ISOTRETINOIN IN ACNE

Presented by:- Dr Rekha Sirvi

Chronic inflammatory disease of the pilosebaceous units, Characterized by Seborrhoea, Formation of comedones, Erythematous papules & pustules, Less frequently Nodules,Deep pustules or pseudocysts.

Aetiology:-• Seborrhoea• Comedone formation• Colonization of the duct with P. acnes• Inflammation

TreatmentoTopical treatment- for mild acneoBenzoyl peroxide- 2.5%, 5% and 10%oTopical antibiotics- tetracycline, erythromycin and clindamycin- 1-4% cr/looRetinoic acid (1st gen.) – 0.01-0.05% gel /croIsotretinoin (2nd gen.)-0.025%-0.05%oAdapalene (3rd gen.)-0.1%oTazarotene (4th gen.)

ORAL THERAPYAntibiotics oTetracyclines – tetracycline(1g/day),, doxycycline(100mg/day), minocycline(100mg/day) and azithromycin(500 mg / day)oDuring pregnancy & lactation- erythromycin oOral therapy- in moderate and moderate/severe acneoOral therapy should be given in combination with topical therapy

Hormonal treatmentso Inhibitors of adrenal androgen production:-

Low-dose glucocorticoids, prednisolone 2.5–5 mg/day at bedtime.

o Inhibition of ovarian androgen production:-Gonadotrophin releasing agonists

Oral isotretinoinoIsotretinoin (13-cis-retinoic acid) is a derivative

of retinol (vitamin A).oThe first retinoid to be synthesized, in 1955,

was isotretinoin & used for disorder of keratinization.oIsotretinoin first approved by the US Food and Drug Administration (FDA) in 1982 for the treatment of severe recalcitrant nodulocystic acneoIt is only oral retinoid known to have a profound effect on sebaceous gland activity & addresses all pathogenic mechanismso A dose of 0.5–1.0 mg/kg/day dramatically reduces sebum excretion by the order of 90% within 6 weeks.

MACHANISM OF ACTIONoIsotretinoin has little or no ability to bind to cellular retinol-binding proteins or retinoic acid nuclear receptors (RARs and RXRs) but act as a pro-drug that is converted intracellularly to metabolites that are agonists for RAR and RXR nuclear receptorsoAtiandrogenic through competitive inhibition of 3-alpha-hydroxysteroid oxidation by retinol dehydrogenase resulting in reduced formation of dihydrotestosterone and androstenedione

oIt normalizes ductal hypercornification, and generally thins the epidermis to produce increased light reflectance – Retinoid glow –oIsotretinoin is the most comedolytic of all antiacne agents.It indirectly lowers P. acnes counts, and exerts an anti-inflammatory effectoIsotretinoin-induced clinical improvement is associated with lowered levels of porphyrins in the sebaceous follicles and reduced concentrations of MMPs in the sebum

Immunoregulatory effects of isotretinoin in patients with acne.Karadag AS, Ertugrul DT, Bilgili SG, Takci Z, Akin KO, Calka O.

Source

Department of Dermatology, Yuzuncu yil University, Faculty of Medicine, Van, Turkey

Abstract

BACKGROUND:

In vitro studies have shown that retinoids influence T-cell differentiation.

OBJECTIVES:

To study the effect of isotretinoin on T-cell differentiation markers in patients with acne.

METHODS:

A total of 37 patients with acne vulgaris (25 female, 12 male, age 19.6 ± 3.7 years) and 30 age- and sex-matched healthy controls (19 female, 11 male, age 20.5 ± 4.4 years) were included in the study. Screening for biochemical parameters in serum samples were done just before initiation (pretreatment) and after 3 months of isotretinoin treatment (post-treatment) in the acne group.

CONCLUSIONS:

This study shows that isotretinoin treatment significantly decreases TNF, IL-4, IL-17 and IFN-γ levels in patients with acne. We failed to show that isotretinoin redirects naive T helper (Th) differentiation preferentially towards the Th2 cell lineage.

