An expert view on the treatment of acne with systemic antibiotics and/or oral isotretinoin in the light of the new European recommendations

In 2003 the European Agency for the Evaluation of Medicinal Products amended the summary product characteristics for oral isotretinoin to standardise information provided from the different countries of the European Community. The Committee for Proprietary Medicinal Products recommended that among others, exclusively severe forms of acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to "adequate courses" of standard therapy with systemic antibacterials and local therapy should benefit from oral isotretinoin. However, no indication was provided on what were considered adequate courses or the possibility given to use oral isotretinoin as first line treatment. The aims of the present report were: 1) to provide a specialist view on when it is appropriate to introduce oral isotretinoin as a second line therapy for acne, taking into consideration optimum dosage and duration of systemic antibiotics prior to the start of the oral isotretinoin, and 2) to support the use of oral isotretinoin as first line therapy in specific cases for acne in clinical practice. The recommendations are based on an exhaustive literature review as well as on the personal experience of the members of an European panel of acne specialists. The EEP agreed with the decision made by the CPMP that oral isotretinoin should be administered as 2nd line therapy in those cases of severe acne, which were resistant to or which did not respond successfully to an initial combination regimen with systemic antibiotics and topical treatments (topical retinoids +/- benzoyl peroxide). However, the members emphasized that a number of prognostic factors, as well as psychosocial morbidity should be taken into account when choosing the regimen and that these factors may influence the use of oral isotretinoin as first line therapy.     

Isotretinoin

Isotretinoin has been the most effective and long-lasting drug for the treatment of severe acne for more than 30 years and can achieve long-term remission in 70–80?% of patients after a single course. New findings concerning its influence on innate immunity, the modulation of growth factors or the time-dependent regulation of genes of inflammation or matrix metabolism contribute to an improved understanding of the dynamic mode of action of isotretinoin. The new evidence-based European S3-guideline recommends the use of Isotretinoin as a first-line medication for the treatment of severe papulopustular or conglobate acne, especially when prognostically unfavorable factors are present: family history of acne, early onset, marked seborrhea, localization on the trunk, scarring, psychosocial disability or persistent/late-type acne. The correlation of a cumulative dose of >?100–120 mg/kg with a reduced relapse rate can be regarded as established in patients with severe acne forms, whereas in milder, “off-label”-treated acne forms, a good clinical outcome can also be achieved with lower cumulative doses.     

High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life

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.     

Clinical and Therapeutic Approach to Childhood Acne: An Update

Abstract:   There is a limited literature reporting on acne in childhood. Childhood acne can be classified in neonatal, infantile, mid-childhood, and prepubertal acne, depending on the age of onset. In this review we will present an update on the clinical approach and therapeutic options when facing prepubertal acne in a child. The use of tetracyclines is contraindicated in children younger than 8 years, and oral isotretinoin is not recommended in children younger than 12 years of age according to the FDA and the European Commission. Nevertheless, there are case reports of 10 patients successfully treated with oral isotretinoin for recalcitrant infantile acne with scarring. Further studies are needed to investigate whether isotretinoin may improve the long-term prognosis of infantile acne, which may be associated with more severe acne in adolescence.     

Low‐cumulative dose isotretinoin treatment in mild‐to‐moderate acne: efficacy in achieving stable remission

Background Aimed at the reduction of post‐treatment relapse of severe acne, the cumulative dose of oral isotretinoin should be ≥120 mg/kg. However, data on the appropriate oral isotretinoin treatment regimen in mild and moderate acne are lacking. Objective The purpose of this study was to determine the efficacy of an isotretinoin‐sparing protocol in inducing permanent remission of mild and moderate acne. Methods In this open, prospective, non‐comparative study, 150 patients affected with mild‐to‐moderate acne were treated with isotretinoin until complete recovery and for a further month of treatment, independent of the total cumulative dose reached. Patients then underwent a 1‐year maintenance therapy with adapalene 0.1% cream. Patients were followed up for a further year, without any treatment. Results A total of 139 patients completed the study. Overall, patients received a mean of 80.92 mg/kg cumulative dose of isotretinoin. In the 2‐year follow‐up, relapse only appeared in 13 patients (9.35%). Conclusion Comparing our findings with published data, this isotretinoin‐sparing regimen was shown to be effective in inducing stable remission and preventing acne relapses in patients with mild‐to‐moderate acne. Low‐cumulative dose regimens may potentially lead to a lower incidence of side‐effects and to lower costs than higher doses.     

