The role of isotretinoin in the treatment of acne: personal observations
Authors: James J. Leyden
Journal: Journal of the American Academy of Dermatology (1998)

Table IIsotretinoin mechanisms of actionSebum suppressionNormalization of follicular epithelial desquamationP. acnes reduction—secondary to decrease in sebumAnti-inflammatory Open table in a new tab This review will summarize our experience over the past 15 years with this remarkable therapy.ISOTRETINOIN CANDIDATESTable IIIsotretinoin indications for patients with acne who are appropriate for treatment with isotretinoin*Nodulocystic acneInflammatory acne with scarringAcne with severe psychological distressGram-negative folliculitisPyoderma facialeSevere acne rosacea* It should be noted that isotretinoin is indicated by the FDA only for the treatment of severe recalcitrant nodulocystic acne or for patients with severe inflammatory acne whose condition has failed to respond to topical therapies. Open table in a new tab Isotretinoin was also used by these dermatologists for less common variants of acne such as granulomatous rosacea, papular rosacea unresponsive to oral antibiotics, and Gram-negative folliculitis.ISOTRETINOIN DOSEClinical trials before FDA approval established a dose response for length of remission but not a clear correlation for clinical responsiveness. Dosing of 1 mg/kg for 4 to 5 months resulted in the lowest rate of relapse, and that dose became the standard recommendation. Although no dose-response relationship was found for the prevalence of side effects, the intensity of side effects appears to be influenced by dose. My own approach has been to start slowly with 0.5 mg/kg and to raise the dose to 1.0 mg/kg if side effects are minimal. This approach is similar to that used by many dermatologists on the consensus panel. The group agreed that the goal should be a minimum total dose of 120 mg/kg, and many in the group continue treatment until a total of 150 mg/kg has been reached. The total time needed to achieve total dose is governed by side effects. Our experience suggests that this approach allows a flexibility that minimizes side effects without compromising clinical response. This cumulative total dose results in 60% of patients requiring no further treatment up to 10 years after a single course of oral therapy. Of those who experience a relapse, approximately 21% require only topical therapy, 16% require oral antibiotics, and 40% require no constant therapy. Approximately 23% of those who experience relapse require additional isotretinoin therapy.10Layton AM Knaggs H Taylor J Cunliffe WJ Isotretinoin for acne vulgaris—10 years later: a safe and successful treatment.Br J Dermatol. 1993; 129: 292-296Crossref PubMed Scopus (198) Google ScholarCommonly asked questions include how soon after a course of isotretinoin can a second course be given and how many courses of isotretinoin can a patient receive. It is rare for a patient to experience a significant relapse within 1 or 2 months of a course of isotretinoin. I have had experience with 6 patients—5 women and 1 man—who experienced a severe relapse within 2 months of a course of isotretinoin. Subsequent courses of isotretinoin, with even higher cumulative total doses of 200 mg/kg, were also followed by prompt relapses. The women had normal hormonal profiles. The basis for this prompt relapse remains obscure. My approach with the conditions of these patients was to use estrogen and/or antiandrogen therapy in the women and prolonged isotretinoin therapy in the man. Two of the women responded poorly to estrogen and antiandrogen therapy, and their conditions were subsequently controlled with prolonged low-dose isotretinoin therapy. Concerns about pregnancy limit the use of isotretinoin on a long-term basis in women. A far more typical patient is one who experiences a significant relapse many months or even years after a course of isotretinoin. My approach with those patients is to give another full course (150 mg/kg) and to repeat the treatment as needed. Over the years I have treated many patients with as many as 5 courses. In women, the option of antiandrogen therapy, such as spironolactone 100 to 200 mg/day and some of the newer oral contraceptives containing norgestimate, is an attractive alternative. The combination of ethinyl estradiol and norgestimate has been shown to increase sex hormone–binding globulin and to decrease free testosterone in healthy women.13Redmond GP Olson WH Lippman JS et al.Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized placebo-controlled trial.Obstet Gynecol. 1997; 89: 615-622Crossref PubMed Scopus (220) Google Scholar In addition, ethinyl estradiol can decrease production of ovarian androgens by suppressing the secretion of pituitary gonadotrophins. The combination of low-dose ethinyl estradiol 35 mg with norgestimate as the progestin has been shown to be effective in treating acne13Redmond GP Olson WH Lippman JS et al.Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized placebo-controlled trial.Obstet Gynecol. 1997; 89: 615-622Crossref PubMed Scopus (220) Google Scholar ; in fact, the triphasic norgestimate oral contraceptive formulation has been approved by the FDA for this indication.ISOTRETINOIN RELAPSE AND FAILURETable IIIPatients with a high probability of relapse or failure with isotretinoinPreteens and young teenagersSinus tract lesionsExcess granulation tissueAndrogen excess Open table in a new tab Preteens and young teenagers with nodulocystic acne respond to isotretinoin therapy but have a high probability of relapse within 2 years and commonly require 2 to 4 courses of therapy before permanent remission occurs. The reasons for this difference in response remain unclear.By far the most common cause of failure to respond to therapy is the poor response of epithelial sinus tracts. Patients with a personal or family history of sinus tract disease (such as pilonidal sinus, hidradenitis, or dissecting cellulitis of the scalp) are prone to form undermining epithelial sinus tracts when sebaceous follicles are disrupted. These lesions are recognizable by their linear, angular configuration and their chromic condition. Patients often describe this as "growing." Typically a lesion has been present for months and has been injected with corticosteroids on several occasions but continues to extend. When the lesions are on the face, they can respond to isotretinoin and then relapse. Trunk lesions are less responsive. Identification of these lesions before isotretinoin therapy can help prepare a patient for the potential need for surgical removal if intralesional steroids and isotretinoin are not successful.Many patients with severe acne will have lesions that have hemorrhagic crusting and result in bleeding when subjected to minimal trauma. Isotretinoin and other retinoids stimulate granulation tissue and cause hemorrhagic or crusted lesions to erupt into pyogenic granuloma-like lesions.14Exner JH Dahod S Pochi PE Pyogenic granuloma-like acne lesions during isotretinoin therapy.Arch Dermatol. 1983; 119: 808-811Crossref PubMed Scopus (80) Google Scholar In addition, severe destructive hemorrhagic lesions with arthralgia, fever, and leukocytosis (acne fulminans) can be precipitated. No formal randomized clinical trials have been conducted to test various approaches to preventing or treating extreme granulation tissue because of the difficulties in accumulating sufficient numbers of patients. My approach is to start isotretinoin very slowly at 0.1 mg/kg/day in combination with topical therapy consisting of compresses and topical corticosteroids; the dose of isotretinoin is then raised slowly to 0.5 mg/kg. When any sign of extreme granulation tissue develops, isotretinoin is stopped until those lesions have healed.Patients who experience spontaneous development of acne fulminans are best treated with oral corticosteroids and local therapy. Once their unusual form of inflammation has subsided, isotretinoin can be used to control the basic acne process.Female patients can have acne as part of their androgen excess state. These patients will respond to a course of isotretinoin but very commonly will experience relapse within 6 months; elevated androgens appear to be a strong-enough stimulus for sebaceous gland regrowth and recurrence of acne. Estrogen and/or antiandrogen therapy is the most likely effective approach. In addition, a subset of these patients has a syndrome known as android obesity. A characteristic habitus of a large upper body with spindly legs and flat buttocks give a "Humpty-Dumpty" look. These patients frequently have diabetes, a tendency for increased triglycerides (which may rise dramatically with isotretinoin therapy), and, most importantly, a higher incidence of uterine cancer.SIDE EFFECTSTable IVPatient populations who may experience greater side effects with isotretinoinCompetitive