cutaneous T-cell lymphoma

Duvic et al.[110] who combined ISO (1 mg/kg/day) along with IFN-α have demonstrated an 82% response in patients with Stage I and Stage II cutaneous T cell lymphoma.

Squamous cell carcinoma

The combination of ISO and IFN-α has also proven valuable in squamous cell carcinoma (SCC) of the skin, with success rates ranging from 17% to 68%.[111],[112]

Another study employing ISO (1 mg/kg/day) in combination with daily radiotherapy also reported a rapid reduction in tumor size.[113]

Thus, ISO can be a valid adjunct to other therapeutic modalities in advanced SCC.

Chemoprevention in high-risk populations

Xeroderma pigmentosum

Kraemer et al.[114] have demonstrated the benefits of ISO in preventing skin cancer in xeroderma pigmentosum. The dose of ISO administered by them was 2 mg/kg/day initially followed by a reduction of 0.5–1 mg/kg/day.

Muir–Torre syndrome

ISO (50 mg/day) along with IFN-α-2a (3 × 106 U s/c) three times a week along with topical ISO demonstrated marked tumor regression.[115]

Resistant dermatophytosis

ISO (20 mg/day) in combination with itraconazole (200 mg/day) along with topical sertaconazole for 1 month has demonstrated to be effective in a 23-year-old man with RD secondary to Trichophyton rubrum. The patient remained in remission even after 6 months of follow-up.[116]

Erythema dyschromicum perstans

EDP is a disorder of pigmentation characterized by asymptomatic, symmetrically distributed ashy gray patches. There have been a number of treatments for EDP with minimal success. Wang et al.[117] have demonstrated the beneficial effects of ISO in EDP. In their case report of a 41-year-old patient with EDP, ISO was started at a dose of 20 mg/day for 4 months following which there was a 90% improvement of the condition. However, when the treatment was stopped, there was a relapse. Owing to this, the patient was once again started on ISO but at a lower dose of 10 mg on an intermittent basis which the patient consumed for almost 7 years. During this period, apart from dryness of the face, no other adverse effect was encountered, thereby suggesting that long-term, low-dose systemic treatment with ISO is effective and safe for EDP. The possible mechanism of ISO here could be based on its anti-inflammatory and immunomodulatory properties.

Other conditions

Certain anecdotal reports of the beneficial properties of ISO have been seen in Kyrle's disease, ulerythema ophryogenes, Ofuji's disease, and scleromyxedema.[118],[119],[120],[121]

 Adverse Effects



Cutaneous

Acne flareXerosisRetinoid dermatitisSkin fragilityS. aureus infectionPyogenic granulomaStickiness of palms and solesUrticariaVasculitis.

Mucosal

CheilitisSoreness of mouth and tongueEpistaxisDryness of the nose and mouth.

Hair

Telogen effluviumAbnormal hair structure.

Nails

OnycholysisParonychiaNail softening.

Ocular

Dry eyesBlepheroconjunctivitisPhotophobiaPterygium.

Bone

Diffuse idiopathic skeletal hyperostosisOsteoporosis.

Gastrointestinal

NauseaDiarrhoeaAbdominal pain.

Neurologic

DepressionMild headacheSuicidal ideation.

Musculoskeletal

ArthralgiaMyalgiaAchilles tendonitis.

Metabolic

Elevated hepatic transaminasesHypercholesterolemiaHypertriglyceridemia.

Retinoid embryopathy

Craniofacial – microcephaly, cleft palate, microphthalmia, and facial asymmetryCentral nervous system – hydrocephalus, cortical agenesis, and mental retardationCardiovascular – Fallot's tetrology, hypoplastic aorta, Transposition of great vesselsOthers – limb abnormalities and anal and vaginal atresia.

 Drug Interactions



Tetracyclines

Increased risk of pseudotumor cerebri with concomitant ISO administrationSymptoms of pseudotumor cerebri include visual disturbances, visual loss, headache, nausea, vomiting, and papilledemaSymptoms tend to resolve when treatment is discontinued.[122]

Vitamin A

Co-administration with ISO results in hypervitaminosisSymptoms include gum inflammation, vertigo, pruritus and dry, and scaly skinThis combination is therefore best avoided.

Teriflunomide

Associated risk of hepatotoxicity with ISO.

Methotrexate

Associated risk of hepatotoxicity with ISO.

Carbamazepine

When concurrently administered with ISO, the level of carbamazepine in the plasma reduces and should be carefully monitored.[123]

Indomethacin

Displaces ISO from albumin, resulting in increased unbound concentration of ISO.[124]

 Monitoring Guidelines



Baseline

Urine pregnancy test (particularly two tests to be done as described in the iPLEDGE section)Liver function testsFasting lipid profileX-ray of the ankles, wrist, and spine in case of long-term therapy.

Once every two monthly

Hepatic and lipid profile.[124]

 Conclusion



Through this discussion, the versatility of ISO can be clearly visualized. Apart from being indispensable for managing nodulocystic acne, ISO has proven to be of value in a number of other dermatologic conditions. Like any other drug, ISO is also associated with a toxicity profile. Therefore, it is mandatory for all clinicians to be adherent to monitoring guidelines whenever a patient is prescribed ISO.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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