Isotretinoin for acne vulgaris—10 years later; a safe and successful treatment

The purpose of this study was to assess the long-term benefit of isotretinoin in otherwise therapy-resistant acne. We also assessed risk factors which might influence the long-term outcome. We studied 88 patients (mean age 20·8 years), most of whom had suffered from acne for many years (mean 7·4 years). They received isotretinoin in an initial dose of 0·5 or 1·0 mg/kg/day. The dose was subsequently adjusted according to response and side-effects. Most patients only required 4 months’therapy to produce at least 85% clinical improvement. The patients were seen up to 10 years post-therapy (mean 9 years). Sixty-one patients were still virtually clear of disease. Of the others, 16% required further treatment with conventional antibiotics and 23% required a second course of isotretinoin. Of those who relapsed, 96% did so within 3 years of stopping therapy. The patients’age, sex, and duration of acne did not influence outcome. However, in patients with predominantly truncal acne, especially when severe, there was an increased incidence of relapse. Sebum excretion is known to correlate with acne severity, but the long-term degree of sebum suppression was found not to be related to relapse. The dose schedule, in particular cumulative dose, was an important factor in determining relapse rate. Those patients who received 0·5 mg/kg daily, or a cumulative dose of < 120 mg/kg, had a significantly higher relapse rate than patients receiving a larger dose. We did not elicit any long-term systemic or biochemical side-effects. We conclude that isotretinoin is a safe and effective therapy. It is capable of producing long-term remission in the majority of acne patients, particularly if given in a dose regimen of 1 mg/kg/day, or a cumulative dose of > 120 mg/kg.     

Isotretinoin and mental health in adolescents: Australian consensus

Acne is a common condition among adolescents and has the potential to negatively impact on the psychological well‐being of those who suffer from it. In particular, depression and suicidal ideation are more common in adolescents with acne. Successful treatment of acne can improve the quality of life and reduce levels of anxiety and depression in these individuals. The current treatment of choice for severe or refractive acne is isotretinoin, a retinoid. While the possible causal association between isotretinoin and mental illness remains a controversial topic, a recent systematic review has presented evidence to support this relationship. In light of this evidence, a group of dermatologists and psychiatrists have collaborated to develop these recommendations to aid the safe prescribing of isotretinoin in adolescents. These clinical suggestions are aimed at practitioners in both disciplines to increase awareness of the current evidence in support of the association between isotretinoin and adolescent depression.     

South‐East Asia study alliance guidelines on the management of acne vulgaris in South‐East Asian patients

The management of acne in South‐East Asia is unique, as Asian skin and local variables require a clinical approach unlike that utilized in other parts of the world. There are different treatment guidelines per country in the region, and a group of leading dermatologists from these countries convened to review these guidelines, discuss current practices and recent advances, and formulate consensus guidelines to harmonize the management of acne vulgaris in the region. Emphasis has been placed on formulating recommendations to impede the development of antibiotic resistance in Propionibacterium acnes. The group adopted the Acne Consensus Conference system for grading acne severity. The group recommends that patients may be treated with topical medications including retinoids, benzoyl peroxide (BPO), salicylic acid, a combination of retinoid and BPO, or a combination of retinoids and BPO with or without antibiotics for mild acne; topical retinoid with topical BPO and a oral antibiotic for moderate acne; and oral isotretinoin if the patient fails first‐line treatment (a 6‐ or 8‐week trial of combined oral antibiotics and topical retinoids with BPO) for severe acne. Maintenance acne treatment using topical retinoids with or without BPO is recommended. To prevent the development of antibiotic resistance, topical antibiotics should not be used as monotherapy or used simultaneously with oral antibiotics. Skin care, comprised of cleansing, moisturizing and sun protection, is likewise recommended. Patient education and good communication is recommended to improve adherence, and advice should be given about the characteristics of the skin care products patients should use.     

Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review

Isotretinoin (13-cis retinoic acid) is an effective treatment for severe cystic or recalcitrant acne vulgaris; however, concerns have been raised regarding its potential association with depression and suicidal behavior. We sought to explore the proposed relationship between isotretinoin use and the risk of depression and attempted and completed suicide in patients with acne vulgaris by performing a systematic literature search for studies reporting primary data on depression and suicidal behavior in patients treated with isotretinoin for acne vulgaris. Nine studies met the qualifying criteria for our analysis. Rates of depression among isotretinoin users ranged from 1% to 11% across studies, with similar rates in oral antibiotic control groups. Overall, studies comparing depression before and after treatment did not show a statistically significant increase in depression diagnoses or depressive symptoms. Some, in fact, demonstrated a trend toward fewer or less severe depressive symptoms after isotretinoin therapy. This decrease was particularly evident in patients with pretreatment scores in the moderate or clinical depression range. No correlation between isotretinoin use and suicidal behavior was reported, although only one retrospective study presented data on this topic. Although the current literature does not support a causative association between isotretinoin use and depression, there are important limitations to many of the studies. The available data on suicidal behavior during isotretinoin treatment are insufficient to establish a meaningful causative association.     