ice skaters, gymnasts, and ballet studentsLong-distance runnersWeightliftersContact sportsHistory of bone injuriesContact lens wearersHistory of nose bleedingFamily history of elevated triglycerides and cholesterolHistory of atopic disease and xerosis Open table in a new tab Significant systemic side effects such as abnormal liver function appear to be rare. In the experience of the consensus group, only mild, usually transient elevated liver enzymes were found in 1000 patients, and these changes did not result in a change of dosage. Skeletal hyperostosis has been observed on radiographs of patients treated with isotretinoin. Other types of bone abnormalities have been reported, but no causal relationship has been determined.DISCUSSIONIn the 15 years that isotretinoin has been available, this therapy has proved to be extraordinarily effective and safe, provided patients and physicians work together to prevent significant side effects. The consensus group felt strongly that isotretinoin should be used as a first-line therapy in patients with severe acne.12Cunliffe WJ Caputo R Cavicchini S et al.Roaccutane treatment guidelines: results of an international study.Dermatology. 1997; 194: 351-357Crossref PubMed Scopus (189) Google Scholar The increasing problem of P. acnes resistance to antibiotics is resulting in more patients with inflammatory acne who are less responsive.15Eady EA Holland KT Cunliffe WJ Should topical antibiotics be used for the treatment of acne vulgaris?.Br J Dermatol. 1982; 107: 235-246Crossref PubMed Scopus (25) Google Scholar, 16Nishijima S Akamatsu H Akamatsu M Kurokawa I Asada Y. The antibiotic susceptibility of Propionibac-terium acnes and Staphylococcus epidermidis isolated from acne patients.J Dermatol (Japan). 1994; 21: 166-171PubMed Google Scholar, 17Oakley A Rademaker M Duffill M Leng R Shewan J. Propionibacterium : resistance of acne to antibiotics.N Z Med J. 1995; 108: 43-44PubMed Google Scholar, 18Eady EA Jones CE Tipper JL Cove JH Cunliffe WJ Layton AM Antibiotic resistant Propionibacterium : need for policies to modify antibiotic usage.Br Med J. 1993; 306: 555-556Crossref PubMed Scopus (169) Google Scholar An ongoing trial in patients with antibiotic-resistant P. acnes indicates that isotretinoin is highly effective; treatment of P. acnes may well become a new indication for this drug. The consensus group also strongly recommended isotretinoin therapy for patients with significant physical scarring and emotional distress. Likewise, a further recommendation was noted for emphasizing the psychosocial aspects of acne and including them as part of the equation for determining therapy.19Simpson N. Effect of isotretinoinon on the quality of life of patients with acne.Pharmacoeconomics. 1994; 6: 108-113Crossref PubMed Scopus (39) Google Scholar, 20Voorhees JJ Psychiatric aspects of the treatment of mild to moderate facial acne.Int J Dermatol. 1990; 29: 719-721Crossref PubMed Scopus (75) Google Scholar, 21Krowchuk DP Stancin T Keskinen R Walker R Bass J Anglin TM The psychosocial effects of acne on adolescents.Pediatr Dermatol. 1991; 8: 332-338Crossref PubMed Scopus (128) Google Scholar, 22Koo JYM Psychological impact of acne: patients perceptions.J Am Acad Dermatol. 1995; 32: S26-S30Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 23MacDonald-Hull S Cunliffe WJ Hughes BR Treatment of the depressed and dysmorphophobic acne patient.Clin Exp Dermatol. 1991; 16: 210-211Crossref PubMed Scopus (50) Google ScholarAlthough there were variations in the doses prescribed, the group agreed that a goal of a cumulative dose of 120 to 150 mg/kg was the current best recommendation.12Cunliffe WJ Caputo R Cavicchini S et al.Roaccutane treatment guidelines: results of an international study.Dermatology. 1997; 194: 351-357Crossref PubMed Scopus (189) Google Scholar In view of the profound effects of the disease and the psychological benefit for the patient and in light of the cost savings over traditional therapy,24Warren KJ Cruz PD Clinical outcome and cost analysis of oral isotretinoin versus conventional regimens in the treatment of moderate acne vulgaris in male patients [abstract].Am Acad Dermatol Washington. 