Acne vulgaris is a common skin disease affecting millions of Americans, from preteens to adults. More than 2 million people are projected to suffer from severe inflammatory-cystic acne; however, it is projected that many remain undiagnosed, and only 10% undergo treatment with oral isotretinoin — the only acne medication indicated for severe recalcitrant nodular acne.1
Due to its consistent efficacy, overall favorable safety profile, and ability to produce sustained remission in most patients after a 16- to 20-week course of therapy, oral isotretinoin remains the treatment of choice among dermatologists for severe inflammatory acne vulgaris that is refractory to other therapies and/or is associated with scarring. At present, no available therapeutic approach is nearly as effective as oral isotretinoin. Additionally, patient satisfaction is very high overall. The dermatology community’s high level of confidence in the efficacy and safety of oral isotretinoin is reflected by the fact that since the inception of the iPLEDGE risk management program, >95% of dermatology practices remain committed to using oral isotretinoin in patients determined to be appropriate candidates for this therapy.
Targeting Multiple Pathogenic Factors
Acne is a complex disease encompassing a variety of pathogenic factors:
- A pivotal trigger is androgen-stimulated sebum production and follicular hyperkeratosis.
- Sebum hypersecretion and follicular hyperkeratosis obstruct the canal of the pilosebaceous unit.
- Prropionibacterium acnes, a facultative anaerobe and commensal inhabitant of skin, proliferates within these affected follicular units on the face, chest, and/or back, resulting in stimulation of inflammation, and probably comedogenesis.
Isotretinoin is the only agent used for the treatment of acne that targets all four pathogenic factors leading to this skin disease. Isotretinoin has been shown to reduce:
1. Sebum secretion and size of sebaceous glands2,4
2. Follicular hyperkeratinization3,5
3. Inflammation6,7
4. Presence of and activity of P. acnes.8,9
Stewart and coworkers assessed sebum secretion by measuring rates of wax ester secretion in 20 patients with active, severe nodulocystic acne resistant to previous therapy.2 Patients taking 1 mg/kg/day isotretinoin for 20 weeks had an average ester secretion rate of one-tenth that of pretreatment levels. Drastic reductions in secretions were observed as early as 2 weeks into therapy. Moreover, the average wax ester secretion was reduced to rates that were well below the range seen in individuals without acne vulgaris and remained below baseline levels for 8 weeks following the end of therapy.2 Farrell and colleagues reported similar results after 12 weeks of isotretinoin therapy at 1 mg/kg/day — 88.3% reduction from baseline, with reductions close to maximum by the fifth and sixth weeks of therapy.3
Along with decreased sebum secretion, isotretinoin also reduces the size of sebaceous glands. After 12 weeks of therapy at a dosage of 1 to 2 mg/kg/d, isotretinoin reduced the cross-sectional areas of sebaceous acini by 87.5%.4 Histological observations — collapse and elongation of sebaceous lobules and marked perifollicular fibrosis — correlated well with clinical response.4
Follicular hyperkeratinization, which leads to obstruction of sebaceous follicles, inflammation and comedo formation, is also reduced with isotretinoin therapy.
Cunliffe and Norris reported a 70% decrease in follicular casts (a measure of comedo formation) with 1 mg/kg/day of isotretinoin used for 4 months,5 and Farrell et al found a 65% reduction in the mean number of acne cysts in patients treated with 1 mg/kg/day isotretinoin after 12 weeks of therapy.3 Reduction in the number of acne cysts continued 8 weeks posttherapy, reaching -87.5% of baseline level.3 Furthermore, the change in the sum of the greatest diameters of the acne cysts from baseline to 12 weeks of therapy was -75.8%.3
Additional studies have reported similar results — 89% reduction in the number of acne lesions after 16 weeks of therapy6 and about 95% reduction in facial inflammatory lesions greater than 4 mm in diameter 12 weeks following a 20-week course of 1 mg/kg/day isotretinoin.7
Early studies evaluating isotretinoin also observed a reduction in the number of P. acnes with therapy — from values of 104/cm2 at baseline to 103/cm2 after 1 month of treatment.8 However, a trend was observed for counts to return to pretreatment levels 2 months after discontinuing therapy. Fifteen years later, Coates and colleagues reported preliminary data demonstrating that isotretinoin significantly reduced total numbers of erythromycin-resistant P. acnes on the skin of acne patients — from 100% prevalence at baseline to 10% prevalence after 20 to 22 weeks of therapy.9
Efficacy Data
Isotretinoin has been studied in dosages of 0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, and up to 2 mg/kg/day. All lead to dramatic improvement in acne; however, the higher dosages are associated with more long-lasting results and increased incidence of side effects.7,10
A 20-week course of isotretinoin therapy in 150 patients led to a 79% and 89% reduction in facial lesion count with 0.1 or 0.5 mg/kg/d and 1 mg/kg/d isotretinoin, respectively.7 Lesion counts continued to decline after completion of therapy — to 9%, 11%, and 5% of baseline numbers for the 0.1, 0.5, 1 mg/kg/d dosages, respectively, at 12 weeks posttherapy.7
Lesion counts on the trunk also improved, but numbers remained higher than those on the face. Similar results were reported with an average dose of 2 mg/kg/d.11 The average number of nodules and cysts per patient was reduced from about 25 at the start of therapy to less than 5 after 4 months of therapy.11
Significant improvement in acne grade has also been observed during therapy and continued for 16 weeks posttherapy.6 In this study, 9 out of 10 patients experienced a greater than 50% improvement of their acne, and severity scores decreased to about 75% of baseline values during the posttherapy evaluation.6 Similarly, all 20 patients receiving 0.1 to 1 mg/kg/d isotretinoin for up to 8 weeks had at least a 60% clearing of cysts larger than 4 mm in diameter by 8 weeks posttherapy.2 Posttreatment, 17 out of the 18 men were completely free of facial acne cysts, and 15 had at least an 80% clearing of acne cysts on the chest and back. The two women in the study responded less well, with 5 and 6 facial acne cysts remaining from the 15 and 16 present at the start of the study; they entered the study with no cysts present on the chest and back.2
