Published on February 19, 2014
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 •
Treatment oTopical oBenzoyl treatment- for mild acne peroxide- 2.5%, 5% and 10% oTopical antibiotics- tetracycline, erythromycin and clindamycin- 1-4% cr/lo oRetinoic acid (1st gen.) – 0.01-0.05% gel /cr oIsotretinoin (2nd gen.)-0.025%-0.05% oAdapalene (3rd gen.)-0.1% oTazarotene (4th gen.)
ORAL THERAPY Antibiotics 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 acne oOral therapy should be given in combination with topical therapy
Hormonal treatments o 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 isotretinoin oIsotretinoin (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 acne oIt is only oral retinoid known to have a profound effect on sebaceous gland activity & addresses all pathogenic mechanisms o A dose of 0.5–1.0 mg/kg/day dramatically reduces sebum excretion by the order of 90% within 6 weeks.
MACHANISM OF ACTION oIsotretinoin 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 receptors oAtiandrogenic through competitive inhibition of 3alpha-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 effect oIsotretinoin-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. Source Department of Dermatology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA. Abstract Isotretinoin is a pro-drug for all-trans retinoic acid, which can induce longterm 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 (TLR2) 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.
INDICATION oNodulocystic acne o Fulminant acne oAcne corporis o Difficult/recalcitrant acne o Moderate acne if scarring is imminent o 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 drug oWomen 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 used oChemical 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, and contact sports should be avoided in the latter part of the treatment. • Excessive alcohol consumption and fattening foods should be avoided. • Blood donation should be avoided while on treatment and for one month after stopping therapy.
DOSINGING oThe 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 Low dosing Escalating dosing Intermittent dosing 0.5 mg/kg/day for seven days each month 0.1–0.2 mg/kg daily for 6–12 months 20 mg o.d. x 1 month introductory dose increased in monthly steps to reach standard dosing Fifteen days treatment period alternating with 15 days of no treatment; not used in acne
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;194(4):351-7 .
Oral isotretinoin. How can we treat difficult acne patient Source Department of Dermatology, University of Pennsylvania, Philadelphia 19104, USA. Abstract Isotretinoin 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 1416 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 Dermatology. 1997;195 Suppl 1:29-33
Treatment of acne with isotretinoin: recommendations based on Australian experience. Cooper AJ; Australian Roaccutane Advisory Board. Source Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales, Australia. firstname.lastname@example.org Abstract Oral 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. Australas J Dermatol. 2003 May;44(2):97-105.
The effectiveness of intermittent isotretinoin treatment in mild or moderate acne. Kaymak Y, Ilter N. Source University of Gazi Health Center, Department of Dermatology, Faculty of Medicine, Ankara, Turkey. Abstract BACKGROUND: 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 Eur Acad Dermatol Venereol. 2006 Nov;20(10):1256-60.
Low-dose isotretinoin in the treatment of acne vulgaris. Amichai B, Shemer A, Grunwald MH. Source Huzot Clinic of Clalit Health Services, Ashkelon, Israel. Abstract BACKGROUND: 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 Am Acad Dermatol. 2006 Apr;54(4):644-6.
Oral isotretinoin for acne, adjusting treatment according to patient's response. Ghaffarpour G, Mazloomi S, Soltani-Arabshahi R, Seyed KS. Source Department of Dermatology, Hazrat-e Rasool University Hospital, Iran University of Medical Sciences, Tehran, Iran. Abstract BACKGROUND: 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. J Drugs Dermatol. 2006 Oct;5(9):878-82.
Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial. Agarwal US, Besarwal RK, Bhola K. Source Department of Dermatology, SMS Medical College and Hospital, Jaipur, Rajasthan, India. email@example.com Abstract BACKGROUND: 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 Indian J Dermatol Venereol Leprol. 2011 Nov-Dec;77(6):688-94.
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. Source Department of Dermatology, Chung-Ang University Hospital, Dongjak-Gu, Seoul 156-755, Korea. Abstract BACKGROUND: 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 sideeffects. 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 treatments CONCLUSIONS: Our study suggests that, when considering tolerability, efficacy and patient satisfaction, low-dose treatment is most suitable for patients with moderate acne. Br J Dermatol. 2011 Jun;164(6):1369-75.
. The role of isotretinoin in acne therapy: why not as first-line therapy? facts and controversies. Rigopoulos D, Larios G, Katsambas AD. Source Department of Dermatology, University of Athens, Andreas Sygros Hospital, 5 Ionos Dragoumi St, 16121 Athens, Greece. firstname.lastname@example.org Abstract Acne 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. Clin Dermatol. 2010 Jan-Feb;28(1):24-30.
High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life. Cyrulnik AA, Viola KV, Gewirtzman AJ, Cohen SR. Source Department of Dermatology, Albert Einstein College of Medicine, New York, NY 10467, USA. Abstract BACKGROUND: 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. Int J Dermatol. 2012 Sep;51(9):1123-30.
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