Treatment outcome of acne vulgaris with oral isotretinoin in 89 patients

This is a retrospective study of 114 patients who received oral isotretinoin for acne vulgaris for a minimum of 6 weeks between January 1994 and March 1995. Relapse was defined as deterioration in acne sufficient to merit systemic therapy, either with antibiotics or with another course of isotretinoin. Patients were considered nonrelapsers after a minimum period of 1 year post-treatment with isotretinoin.
Case notes were traced and the following data were retrieved: age, sex, duration of acne, site of acne, previous treatment with either antibiotics or isotretinoin, indications for treatment, total cumulative dose of oral isotretinoin, average daily dose of isotretinoin,
response, relapse, time taken to relapse, and subsequent treatment. Those with either complete or partial (>80%) clearance were considered as responders because of the difficulty in categorizing them accurately due to the retrospective nature of the study. A telephone interview was conducted as far as possible with all patients who had an inadequate follow-up period to ascertain if they had relapsed, i.e. if they had been prescribed systemic therapy for further flares of acne. Analyses of laboratory abnormalities were performed only in patients who had serial alanine aminotransferase (ALT), total cholesterol, and triglyceride readings.
Data were analyzed using the chi-squared test, Student's t -test, Mann–Whitney U -test, and Fisher's exact test.
Of the 114 cases studied, 21 were excluded because of the following reasons: no weight was documented, 12; antibiotics were started immediately after completion of treatment making it impossible to document relapse, 2; patients were not seen at all after completing treatment and were uncontactable, 7. A further four cases with a break of 4 weeks or more during treatment were excluded as the accuracy of the calculated total cumulative dose of isotretinoin may be affected, given the half-life of 10–20 h.     

Isotretinoin use and subsequent depression and suicide: presenting the evidence

The growing number of reported cases of depression and suicide associated with isotretinoin (a retinoid receptor agonist) use in patients with acne has prompted concern among dermatologists, patients, and their relatives and has triggered new warnings from regulators including depression-related, patient-informed consent forms. In establishing a cause-effect relationship, it is useful to judiciously consider whether there is an association, what is the nature of that association, if there is a plausible biological mechanism of action, the validity and reliability of measures used and the strength of study designs. Hoffmann-La Roche estimates that by April 2001 approximately 12 million patients worldwide have used isotretinoin, with 5 million patients in the US.A MEDLINE search between January 1966 and May 14 2003 of the published medical literature found 24 documented cases of isotretinoin-associated depression, with 3 suicides. One additional patient committed suicide during the fourth month of isotretinoin treatment and 3 further patients attempted suicide by taking an overdose of isotretinoin. The US FDA's Adverse Event Reporting System (AERS) contains almost 23,000 reports for isotretinoin from its approval in 1982 to December 2002. As of November 30, 2002, AERS contained 3,104 reports (US and foreign) with at least one reported psychiatric event. The FDA is aware of 173 reports of suicide (both US and foreign) in association with isotretinoin. Reports of positive dechallenge and rechallenge present a strong signal pointing to an association between isotretinoin and depression. A Hoffmann-La Roche sponsored epidemiological study failed to find any evidence of an association between isotretinoin and depression or suicide. However, the design of the study was flawed and the evidence was deemed inconclusive. Further studies using strong study designs, reliable and valid measures, and adequate sample sizes may bring us closer to the answer. The evidence suggesting a relationship between isotretinoin and depression needs to be weighed against the increasing prevalence of depression among adolescents and young adults and the psychological impact of acne. The literature contains credible evidence that isotretinoin treatment may reduce the psychosocial impact of acne in some patients. At the present time, there is no known pharmacological mechanism that would account for psychiatric symptomatology as a result of isotretinoin treatment; however, retinoid receptors are widely distributed in the brain and more research is needed to ascertain whether they have a role in depression. In the meantime, for the practitioner, the obvious benefit of isotretinoin in treating acne should encourage continued use. However, patients and their relatives must be informed and depressive symptoms should be actively assessed at each visit and, if necessary, referral to a psychiatrist, antidepressant therapy or discontinuation of isotretinoin should be considered.     

Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review

Isotretinoin (13-cis retinoic acid) is an effective treatment for severe cystic or recalcitrant acne vulgaris; however, concerns have been raised regarding its potential association with depression and suicidal behavior. We sought to explore the proposed relationship between isotretinoin use and the risk of depression and attempted and completed suicide in patients with acne vulgaris by performing a systematic literature search for studies reporting primary data on depression and suicidal behavior in patients treated with isotretinoin for acne vulgaris. Nine studies met the qualifying criteria for our analysis. Rates of depression among isotretinoin users ranged from 1% to 11% across studies, with similar rates in oral antibiotic control groups. Overall, studies comparing depression before and after treatment did not show a statistically significant increase in depression diagnoses or depressive symptoms. Some, in fact, demonstrated a trend toward fewer or less severe depressive symptoms after isotretinoin therapy. This decrease was particularly evident in patients with pretreatment scores in the moderate or clinical depression range. No correlation between isotretinoin use and suicidal behavior was reported, although only one retrospective study presented data on this topic. Although the current literature does not support a causative association between isotretinoin use and depression, there are important limitations to many of the studies. The available data on suicidal behavior during isotretinoin treatment are insufficient to establish a meaningful causative association.     

Low dose of isotretinoin: A comprehensive review

Isotretinoin is a first‐generation retinoid initially approved for the treatment of severe cases of acne vulgaris (nodulocystic acne). Because of its broad anti‐inflammatory and immunomodulatory properties, it has been used beyond its initial approval in a myriad of other indications. Adverse effects of isotretinoin vary from xerosis to teratogenicity. Herein, we reviewed the literature, through date‐unlimited PubMed search, from inception till December 2019, using the following search terms: “low‐dose isotretinoin” and “dermatology,” “isotretinoin and safety,” “isotretinoin, off‐label uses,” “isotretinoin and male fertility,” “isotretinoin, iPLEDGE system,” aiming to deliver a therapeutic update relevant to clinical practice. All English‐language articles were considered with no limitation based on the articles' type. Low‐dose isotretinoin is not limited to old and novel dermatological conditions, but also showed promising results in the field of infertility and safety in the field of gastroenterology. We also highlight on the safety profile of the drug and experts' recommendations to enhance safety measures to decrease fetal risk while on isotretinoin.     

Cosmetic therapies for Chinese patients with acne taking concomitant or recent intake of oral isotretinoin: A retrospective study

Background

The current standard recommendation is to initiate the cosmetic therapies after discontinuing taking oral isotretinoin for at least 6 months. However, this recommendation has been questioned in several recent publications, and it is difficult to operate in clinical practice as early initiation of effective treatment is desirable for patients with acne sequelae.

Objective

The purpose of this study is to evaluate the efficacy and safety of chemical peeling and light/laser or radiofrequency treatments combined with oral isotretinoin for patients with acne vulgaris and acne scars.

Method

A retrospective study of 511 patients on/or recently administered with isotretinoin treated with glycolic acid, intense pulsed light, nonablative fractional laser, fractional radiofrequency, and ablative carbon dioxide laser. A total of 1352 interventions were performed. The medical follow-up lasted for at least 1 year. The efficacy and safety of different procedures were evaluated.

Results

A total of 511 patients, who were treated with isotretinoin orally or stopped for <6 months, received 477 sessions of glycolic acid chemical peeling treatment, 588 sessions of intense pulsed light treatment, 61 sessions of nonablative fractional laser treatment, 101 sessions of fractional radiofrequency treatment, and 125 sessions of ablative fractional carbon dioxide laser treatment. No hypertrophic scars and keloids were found, and the incidence of serious adverse reactions such as scarring, erythema, blisters, and postinflammatory hyperpigmentation did not increase.

Conclusions

It is safe to perform skin procedures in patients with acne and acne scars during or after discontinuation of isotretinoin for <6 months. Invasive treatments such as ablative fractional carbon dioxide laser treatment can be performed, as appropriate, by an experienced physician. The guideline of avoiding chemical and physical procedures in such patients taking oral isotretinoin should to revised.     

Isotretinoin: dose,duration and relapse. What does 30 years of usage tell us?

With 30 years of clinical use, it is appropriate to review the use of isotretinoin. We now understand that retinoids influence cellular growth, differentiation, morphogenesis and apoptosis, inhibit tumour promotion and malignant cell growth, exert immuno‐modulatory actions and alter cellular cohesiveness. This has expanded the indications of isotretinoin from just acne and rosacea to a wide range of inflammatory and malignant skin disorders. While the standard dose of 0.5 to 1 mg/kg per day for 4 months to a cumulative dose of 120–140 mg/kg per day has served us well in the management of acne vulgaris, there is emerging evidence that much lower dosages (as low as 5 mg/day) are just as effective but have significantly fewer adverse effects. Relapse of acne vulgaris continues to be a problem but we are beginning to recognise that this is related less to the cumulative dose and more to the length of sebaceous gland suppression. Other factors important for relapse include a macrocomedonal pattern of acne, smoking and age, both younger (under 14 years) and older (over 25 years). After 30 years of use, we now understand why isotretinoin is such an effective drug. Not only does it clear acne in almost all patients, long‐term remission can be achieved in 70–80% of patients with a single course. Important changes in the use of isotretinoin include using a lower daily dose for a longer period of time. New indications continue to emerge, particularly as a potential treatment for both intrinsic and extrinsic (photo) aging. Teratogenicity however, remains a very significant concern.     