Likewise, another study found a 30% improvement in acne grade at 4 weeks of therapy, which further improved to 80% by 16 weeks. Patients also experienced an 80% reduction in non-inflamed lesions, 90% reduction in small, inflamed lesions, and 90% reduction in deep inflammatory lesions.12
Prolonged Duration of Response
A notable characteristic of isotretinoin is its long-term remission rates. Treatment with 1 mg/kg/day of isotretinoin for 4 months was associated with only a 13% relapse rate.5 Nearly 9 out of 10 patients remained acne-free. Relapse rate, however, is dose-dependent. In the study, relapse rate for patients receiving isotretinoin 0.5 mg/kg/day was 42%, significantly higher than in the 1.0 mg/kg/day dose (P<.01).5 Strauss and coworkers also reported lower retreatment rates with 1 mg/kg/day isotretinoin vs the 0.5 and 0.1 mg/kg/day dose — 10%, 20%, 42%, respectively.7 Indeed, patients who received <100 mg/kg isotretinoin during a course of therapy were 8.2 times more likely to have a recurrence of acne than patients who received >100 mg/kg of isotretinoin.10
Relapse after isotretinoin therapy, however, is not an indication of failed treatment.
In a study following 88 patients for 10 years, of the patients who relapsed, most were retreated with less-aggressive agents — 21% with topical therapy (benzoyl peroxide, retinoic acid, or an antibiotic) and 16% with oral antibiotics. Less than one-fourth required further isotretinoin therapy.13 If relapse occurred, it did so within the first 3 years after isotretinoin therapy. The majority of relapse cases (78%) occurred within 18 months.
Similar results were seen in 179 patients evaluated 3 years after isotretinoin therapy — 34.6% required no additional therapy; 15.6% required topical therapy; 26.8% required oral antibiotics and topical therapy; and 22.9% required additional isotretinoin.10 Thus, nearly 8 in 10 patients maintained a complete resolution or experienced a marked reduction in the severity of their acne after a single course of isotretinoin therapy that lasted well beyond the last dose of isotretinoin.10
Comparison of Oral Isotretinoin with Antibiotic Therapy
In an attempt to identify the current best practice for systemic therapy of severe acne using hormonal approaches, tetracyclines, and isotretinoin, Holst Larsen and Jemec conducted a review of the literature published between 1975 and 2002.14 A total of 35 papers were identified, but 11 were excluded due to unclear endpoints, non-clinical effect variables, or subjective assessments felt to be poorly substantiated scientifically. Unfortunately, the remaining papers had considerable variability and a meta-analysis could be not performed. Rather, the authors assessed the percentage of positive results by whatever variable was reported and calculated the mean weighted effects.
Comparison of the mean weighted effects of treatment suggested that isotretinoin was the most effective therapy (85% improvement versus baseline) followed by cyproterone acetate plus ethinyloestradiol (65% improvement) and tetracycline (54% improvement).14 The authors concluded that isotretinoin is currently the only agent offering the possibility of systemic monotherapy for acne based on treatment goals set for other dermatologic diseases (i.e., ≥80% reduction in disease severity in ≥70% of all patients).
When costs of therapy were assessed in an Australia cost-benefit study, a single, 20-week course of isotretinoin was 26% less expensive and significantly more effective than 2.5 years of continuous oral antibiotic therapy used in conjunction with topical therapies.15
Patient Satisfaction with Therapy
Acne is a disease that affects individuals physically, emotionally, and socially. Simpson has reviewed a number of studies all demonstrating that acne adversely impacts quality of life.16 These study results included the following:
• Most patients with facial acne received unkind comments from peers and coworkers.
• 70% of patients expressed feelings of shame or embarrassment.
• 63% of patients expressed anxiety.
• 60% of patients reported that acne affected their social life.
Unemployment levels were also found to be significantly higher in patients with acne compared to those without acne — 16.2% vs. 9.2% in males and 14.3% vs. 8.7% in females (P<.001).17
Treating individuals successfully for their acne ought to help in improving their self-esteem, confidence, and quality of life. As discussed previously, isotretinoin is associated with a high success of lowering lesion counts, decreasing severity of disease, clearing acne cysts, and prolonging remission.
Most likely due to its reputation as an extremely effective agent, isotretinoin therapy is often adhered to. Patients taking isotretinoin showed a high rate of adherence to therapy. In 133 patients taking isotretinoin for the first time, medical adherence was 87.5% (calculated as the number of tablets used divided by the number of tablets that should have been used x 100).18
In this same trial, the Dermatology Life Quality Index (DQLI) indicated more satisfaction for patients taking isotretinoin (n=328) than for patients taking non-isotretinoin therapy (n=75) — 15.5 vs. 26.9.18 DQLI score for patients taking isotretinoin for the first time (n=133) was even lower at 7.5.18
A study using follow-up questionnaires at 4 months and 1 year after initiating acne therapy found that significantly more patients treated with isotretinoin rated the outcomes of therapy as “excellent” or “very good” compared with patients treated with other regimens. (See Figure 1.)19
At 4 months, treatment with isotretinoin was also associated with significantly better DQLI scores and SF-36 (physical and social functioning, role limitations, mental health, energy and vitality, pain, general perception of health) dimension scores than other treatment methods.19 At 1 year, self-esteem scores were also higher in patients treated with isotretinoin than with other methods,19 indicating that isotretinoin leads to high levels of patient satisfaction.