Br J Dermatol. 2012 Aug;167(2):433-5.

Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients.Dispenza MC, Wolpert EB, Gilliland KL, Dai JP, Cong Z, Nelson AM, Thiboutot DM.

SourceDepartment of Dermatology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.AbstractIsotretinoin is a pro-drug for all-trans retinoic acid, which can induce long-term remissions of acne; however, its complete mechanism of action is unknown.Compared with normal subjects, peripheral blood monocytes from acne patients expressed significantly higher levels of Toll-like receptor 2 (TLR-2) and exhibited significantly greater induction of TLR-2 expression following P. acnes stimulation. Treatment of patients with isotretinoin significantly decreased monocyte TLR-2 expression and subsequent inflammatory cytokine response to P. acnes after 1 week of therapy. This effect was sustained 6 months following cessation of therapy, indicating that TLR-2 modulation may be involved in the durable therapeutic response to isotretinoin. This study demonstrates that isotretinoin exerts immunomodulatory effects in patients and sheds light on a potential mechanism for its long-term effects on acne.

J Invest Dermatol. 2012 Sep;132(9):2198-205.

INDICATIONoNodulocystic acneo Fulminant acneoAcne corporiso Difficult/recalcitrant acneo Moderate acne if scarring is imminento Acne associated with psychologic distress

PRECAUTION oIsotretinoin should only be used by experts those who know acne well and are well versed with all aspects of the drugoWomen of childbearing age

• Should have two negative pregnancy tests before their initial prescription,show proof of another negative pregnancy test before & each monthly repeat prescription• Use two forms of contraception throughout therapy and

for 30 days after treatment • They must enter these forms of contraception into the

registry

oLiver enzymes and lipids should be checked before treatment and 1 month after the maximum dosage has been usedoChemical and physical peeling should be avoided during treatment and for 6 months afterwards and that wax depilation should be avoided during and 6 weeks post-therapy

SOME DO’S AND DON’TS by patients• Isotretinoin should be taken after proper meals.• Isotretinoin should not be shared with friends.• Threading, waxing, strenuous work-outs, andcontact sports should be avoided in the latter partof the treatment.• Excessive alcohol consumption and fatteningfoods should be avoided.• Blood donation should be avoided while ontreatment and for one month after stoppingtherapy.

DOSINGINGoThe dose of isotretinoin is 0.5–1.0 mg/kg body weight, in two divided doses given after meals. Isotretinoin absorption is only 20% in fasted state versus 40% in the fed state.oThe treatment is continued till a cumulative dose of 120 mg/kg has been achieved.oThis typically may take 6–8 months.

ORAL ISOTRETINOIN: DIFFERENT REGIMENS

Standard dosing 0.5–1.0 mg/kg daily in two divided doses

Pulse dosing 0.5 mg/kg/day for seven days each month

Low dosing 0.1–0.2 mg/kg daily for 6–12 months

Escalating dosing

20 mg o.d. x 1 month introductory dose increasedin monthly steps to reach standard dosing

Intermittent dosing

Fifteen days treatment period alternating with 15 days ofno treatment; not used in acne

Adverse effect

Dermatology. 1997;194(4):351-7.

Oral Isotretinoin (Roaccutane) treatment guidelines: results of an international survey.

Cunliffe WJ, van de Kerkhof PC, Caputo R, Cavicchini S, Cooper A, Fyrand OL, Gollnick H, Layton AM, Leyden JJ, Mascaró JM, Ortonne JP, Shalita A.

Abstract

BACKGROUND:

Oral isotretinoin (Roaccutane) revolutionized the treatment of acne when it was introduced in 1982.

METHODS:

Twelve dermatologists from several countries with a special interest in acne treatment met to formally review the survey of their last 100 acne patients treated with oral isotretinoin. The primary purpose of the survey was to identify the types of acne patients who were prescribed oral isotretinoin and how the patients were managed.