Isotretinoin therapy and the incidence of acne relapse: a nested case-control study

Background Previous studies on predictors of acne relapse in patients treated with isotretinoin had either small sample sizes, short follow‐up periods, or lacked population‐based data. Objectives To identify and quantify predictors of acne relapse, and predictors of receiving a second isotretinoin treatment. Methods Using the Régie de l’Assurance Maladie du Québec (RAMQ) and Quebec’s hospital discharge (Med‐Écho) administrative databases, a population‐based cohort of 17 351 first‐time isotretinoin users was assembled between 1984 and 2003. A nested case–control analysis was performed to determine predictors of acne relapse (as defined by receiving an antiacne medication). A second nested case–control analysis was performed to determine predictors of receiving a second isotretinoin treatment. The index date of cases was the calendar date of dispensing an antiacne medication (isotretinoin or other). Five controls were matched to each case on follow‐up time. Rate ratios were estimated using conditional logistic regression. Results A total of 7100 (41%) subjects experienced an acne relapse. These were matched to 35 500 controls. Being male, under 16 years of age and living in an urban area, and receiving isotretinoin cumulative doses greater than 2450 mg and an isotretinoin treatment longer than 121 days were statistically associated (P < 0·05) with acne relapse. The publishing of the different Canadian acne guidelines had no impact on the incidence of acne relapse (P > 0·05). A total of 4443 (26%) subjects required a second isotretinoin treatment. These were matched to 22 215 controls. There was a greater probability of receiving a second isotretinoin treatment after the publishing of the Canadian acne guidelines (P < 0·05). Conclusion A relatively high rate of subjects experienced an acne relapse after an isotretinoin treatment.     

Predictive factors for failure of isotretinoin treatment in acne patients: results from a cohort of 237 patients.

BACKGROUND: The efficacy of oral isotretinoin in acne has been established, though the role of the mean daily dose (MDD) is still unclear. OBJECTIVE: To determine the predictive factors of resistance to oral isotretinoin and the role of the MDD of isotretinoin on relapse of acne while taking into account patient characteristics and the total cumulative dose (TCD). METHODS: Two hundred and thirty-seven patients treated with oral isotretinoin for the first time were enrolled by a single dermatologist. Patients with closed comedonal acne and with hyperandrogenism received adequate therapy prior to isotretinoin. RESULTS: Closed comedonal acne was the only predictive factor of resistance to isotretinoin with an adjusted OR = 2.7 (95% CI: 1.0-7.3). The estimated rates of relapse at 1, 3 and 5 years were 14, 40 and 48%, respectively. Age and grade of facial acne were the only predictive factors for relapse with adjusted relative risks of 0.6 (95% CI: 0.4-0.8) for age >/= 20 and 1.5 (95% CI: 1.0-2.2) for grade > 3. CONCLUSION: MDD, TCD, closed comedonal acne and hyperandrogenism that have been adequately treated prior to isotretinoin treatment had no prognostic value for relapse.     

Adult female acne: a guide to clinical practice

Background: Acne in women is often associated with anxiety and depression, and may persist from adolescence as well as manifest for the first time in adulthood. Genetic and hormonal factors contribute to its etiopathogenesis, and maintenance treatment is required, usually for years, due to its clinical evolution.Objective: To develop a guide for the clinical practice of adult female acne.Methods: A team of five experts with extensive experience in acne conducted a literature review of the main scientific evidence and met to discuss the best practices and personal experiences to develop a guide containing recommendations for the clinical practice of adult female acne.Results: The group of specialists reached consensus on the main guidelines for clinical practice, providing detailed recommendations on clinical picture, etiopathogenesis, laboratory investigation and treatment of adult female acne.Conclusion: Different from teenage acne, adult female acne presents some characteristics and multiple etiopathogenic factors that make its management more complex. This guide provides recommendations for best clinical practices and therapeutic decisions. However, the authors consider that additional studies are needed in order to provide more evidence for adult female acne to be better understood.