Likewise, Layton and colleagues reported that Assessments of the Psychological and Social Effects of Acne (APSEA) scores 6 months after the end of therapy were significantly lower for patients treated with isotretinoin (n=58) than for patients treated with antibiotics (n=42).20 Interestingly, at the end of therapy (4 months), APSEA scores for both groups were similar. Less satisfaction with antibiotics 6 months after therapy may be due to the deterioration of the mean acne grade that was achieved at the completion of this treatment — from ~0.71 to ~1.2. Mean acne grade from the end of therapy to 6 months after therapy continued to improve for patients treated with isotretinoin —from ~0.13 to 0.01.20
Side Effects
Isotretinoin is highly effective and an excellent option for patients with severe acne, provided it is used with its precautions and warnings followed. After more than a quarter of a century of clinical experience with isotretinoin, dermatologists are well aware of its adverse effects and its teratogenic properties if used in pregnant women.21 With the introduction of iPLEDGE, proper counseling and monitoring to maintain the safety of patients using this agent has been mandated.
Over time, the use of the program has become more facile for practitioners, their staff, and their patients. The iPLEDGE program has recently implemented several adjustments designed to facilitate the prescribing process for dermatologists and their patients (Table 1).
It is anticipated that patients treated with oral isotretinoin will develop dryness of the skin, lips and eyes. Appropriate moisturizers for skin and lips, and ocular lubricants, reduce the magnitude of these reactions, which resolve within weeks after discontinuing isotretinoin therapy.
It is important to recognize that although the majority of patients treated for acne vulgaris with isotretinoin complete their course of therapy without any major adverse events or complications, potential adverse events such as marked hyperlipidemia, myalgias, hair thinning, and pseudotumor cerebri have been observed.21,22 With appropriate monitoring and recognition, discontinuation of therapy results in resolution of the adverse event.
Although idiosyncratic reactions may possibly occur uncommonly, such as changes in mood and feelings of depression, it has not been substantiated definitively that use of oral isotretinoin can lead to suicidal ideation.22 In fact, feelings of depression are often correlated with the patients emotional concerns about their acne. Clearance of acne vulgaris with isotretinoin typically leads to improvements in self-esteem and enhanced quality of life.22 As with any therapy, the clinician must evaluate each patient individually and weigh the risks versus benefits of therapy.
Fortunately, the majority of patients treated with isotretinoin for acne vulgaris achieve a highly successful outcome. It is suggested that isotretinoin be ingested with food in order to improve bioavailability by maximizing absorption of the drug from the gastrointestinal tract.
Pregnancy prevention is very important in females of childbearing potential undergoing treatment with isotretinoin both during treatment and for 1 month after discontinuation of isotretinoin use due to the high potential for teratogenicity. Patient education and compliance with the steps outlined in the iPLEDGE program are very important. Additionally, patients should be informed to not share isotretinoin with others. There is no evidence of teratogenicity in females who conceive with males who are ingesting isotretinoin.22
Summary of Points
Isotretinoin is the only agent available that targets all four pathogenic factors leading to acne, contributing to its clinical success.
In the 25 years that it has been available, several studies have found isotretinoin to be very effective in improving acne severity and providing impressive long-term remission. Given its efficacy record, the Clinical Guideline Task Force of the American Academy of Dermatology recommends it based on consistent and good-quality patient-oriented evidence — its strongest recommendation ranking.23 Patient satisfaction ratings after treatment with isotretinoin are highly favorable.
Acne vulgaris is a common skin disease affecting millions of Americans, from preteens to adults. More than 2 million people are projected to suffer from severe inflammatory-cystic acne; however, it is projected that many remain undiagnosed, and only 10% undergo treatment with oral isotretinoin — the only acne medication indicated for severe recalcitrant nodular acne.1
Due to its consistent efficacy, overall favorable safety profile, and ability to produce sustained remission in most patients after a 16- to 20-week course of therapy, oral isotretinoin remains the treatment of choice among dermatologists for severe inflammatory acne vulgaris that is refractory to other therapies and/or is associated with scarring. At present, no available therapeutic approach is nearly as effective as oral isotretinoin. Additionally, patient satisfaction is very high overall. The dermatology community’s high level of confidence in the efficacy and safety of oral isotretinoin is reflected by the fact that since the inception of the iPLEDGE risk management program, >95% of dermatology practices remain committed to using oral isotretinoin in patients determined to be appropriate candidates for this therapy.
Targeting Multiple Pathogenic Factors
Acne is a complex disease encompassing a variety of pathogenic factors:
- A pivotal trigger is androgen-stimulated sebum production and follicular hyperkeratosis.
- Sebum hypersecretion and follicular hyperkeratosis obstruct the canal of the pilosebaceous unit.
- Prropionibacterium acnes, a facultative anaerobe and commensal inhabitant of skin, proliferates within these affected follicular units on the face, chest, and/or back, resulting in stimulation of inflammation, and probably comedogenesis.