RESULTS:

Of the 1,000 patients reviewed, 55% of those who received oral isotretinoin had those indications treated historically, i.e. severe nodular cystic acne or severe inflammatory acne, not responding to conventional treatment. Forty-five percent of patients who were prescribed oral isotretinoin however had either moderate or mild acne. Most patients in this group had moderate acne (85%). However, 7.3% had mild acne on physical examination. The criteria for prescribing oral isotretinoin in this less severe group of patients included acne that improves < 50% after 6 months of conventional oral antibiotic and topical combination therapy, acne that scars, acne that induces psychological distress and acne that significantly relapses during or quickly after conventional therapy. Treatment is usually initiated at daily doses of 0.5 mg/kg (but may be higher) and is increased to 1.0 mg/kg. Most of the physicians aimed to achieve a cumulative dose of > 100-120 mg/kg. Significant cost savings when treating acne patients with oral isotretinoin as compared to other treatment modalities were further proven in this study.

CONCLUSIONS:

Our recommendation is that oral isotretinoin should be prescribed not only to patients with severe disease but also to patients with less severe acne, especially if there is scarring and significant psychological stress associated with their disease. Acne patients should, where appropriate, be prescribed isotretinoin sooner rather than later.

Dermatology. 1997;195 Suppl 1:29-33

Oral isotretinoin. How can we treat difficult acne patientSourceDepartment of Dermatology, University of Pennsylvania, Philadelphia 19104, USA.AbstractIsotretinoin therapy (120 mg/kg) normally results in complete clearing of nodulocystic acne followed by prolonged remission, and many patients remain free of disease. Four groups of patients respond poorly or have a high rate of relapse. Preteens and young teenagers show a high rate of relapse and several courses of treatment are usually needed; 14 of 20 under the age of 12 years, 21 of 47 aged 12-14 and 23 of 66 aged 14-16 relapsed within 1 year. Individuals with linear lesions consisting of undermining tracks of follicular epithelium often show only a partial response. These individuals typically have a history of other 'sinus track' disease such as pilonidial sinus and hidradenitis, either themselves or other family members

Australas J Dermatol. 2003 May;44(2):97-105.

Treatment of acne with isotretinoin: recommendations based on Australian experience.Cooper AJ; Australian Roaccutane Advisory Board.SourceRoyal North Shore Hospital, Pacific Highway, St Leonards, New South Wales, Australia. acooper@med.usyd.edu.auAbstractOral isotretinoin revolutionized acne treatment when it was introduced in 1982 in the USA. However, its use was restricted to patients with severe nodulocystic acne. Today its use worldwide has expanded to treat also patients with less severe but scarring acne who are responding unsatisfactorily to conventional therapies. These recommendations assess the potential for use of oral isotretinoin as a safe and effective treatment for severe nodulocystic acne unresponsive to conventional therapy, and acne of any severity that causes scarring or is associated with psychological distress.

J Eur Acad Dermatol Venereol. 2006 Nov;20(10):1256-60.

The effectiveness of intermittent isotretinoin treatment in mild or moderate acne.Kaymak Y, Ilter N.SourceUniversity of Gazi Health Center, Department of Dermatology, Faculty of Medicine, Ankara, Turkey.AbstractBACKGROUND:Isotretinoin is the only drug that affects almost all factors in acne pathogenesis. Recently, its use for the treatment of chronic mild or moderate acne unresponsive to long-term antibiotic therapy, and with a tendency to cause scarring and leading to negative psychological effects, has became popular. The aim of the study was to investigate the effectiveness of intermittent isotretinoin treatment in mild or moderate acne.METHODS:Sixty patients with mild or moderate acne localized to the face were enrolled in the study. The treatment regimen consisted of isotretinoin, 0.5-0.75 mg/kg per day, applied for 1 week every 4 weeks for a total period of 6 months, according to the degree of acne and number of inflammatory lesions.RESULTS:Forty-one (68.3%) of the 60 patients completed the 6-month therapy. At the end of the treatment complete improvement was observed in 34 patients (82.9%) out of 41. All adverse effects were mild and discontinuation of the treatment was not necessary.CONCLUSION:Intermittent isotretinoin treatment was found to be a safe and effective choice for patients with mild or moderate acne.