Isotretinoin is the only agent used for the treatment of acne that targets all four pathogenic factors leading to this skin disease. Isotretinoin has been shown to reduce:
1. Sebum secretion and size of sebaceous glands2,4
2. Follicular hyperkeratinization3,5
3. Inflammation6,7
4. Presence of and activity of P. acnes.8,9
Stewart and coworkers assessed sebum secretion by measuring rates of wax ester secretion in 20 patients with active, severe nodulocystic acne resistant to previous therapy.2 Patients taking 1 mg/kg/day isotretinoin for 20 weeks had an average ester secretion rate of one-tenth that of pretreatment levels. Drastic reductions in secretions were observed as early as 2 weeks into therapy. Moreover, the average wax ester secretion was reduced to rates that were well below the range seen in individuals without acne vulgaris and remained below baseline levels for 8 weeks following the end of therapy.2 Farrell and colleagues reported similar results after 12 weeks of isotretinoin therapy at 1 mg/kg/day — 88.3% reduction from baseline, with reductions close to maximum by the fifth and sixth weeks of therapy.3
Along with decreased sebum secretion, isotretinoin also reduces the size of sebaceous glands. After 12 weeks of therapy at a dosage of 1 to 2 mg/kg/d, isotretinoin reduced the cross-sectional areas of sebaceous acini by 87.5%.4 Histological observations — collapse and elongation of sebaceous lobules and marked perifollicular fibrosis — correlated well with clinical response.4
Follicular hyperkeratinization, which leads to obstruction of sebaceous follicles, inflammation and comedo formation, is also reduced with isotretinoin therapy.
Cunliffe and Norris reported a 70% decrease in follicular casts (a measure of comedo formation) with 1 mg/kg/day of isotretinoin used for 4 months,5 and Farrell et al found a 65% reduction in the mean number of acne cysts in patients treated with 1 mg/kg/day isotretinoin after 12 weeks of therapy.3 Reduction in the number of acne cysts continued 8 weeks posttherapy, reaching -87.5% of baseline level.3 Furthermore, the change in the sum of the greatest diameters of the acne cysts from baseline to 12 weeks of therapy was -75.8%.3
Additional studies have reported similar results — 89% reduction in the number of acne lesions after 16 weeks of therapy6 and about 95% reduction in facial inflammatory lesions greater than 4 mm in diameter 12 weeks following a 20-week course of 1 mg/kg/day isotretinoin.7
Early studies evaluating isotretinoin also observed a reduction in the number of P. acnes with therapy — from values of 104/cm2 at baseline to 103/cm2 after 1 month of treatment.8 However, a trend was observed for counts to return to pretreatment levels 2 months after discontinuing therapy. Fifteen years later, Coates and colleagues reported preliminary data demonstrating that isotretinoin significantly reduced total numbers of erythromycin-resistant P. acnes on the skin of acne patients — from 100% prevalence at baseline to 10% prevalence after 20 to 22 weeks of therapy.9
Efficacy Data
Isotretinoin has been studied in dosages of 0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, and up to 2 mg/kg/day. All lead to dramatic improvement in acne; however, the higher dosages are associated with more long-lasting results and increased incidence of side effects.7,10
A 20-week course of isotretinoin therapy in 150 patients led to a 79% and 89% reduction in facial lesion count with 0.1 or 0.5 mg/kg/d and 1 mg/kg/d isotretinoin, respectively.7 Lesion counts continued to decline after completion of therapy — to 9%, 11%, and 5% of baseline numbers for the 0.1, 0.5, 1 mg/kg/d dosages, respectively, at 12 weeks posttherapy.7
Lesion counts on the trunk also improved, but numbers remained higher than those on the face. Similar results were reported with an average dose of 2 mg/kg/d.11 The average number of nodules and cysts per patient was reduced from about 25 at the start of therapy to less than 5 after 4 months of therapy.11
Significant improvement in acne grade has also been observed during therapy and continued for 16 weeks posttherapy.6 In this study, 9 out of 10 patients experienced a greater than 50% improvement of their acne, and severity scores decreased to about 75% of baseline values during the posttherapy evaluation.6 Similarly, all 20 patients receiving 0.1 to 1 mg/kg/d isotretinoin for up to 8 weeks had at least a 60% clearing of cysts larger than 4 mm in diameter by 8 weeks posttherapy.2 Posttreatment, 17 out of the 18 men were completely free of facial acne cysts, and 15 had at least an 80% clearing of acne cysts on the chest and back. The two women in the study responded less well, with 5 and 6 facial acne cysts remaining from the 15 and 16 present at the start of the study; they entered the study with no cysts present on the chest and back.2
Likewise, another study found a 30% improvement in acne grade at 4 weeks of therapy, which further improved to 80% by 16 weeks. Patients also experienced an 80% reduction in non-inflamed lesions, 90% reduction in small, inflamed lesions, and 90% reduction in deep inflammatory lesions.12
Prolonged Duration of Response
A notable characteristic of isotretinoin is its long-term remission rates. Treatment with 1 mg/kg/day of isotretinoin for 4 months was associated with only a 13% relapse rate.5 Nearly 9 out of 10 patients remained acne-free. Relapse rate, however, is dose-dependent. In the study, relapse rate for patients receiving isotretinoin 0.5 mg/kg/day was 42%, significantly higher than in the 1.0 mg/kg/day dose (P<.01).5 Strauss and coworkers also reported lower retreatment rates with 1 mg/kg/day isotretinoin vs the 0.5 and 0.1 mg/kg/day dose — 10%, 20%, 42%, respectively.7 Indeed, patients who received <100 mg/kg isotretinoin during a course of therapy were 8.2 times more likely to have a recurrence of acne than patients who received >100 mg/kg of isotretinoin.10
Relapse after isotretinoin therapy, however, is not an indication of failed treatment.
In a study following 88 patients for 10 years, of the patients who relapsed, most were retreated with less-aggressive agents — 21% with topical therapy (benzoyl peroxide, retinoic acid, or an antibiotic) and 16% with oral antibiotics. Less than one-fourth required further isotretinoin therapy.13 If relapse occurred, it did so within the first 3 years after isotretinoin therapy. The majority of relapse cases (78%) occurred within 18 months.
Similar results were seen in 179 patients evaluated 3 years after isotretinoin therapy — 34.6% required no additional therapy; 15.6% required topical therapy; 26.8% required oral antibiotics and topical therapy; and 22.9% required additional isotretinoin.10 Thus, nearly 8 in 10 patients maintained a complete resolution or experienced a marked reduction in the severity of their acne after a single course of isotretinoin therapy that lasted well beyond the last dose of isotretinoin.10
Comparison of Oral Isotretinoin with Antibiotic Therapy
In an attempt to identify the current best practice for systemic therapy of severe acne using hormonal approaches, tetracyclines, and isotretinoin, Holst Larsen and Jemec conducted a review of the literature published between 1975 and 2002.14 A total of 35 papers were identified, but 11 were excluded due to unclear endpoints, non-clinical effect variables, or subjective assessments felt to be poorly substantiated scientifically. Unfortunately, the remaining papers had considerable variability and a meta-analysis could be not performed. Rather, the authors assessed the percentage of positive results by whatever variable was reported and calculated the mean weighted effects.
Comparison of the mean weighted effects of treatment suggested that isotretinoin was the most effective therapy (85% improvement versus baseline) followed by cyproterone acetate plus ethinyloestradiol (65% improvement) and tetracycline (54% improvement).14 The authors concluded that isotretinoin is currently the only agent offering the possibility of systemic monotherapy for acne based on treatment goals set for other dermatologic diseases (i.e., ≥80% reduction in disease severity in ≥70% of all patients).
When costs of therapy were assessed in an Australia cost-benefit study, a single, 20-week course of isotretinoin was 26% less expensive and significantly more effective than 2.5 years of continuous oral antibiotic therapy used in conjunction with topical therapies.15
Patient Satisfaction with Therapy
Acne is a disease that affects individuals physically, emotionally, and socially. Simpson has reviewed a number of studies all demonstrating that acne adversely impacts quality of life.16 These study results included the following:
• Most patients with facial acne received unkind comments from peers and coworkers.
• 70% of patients expressed feelings of shame or embarrassment.
• 63% of patients expressed anxiety.
• 60% of patients reported that acne affected their social life.
Unemployment levels were also found to be significantly higher in patients with acne compared to those without acne — 16.2% vs. 9.2% in males and 14.3% vs. 8.7% in females (P<.001).17
Treating individuals successfully for their acne ought to help in improving their self-esteem, confidence, and quality of life. As discussed previously, isotretinoin is associated with a high success of lowering lesion counts, decreasing severity of disease, clearing acne cysts, and prolonging remission.
Most likely due to its reputation as an extremely effective agent, isotretinoin therapy is often adhered to. Patients taking isotretinoin showed a high rate of adherence to therapy. In 133 patients taking isotretinoin for the first time, medical adherence was 87.5% (calculated as the number of tablets used divided by the number of tablets that should have been used x 100).18
In this same trial, the Dermatology Life Quality Index (DQLI) indicated more satisfaction for patients taking isotretinoin (n=328) than for patients taking non-isotretinoin therapy (n=75) — 15.5 vs. 26.9.18 DQLI score for patients taking isotretinoin for the first time (n=133) was even lower at 7.5.18
A study using follow-up questionnaires at 4 months and 1 year after initiating acne therapy found that significantly more patients treated with isotretinoin rated the outcomes of therapy as “excellent” or “very good” compared with patients treated with other regimens. (See Figure 1.)19
At 4 months, treatment with isotretinoin was also associated with significantly better DQLI scores and SF-36 (physical and social functioning, role limitations, mental health, energy and vitality, pain, general perception of health) dimension scores than other treatment methods.19 At 1 year, self-esteem scores were also higher in patients treated with isotretinoin than with other methods,19 indicating that isotretinoin leads to high levels of patient satisfaction.
Likewise, Layton and colleagues reported that Assessments of the Psychological and Social Effects of Acne (APSEA) scores 6 months after the end of therapy were significantly lower for patients treated with isotretinoin (n=58) than for patients treated with antibiotics (n=42).20 Interestingly, at the end of therapy (4 months), APSEA scores for both groups were similar. Less satisfaction with antibiotics 6 months after therapy may be due to the deterioration of the mean acne grade that was achieved at the completion of this treatment — from ~0.71 to ~1.2. Mean acne grade from the end of therapy to 6 months after therapy continued to improve for patients treated with isotretinoin —from ~0.13 to 0.01.20
Side Effects
Isotretinoin is highly effective and an excellent option for patients with severe acne, provided it is used with its precautions and warnings followed. After more than a quarter of a century of clinical experience with isotretinoin, dermatologists are well aware of its adverse effects and its teratogenic properties if used in pregnant women.21 With the introduction of iPLEDGE, proper counseling and monitoring to maintain the safety of patients using this agent has been mandated.
Over time, the use of the program has become more facile for practitioners, their staff, and their patients. The iPLEDGE program has recently implemented several adjustments designed to facilitate the prescribing process for dermatologists and their patients (Table 1).
It is anticipated that patients treated with oral isotretinoin will develop dryness of the skin, lips and eyes. Appropriate moisturizers for skin and lips, and ocular lubricants, reduce the magnitude of these reactions, which resolve within weeks after discontinuing isotretinoin therapy.