J Am Acad Dermatol. 2006 Apr;54(4):644-6.

Low-dose isotretinoin in the treatment of acne vulgaris.Amichai B, Shemer A, Grunwald MH.SourceHuzot Clinic of Clalit Health Services, Ashkelon, Israel.AbstractBACKGROUND:The efficacy of isotretinoin at 0.5 to 1.0 mg/kg per day in the treatment of acne is well established and considered safe, although it is sometimes not easily tolerated because of its cutaneous side effects.OBJECTIVE:The purpose of this study was to determine the efficacy of low-dose isotretinoin in the treatment of acne.METHODS:In this prospective, noncomparative, open-label study, 638 patients, both male and female, with moderate acne were enrolled and treated with isotretinoin at 20 mg/d (approximately 0.3-0.4 mg/kg per day) for 6 months. The patients were divided into two age groups: 12 to 20 and 21 to 35 years old. Patients were evaluated at 2-month intervals by means of clinical and laboratory examinations. A 4-year follow-up was also carried out.RESULTS:At the end of the treatment phase, good results were observed in 94.8% of the patients aged 12 to 20 years, and in 92.6% of the patients aged 21 to 35 years. Failure of the treatment occurred in 5.2% and 7.4% of the two groups, respectively. Twenty-one patients dropped out of the study because of lack of compliance, and another patient discontinued participation because of a laboratory side effect. During the 4-year follow-up period, relapses of the acne occurred in 3.9% of the patients aged 12 to 20 years and in 5.9% of the patients aged 21 to 35 years. Elevated serum lipid levels (up to 20% higher than the upper limit of normal value) were found in 4.2% of the patients and abnormal (<twice the upper limit of normal values) liver tests were observed in 4.8%.LIMITATIONS:This was a noncomparative, open-label study.CONCLUSION:Six months of treatment with low-dose isotretinoin (20 mg/d) was found to be effective in the treatment of moderate acne, with a low incidence of severe side effects and at a lower cost than higher doses.

J Drugs Dermatol. 2006 Oct;5(9):878-82.

Oral isotretinoin for acne, adjusting treatment according to patient's response.Ghaffarpour G, Mazloomi S, Soltani-Arabshahi R, Seyed KS.SourceDepartment of Dermatology, Hazrat-e Rasool University Hospital, Iran University of Medical Sciences, Tehran, Iran.AbstractBACKGROUND:Oral isotretinoin is an established effective therapy for acne. No published data is available on the efficacy and side effects of this drug in Iranian patients.PATIENTS AND METHODS:A total of 132 acne patients with a mean age of 22.9 +/- 6.2 years were treated with oral isotretinoin (Roaccutane) and followed-up from 1999 through 2005. Each patient was started with a dose of 0.75 mg/kg per day until all active lesions healed, followed by a maintenance dose of 20 mg/kg per day for one more month. Laboratory tests were done at monthly intervals. Evaluation of clinical response was based on Leeds technique. Patients were followed-up for a mean period of 4.4 years.RESULTS:Most of the patients had severe nodulocystic acne involving both trunk and face. Treatment was continued for 6.6 +/- 2.5 months with a cumulative dose of 111.5 mg/kg +/- 33.9. The mean final improvement rate was 96.7% (95% CI, 84.9% to 108.5%). There was no correlation between improvement rate and age, sex, duration of acne, length of treatment, or cumulative dose. Side effects were generally mild and treated conservatively. In the follow-up, period 18.35% experienced relapse after a mean interval of 1.28 years, 9.17% required a second course of isotretinoin, and only one case needed 3 courses of treatment.CONCLUSION:Isotretinoin is an effective and safe treatment for acne in Iranian patients. Starting treatment with a high dose and modifying the length of treatment based on the therapeutic response in each patient, might lead to a rapid and good response rate with minimal side effects.