It is important to recognize that although the majority of patients treated for acne vulgaris with isotretinoin complete their course of therapy without any major adverse events or complications, potential adverse events such as marked hyperlipidemia, myalgias, hair thinning, and pseudotumor cerebri have been observed.21,22 With appropriate monitoring and recognition, discontinuation of therapy results in resolution of the adverse event.
Although idiosyncratic reactions may possibly occur uncommonly, such as changes in mood and feelings of depression, it has not been substantiated definitively that use of oral isotretinoin can lead to suicidal ideation.22 In fact, feelings of depression are often correlated with the patients emotional concerns about their acne. Clearance of acne vulgaris with isotretinoin typically leads to improvements in self-esteem and enhanced quality of life.22 As with any therapy, the clinician must evaluate each patient individually and weigh the risks versus benefits of therapy.
Fortunately, the majority of patients treated with isotretinoin for acne vulgaris achieve a highly successful outcome. It is suggested that isotretinoin be ingested with food in order to improve bioavailability by maximizing absorption of the drug from the gastrointestinal tract.
Pregnancy prevention is very important in females of childbearing potential undergoing treatment with isotretinoin both during treatment and for 1 month after discontinuation of isotretinoin use due to the high potential for teratogenicity. Patient education and compliance with the steps outlined in the iPLEDGE program are very important. Additionally, patients should be informed to not share isotretinoin with others. There is no evidence of teratogenicity in females who conceive with males who are ingesting isotretinoin.22
Summary of Points
Isotretinoin is the only agent available that targets all four pathogenic factors leading to acne, contributing to its clinical success.
In the 25 years that it has been available, several studies have found isotretinoin to be very effective in improving acne severity and providing impressive long-term remission. Given its efficacy record, the Clinical Guideline Task Force of the American Academy of Dermatology recommends it based on consistent and good-quality patient-oriented evidence — its strongest recommendation ranking.23 Patient satisfaction ratings after treatment with isotretinoin are highly favorable.
Acne vulgaris is a common skin disease affecting millions of Americans, from preteens to adults. More than 2 million people are projected to suffer from severe inflammatory-cystic acne; however, it is projected that many remain undiagnosed, and only 10% undergo treatment with oral isotretinoin — the only acne medication indicated for severe recalcitrant nodular acne.1
Due to its consistent efficacy, overall favorable safety profile, and ability to produce sustained remission in most patients after a 16- to 20-week course of therapy, oral isotretinoin remains the treatment of choice among dermatologists for severe inflammatory acne vulgaris that is refractory to other therapies and/or is associated with scarring. At present, no available therapeutic approach is nearly as effective as oral isotretinoin. Additionally, patient satisfaction is very high overall. The dermatology community’s high level of confidence in the efficacy and safety of oral isotretinoin is reflected by the fact that since the inception of the iPLEDGE risk management program, >95% of dermatology practices remain committed to using oral isotretinoin in patients determined to be appropriate candidates for this therapy.
Targeting Multiple Pathogenic Factors
Acne is a complex disease encompassing a variety of pathogenic factors:
- A pivotal trigger is androgen-stimulated sebum production and follicular hyperkeratosis.
- Sebum hypersecretion and follicular hyperkeratosis obstruct the canal of the pilosebaceous unit.
- Prropionibacterium acnes, a facultative anaerobe and commensal inhabitant of skin, proliferates within these affected follicular units on the face, chest, and/or back, resulting in stimulation of inflammation, and probably comedogenesis.
Isotretinoin is the only agent used for the treatment of acne that targets all four pathogenic factors leading to this skin disease. Isotretinoin has been shown to reduce:
1. Sebum secretion and size of sebaceous glands2,4
2. Follicular hyperkeratinization3,5
3. Inflammation6,7
4. Presence of and activity of P. acnes.8,9
Stewart and coworkers assessed sebum secretion by measuring rates of wax ester secretion in 20 patients with active, severe nodulocystic acne resistant to previous therapy.2 Patients taking 1 mg/kg/day isotretinoin for 20 weeks had an average ester secretion rate of one-tenth that of pretreatment levels. Drastic reductions in secretions were observed as early as 2 weeks into therapy. Moreover, the average wax ester secretion was reduced to rates that were well below the range seen in individuals without acne vulgaris and remained below baseline levels for 8 weeks following the end of therapy.2 Farrell and colleagues reported similar results after 12 weeks of isotretinoin therapy at 1 mg/kg/day — 88.3% reduction from baseline, with reductions close to maximum by the fifth and sixth weeks of therapy.3
Along with decreased sebum secretion, isotretinoin also reduces the size of sebaceous glands. After 12 weeks of therapy at a dosage of 1 to 2 mg/kg/d, isotretinoin reduced the cross-sectional areas of sebaceous acini by 87.5%.4 Histological observations — collapse and elongation of sebaceous lobules and marked perifollicular fibrosis — correlated well with clinical response.4
Follicular hyperkeratinization, which leads to obstruction of sebaceous follicles, inflammation and comedo formation, is also reduced with isotretinoin therapy.
Cunliffe and Norris reported a 70% decrease in follicular casts (a measure of comedo formation) with 1 mg/kg/day of isotretinoin used for 4 months,5 and Farrell et al found a 65% reduction in the mean number of acne cysts in patients treated with 1 mg/kg/day isotretinoin after 12 weeks of therapy.3 Reduction in the number of acne cysts continued 8 weeks posttherapy, reaching -87.5% of baseline level.3 Furthermore, the change in the sum of the greatest diameters of the acne cysts from baseline to 12 weeks of therapy was -75.8%.3
Additional studies have reported similar results — 89% reduction in the number of acne lesions after 16 weeks of therapy6 and about 95% reduction in facial inflammatory lesions greater than 4 mm in diameter 12 weeks following a 20-week course of 1 mg/kg/day isotretinoin.7
Early studies evaluating isotretinoin also observed a reduction in the number of P. acnes with therapy — from values of 104/cm2 at baseline to 103/cm2 after 1 month of treatment.8 However, a trend was observed for counts to return to pretreatment levels 2 months after discontinuing therapy. Fifteen years later, Coates and colleagues reported preliminary data demonstrating that isotretinoin significantly reduced total numbers of erythromycin-resistant P. acnes on the skin of acne patients — from 100% prevalence at baseline to 10% prevalence after 20 to 22 weeks of therapy.9
Efficacy Data
Isotretinoin has been studied in dosages of 0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, and up to 2 mg/kg/day. All lead to dramatic improvement in acne; however, the higher dosages are associated with more long-lasting results and increased incidence of side effects.7,10
A 20-week course of isotretinoin therapy in 150 patients led to a 79% and 89% reduction in facial lesion count with 0.1 or 0.5 mg/kg/d and 1 mg/kg/d isotretinoin, respectively.7 Lesion counts continued to decline after completion of therapy — to 9%, 11%, and 5% of baseline numbers for the 0.1, 0.5, 1 mg/kg/d dosages, respectively, at 12 weeks posttherapy.7
Lesion counts on the trunk also improved, but numbers remained higher than those on the face. Similar results were reported with an average dose of 2 mg/kg/d.11 The average number of nodules and cysts per patient was reduced from about 25 at the start of therapy to less than 5 after 4 months of therapy.11
Significant improvement in acne grade has also been observed during therapy and continued for 16 weeks posttherapy.6 In this study, 9 out of 10 patients experienced a greater than 50% improvement of their acne, and severity scores decreased to about 75% of baseline values during the posttherapy evaluation.6 Similarly, all 20 patients receiving 0.1 to 1 mg/kg/d isotretinoin for up to 8 weeks had at least a 60% clearing of cysts larger than 4 mm in diameter by 8 weeks posttherapy.2 Posttreatment, 17 out of the 18 men were completely free of facial acne cysts, and 15 had at least an 80% clearing of acne cysts on the chest and back. The two women in the study responded less well, with 5 and 6 facial acne cysts remaining from the 15 and 16 present at the start of the study; they entered the study with no cysts present on the chest and back.2
Likewise, another study found a 30% improvement in acne grade at 4 weeks of therapy, which further improved to 80% by 16 weeks. Patients also experienced an 80% reduction in non-inflamed lesions, 90% reduction in small, inflamed lesions, and 90% reduction in deep inflammatory lesions.12
Prolonged Duration of Response
A notable characteristic of isotretinoin is its long-term remission rates. Treatment with 1 mg/kg/day of isotretinoin for 4 months was associated with only a 13% relapse rate.5 Nearly 9 out of 10 patients remained acne-free. Relapse rate, however, is dose-dependent. In the study, relapse rate for patients receiving isotretinoin 0.5 mg/kg/day was 42%, significantly higher than in the 1.0 mg/kg/day dose (P<.01).5 Strauss and coworkers also reported lower retreatment rates with 1 mg/kg/day isotretinoin vs the 0.5 and 0.1 mg/kg/day dose — 10%, 20%, 42%, respectively.7 Indeed, patients who received <100 mg/kg isotretinoin during a course of therapy were 8.2 times more likely to have a recurrence of acne than patients who received >100 mg/kg of isotretinoin.10
Relapse after isotretinoin therapy, however, is not an indication of failed treatment.
In a study following 88 patients for 10 years, of the patients who relapsed, most were retreated with less-aggressive agents — 21% with topical therapy (benzoyl peroxide, retinoic acid, or an antibiotic) and 16% with oral antibiotics. Less than one-fourth required further isotretinoin therapy.13 If relapse occurred, it did so within the first 3 years after isotretinoin therapy. The majority of relapse cases (78%) occurred within 18 months.
Similar results were seen in 179 patients evaluated 3 years after isotretinoin therapy — 34.6% required no additional therapy; 15.6% required topical therapy; 26.8% required oral antibiotics and topical therapy; and 22.9% required additional isotretinoin.10 Thus, nearly 8 in 10 patients maintained a complete resolution or experienced a marked reduction in the severity of their acne after a single course of isotretinoin therapy that lasted well beyond the last dose of isotretinoin.10
Comparison of Oral Isotretinoin with Antibiotic Therapy
In an attempt to identify the current best practice for systemic therapy of severe acne using hormonal approaches, tetracyclines, and isotretinoin, Holst Larsen and Jemec conducted a review of the literature published between 1975 and 2002.14 A total of 35 papers were identified, but 11 were excluded due to unclear endpoints, non-clinical effect variables, or subjective assessments felt to be poorly substantiated scientifically. Unfortunately, the remaining papers had considerable variability and a meta-analysis could be not performed. Rather, the authors assessed the percentage of positive results by whatever variable was reported and calculated the mean weighted effects.
Comparison of the mean weighted effects of treatment suggested that isotretinoin was the most effective therapy (85% improvement versus baseline) followed by cyproterone acetate plus ethinyloestradiol (65% improvement) and tetracycline (54% improvement).14 The authors concluded that isotretinoin is currently the only agent offering the possibility of systemic monotherapy for acne based on treatment goals set for other dermatologic diseases (i.e., ≥80% reduction in disease severity in ≥70% of all patients).