Indian J Dermatol Venereol Leprol. 2011 Nov-Dec;77(6):688-94.

Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial.Agarwal US, Besarwal RK, Bhola K.SourceDepartment of Dermatology, SMS Medical College and Hospital, Jaipur, Rajasthan, India. dr.usag@gmail.comAbstractBACKGROUND:Oral isotretinoin is recommended for severe nodulocystic acne in the doses of 1-2 mg/kg/day which is usually associated with higher incidence of adverse effects. To reduce the incidence of side-effects and to make it more cost-effective, the lower dose regimen of isotretinoin has been used.AIM:To compare the efficacy and tolerability of oral isotretinoin in daily, alternate, pulse and low-dose regimens in acne of all types and also to assess whether it can be used for mild and moderate acne also.METHODS:One hundred and twenty patients with acne were randomized into four different treatment regimens each consisting of 30 patients. Group A was prescribed isotretinoin 1 mg/kg/day, Group B 1 mg/kg alternate day, Group C 1 mg/kg/day for one week/four weeks and Group D 20 mg every alternate day for 16 weeks. Patients were further followed for eight weeks to see any relapse. Side-effects were also recorded.RESULTS:Though the daily high dose treatment Group A performed better initially at eight weeks, at the end of therapy at 16 weeks results were comparable in Group A , B and D. Patients with severe acne did better in Group A than in Group B, C and D. Patients with mild acne had almost similar results in all the groups while patients with moderate acne did better in Group A, B and D. Frequency and severity of treatment-related side-effects were significantly higher in treatment Group A as compared to Group B, C and D.CONCLUSION:We conclude that for severe acne either conventional high doses of isotretinoin may be used or we can give conventional high dose for initial eight weeks and later maintain on low doses. Use of isotretinoin should be considered in mild to moderate acne also, in low doses; 20 mg, alternate day seems to be an effective and safe treatment option in such cases

Br J Dermatol. 2011 Jun;164(6):1369-75.

Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study.Lee JW, Yoo KH, Park KY, Han TY, Li K, Seo SJ, Hong CK.SourceDepartment of Dermatology, Chung-Ang University Hospital, Dongjak-Gu, Seoul 156-755, Korea.AbstractBACKGROUND:The efficacy of conventional isotretinoin treatment (0·5-1·0 mg kg⁻¹ daily for 16-32 weeks, reaching a cumulative dose of 120 mg kg⁻¹) for acne has been well established. To date, there are many reports regarding the efficacy of low-dose and intermittent isotretinoin treatment in patients with acne. Data comparing these three therapeutic regimens simultaneously, however, are unavailable.OBJECTIVES:To evaluate the clinical efficacy and tolerability of low-dose and intermittent isotretinoin regimens and to compare them directly with conventional isotretinoin treatment.METHODS:In this study, 60 patients with moderate acne were enrolled and randomized to receive either isotretinoin at 0·5-0·7 mg kg⁻¹ daily (group A), isotretinoin at 0·25-0·4 mg kg⁻¹ daily (group B) or isotretinoin at 0·5-0·7 mg kg⁻¹ daily for 1 week out of every 4 weeks (group C). The total period of drug administration was 6 weeks in group C, and 24 weeks in groups A and B. Evaluations included global acne grading system (GAGS) scores, lesion counts (inflammatory and noninflammatory), patient satisfaction and side-effects. A 1-year follow-up evaluation after the end of treatment was also performed.RESULTS:Differences in GAGS scores were statistically significant between groups A and C (P < 0·001) and groups B and C (P = 0·044). There was no significant difference between groups A and B. For the number of inflammatory lesions, there were statistically significant differences between groups B and C (P = 0·048) and groups C and A (P = 0·005). There was no significant difference between groups A and B. For the number of noninflammatory lesions, there were statistically significant differences between groups B and C (P = 0·046) and groups C and A (P=0·006). There was no significant difference between groups A and B. These results suggest that the conventional and low-dose regimens have similar efficacy. Intermittent treatment had less effect than either conventional or low-dose treatmentsCONCLUSIONS:

Our study suggests that, when considering tolerability, efficacy and patient satisfaction, low-dose treatment is most suitable for patients with moderate acne.

Clin Dermatol. 2010 Jan-Feb;28(1):24-30.

.The role of isotretinoin in acne therapy: why not as first-line therapy? facts and controversies.Rigopoulos D, Larios G, Katsambas AD.SourceDepartment of Dermatology, University of Athens, Andreas Sygros Hospital, 5 Ionos Dragoumi St, 16121 Athens, Greece. drigop@hol.grAbstractAcne is one of the most prevalent diseases in dermatology: Millions of people worldwide experience this distressing condition. To determine the appropriate therapeutic strategy, there is a strong need for a standardized classification system of acne. The exact molecular mechanism of action of isotretinoin is not completely understood; however, oral isotretinoin targets simultaneously at all major mechanisms of acne pathogenesis. Various mass media reports about the risk of teratogenicity and depression from isotretinoin usage as well as the creation of intense prevention programs have created an obstacle to the use of the most active available drug against acne, presenting isotretinoin as a very dangerous regimen. According to recommendations of several international experts, which we share, oral isotretinoin may be prescribed not only to patients with severe disease but indications should be broadened to also include patients with less severe forms of acne, especially in cases with scarring, significant psychologic stress, or failure to respond to conventional therapy.

Int J Dermatol. 2012 Sep;51(9):1123-30.

High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life.Cyrulnik AA, Viola KV, Gewirtzman AJ, Cohen SR.SourceDepartment of Dermatology, Albert Einstein College of Medicine, New York, NY 10467, USA.AbstractBACKGROUND:Isotretinoin, for acne treatment, is associated with high rates of permanent remission. However, at recommended doses of 0.5-1.0 mg/kg/day for 5-6 months [average cumulative dose: 120-150 mg/kg], more than 20% of patients experience a relapse within two years that requires further medical management.OBJECTIVE:To examine outcomes of high-dose isotretinoin in a cohort with cystic acne, as well as measuring its impact on quality of life (QOL).METHODS:A single dermatologist, single institution investigation within an academic tertiary care center in Bronx, NY. Eighty patients with nodulocystic acne, maintained on oral isotretinoin at a dose of 1.3 mg/kg/day or greater, were studied from 2006-2009 while additionally participating in a QOL survey. Main outcome measures included documented events, acne clearance, presence of relapse, and quality of life parameters.RESULTS:The mean daily dose of isotretinoin was 1.6 mg/kg/day for an average time course of 178 days [cumulative dose: 290 mg/kg]. No side effects or laboratory abnormalities led to discontinuation of treatment. There were no psychiatric symptoms. One-hundred percent (100%) of patients were disease-free upon completion of treatment. During the three-year study period, 10 patients (12.5%) developed a relapse that required an additional course of isotretinoin. Analysis of QOL domains (self-perception, role-social, symptoms) revealed significant improvement following isotretinoin therapy (p = 0.0124, p = 0.0066, p = 0.0265, respectively).CONCLUSIONS:Isotretinoin prescribed at 1.5 mg/kg/day or greater for 5-6 months [cumulative total dose of 290 mg/kg] is safe and effective compared to current standard dosing practices. We propose the use of high-dose isotretinoin (>1.3 mg/kg/day) as a treatment option in severe nodulocystic acne and encourage larger, prospective, multicenter studies into this therapeutic approach.

THANKS