When costs of therapy were assessed in an Australia cost-benefit study, a single, 20-week course of isotretinoin was 26% less expensive and significantly more effective than 2.5 years of continuous oral antibiotic therapy used in conjunction with topical therapies.15
Patient Satisfaction with Therapy
Acne is a disease that affects individuals physically, emotionally, and socially. Simpson has reviewed a number of studies all demonstrating that acne adversely impacts quality of life.16 These study results included the following:
• Most patients with facial acne received unkind comments from peers and coworkers.
• 70% of patients expressed feelings of shame or embarrassment.
• 63% of patients expressed anxiety.
• 60% of patients reported that acne affected their social life.
Unemployment levels were also found to be significantly higher in patients with acne compared to those without acne — 16.2% vs. 9.2% in males and 14.3% vs. 8.7% in females (P<.001).17
Treating individuals successfully for their acne ought to help in improving their self-esteem, confidence, and quality of life. As discussed previously, isotretinoin is associated with a high success of lowering lesion counts, decreasing severity of disease, clearing acne cysts, and prolonging remission.
Most likely due to its reputation as an extremely effective agent, isotretinoin therapy is often adhered to. Patients taking isotretinoin showed a high rate of adherence to therapy. In 133 patients taking isotretinoin for the first time, medical adherence was 87.5% (calculated as the number of tablets used divided by the number of tablets that should have been used x 100).18
In this same trial, the Dermatology Life Quality Index (DQLI) indicated more satisfaction for patients taking isotretinoin (n=328) than for patients taking non-isotretinoin therapy (n=75) — 15.5 vs. 26.9.18 DQLI score for patients taking isotretinoin for the first time (n=133) was even lower at 7.5.18
A study using follow-up questionnaires at 4 months and 1 year after initiating acne therapy found that significantly more patients treated with isotretinoin rated the outcomes of therapy as “excellent” or “very good” compared with patients treated with other regimens. (See Figure 1.)19
At 4 months, treatment with isotretinoin was also associated with significantly better DQLI scores and SF-36 (physical and social functioning, role limitations, mental health, energy and vitality, pain, general perception of health) dimension scores than other treatment methods.19 At 1 year, self-esteem scores were also higher in patients treated with isotretinoin than with other methods,19 indicating that isotretinoin leads to high levels of patient satisfaction.
Likewise, Layton and colleagues reported that Assessments of the Psychological and Social Effects of Acne (APSEA) scores 6 months after the end of therapy were significantly lower for patients treated with isotretinoin (n=58) than for patients treated with antibiotics (n=42).20 Interestingly, at the end of therapy (4 months), APSEA scores for both groups were similar. Less satisfaction with antibiotics 6 months after therapy may be due to the deterioration of the mean acne grade that was achieved at the completion of this treatment — from ~0.71 to ~1.2. Mean acne grade from the end of therapy to 6 months after therapy continued to improve for patients treated with isotretinoin —from ~0.13 to 0.01.20
Side Effects
Isotretinoin is highly effective and an excellent option for patients with severe acne, provided it is used with its precautions and warnings followed. After more than a quarter of a century of clinical experience with isotretinoin, dermatologists are well aware of its adverse effects and its teratogenic properties if used in pregnant women.21 With the introduction of iPLEDGE, proper counseling and monitoring to maintain the safety of patients using this agent has been mandated.
Over time, the use of the program has become more facile for practitioners, their staff, and their patients. The iPLEDGE program has recently implemented several adjustments designed to facilitate the prescribing process for dermatologists and their patients (Table 1).
It is anticipated that patients treated with oral isotretinoin will develop dryness of the skin, lips and eyes. Appropriate moisturizers for skin and lips, and ocular lubricants, reduce the magnitude of these reactions, which resolve within weeks after discontinuing isotretinoin therapy.
It is important to recognize that although the majority of patients treated for acne vulgaris with isotretinoin complete their course of therapy without any major adverse events or complications, potential adverse events such as marked hyperlipidemia, myalgias, hair thinning, and pseudotumor cerebri have been observed.21,22 With appropriate monitoring and recognition, discontinuation of therapy results in resolution of the adverse event.
Although idiosyncratic reactions may possibly occur uncommonly, such as changes in mood and feelings of depression, it has not been substantiated definitively that use of oral isotretinoin can lead to suicidal ideation.22 In fact, feelings of depression are often correlated with the patients emotional concerns about their acne. Clearance of acne vulgaris with isotretinoin typically leads to improvements in self-esteem and enhanced quality of life.22 As with any therapy, the clinician must evaluate each patient individually and weigh the risks versus benefits of therapy.
Fortunately, the majority of patients treated with isotretinoin for acne vulgaris achieve a highly successful outcome. It is suggested that isotretinoin be ingested with food in order to improve bioavailability by maximizing absorption of the drug from the gastrointestinal tract.
Pregnancy prevention is very important in females of childbearing potential undergoing treatment with isotretinoin both during treatment and for 1 month after discontinuation of isotretinoin use due to the high potential for teratogenicity. Patient education and compliance with the steps outlined in the iPLEDGE program are very important. Additionally, patients should be informed to not share isotretinoin with others. There is no evidence of teratogenicity in females who conceive with males who are ingesting isotretinoin.22
Summary of Points
Isotretinoin is the only agent available that targets all four pathogenic factors leading to acne, contributing to its clinical success.
In the 25 years that it has been available, several studies have found isotretinoin to be very effective in improving acne severity and providing impressive long-term remission. Given its efficacy record, the Clinical Guideline Task Force of the American Academy of Dermatology recommends it based on consistent and good-quality patient-oriented evidence — its strongest recommendation ranking.23 Patient satisfaction ratings after treatment with isotretinoin are highly favorable.