1996; Google Scholar the group recommended widening the use of isotretinoin in acne. This review will summarize our experience over the past 15 years with this remarkable therapy. ISOTRETINOIN CANDIDATESTable IIIsotretinoin indications for patients with acne who are appropriate for treatment with isotretinoin*Nodulocystic acneInflammatory acne with scarringAcne with severe psychological distressGram-negative folliculitisPyoderma facialeSevere acne rosacea* It should be noted that isotretinoin is indicated by the FDA only for the treatment of severe recalcitrant nodulocystic acne or for patients with severe inflammatory acne whose condition has failed to respond to topical therapies. Open table in a new tab Isotretinoin was also used by these dermatologists for less common variants of acne such as granulomatous rosacea, papular rosacea unresponsive to oral antibiotics, and Gram-negative folliculitis. Isotretinoin was also used by these dermatologists for less common variants of acne such as granulomatous rosacea, papular rosacea unresponsive to oral antibiotics, and Gram-negative folliculitis. ISOTRETINOIN DOSEClinical trials before FDA approval established a dose response for length of remission but not a clear correlation for clinical responsiveness. Dosing of 1 mg/kg for 4 to 5 months resulted in the lowest rate of relapse, and that dose became the standard recommendation. Although no dose-response relationship was found for the prevalence of side effects, the intensity of side effects appears to be influenced by dose. My own approach has been to start slowly with 0.5 mg/kg and to raise the dose to 1.0 mg/kg if side effects are minimal. This approach is similar to that used by many dermatologists on the consensus panel. The group agreed that the goal should be a minimum total dose of 120 mg/kg, and many in the group continue treatment until a total of 150 mg/kg has been reached. The total time needed to achieve total dose is governed by side effects. Our experience suggests that this approach allows a flexibility that minimizes side effects without compromising clinical response. This cumulative total dose results in 60% of patients requiring no further treatment up to 10 years after a single course of oral therapy. Of those who experience a relapse, approximately 21% require only topical therapy, 16% require oral antibiotics, and 40% require no constant therapy. Approximately 23% of those who experience relapse require additional isotretinoin therapy.10Layton AM Knaggs H Taylor J Cunliffe WJ Isotretinoin for acne vulgaris—10 years later: a safe and successful treatment.Br J Dermatol. 1993; 129: 292-296Crossref PubMed Scopus (198) Google ScholarCommonly asked questions include how soon after a course of isotretinoin can a second course be given and how many courses of isotretinoin can a patient receive. It is rare for a patient to experience a significant relapse within 1 or 2 months of a course of isotretinoin. I have had experience with 6 patients—5 women and 1 man—who experienced a severe relapse within 2 months of a course of isotretinoin. Subsequent courses of isotretinoin, with even higher cumulative total doses of 200 mg/kg, were also followed by prompt relapses. The women had normal hormonal profiles. The basis for this prompt relapse remains obscure. My approach with the conditions of these patients was to use estrogen and/or antiandrogen therapy in the women and prolonged isotretinoin therapy in the man. Two of the women responded poorly to estrogen and antiandrogen therapy, and their conditions were subsequently controlled with prolonged low-dose isotretinoin therapy. Concerns about pregnancy limit the use of isotretinoin on a long-term basis in women. A far more typical patient is one who experiences a significant relapse many months or even years after a course of isotretinoin. My approach with those patients is to give another full course (150 mg/kg) and to repeat the treatment as needed. Over the years I have treated many patients with as many as 5 courses. In women, the option of antiandrogen therapy, such as spironolactone 100 to 200 mg/day and some of the newer oral contraceptives containing norgestimate, is an attractive alternative. The combination of ethinyl estradiol and norgestimate has been shown to increase sex hormone–binding globulin and to decrease free testosterone in healthy women.13Redmond GP Olson WH Lippman JS et al.Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized placebo-controlled trial.Obstet Gynecol. 1997; 89: 615-622Crossref PubMed Scopus (220) Google Scholar In addition, ethinyl estradiol can decrease production of ovarian androgens by suppressing the secretion of pituitary gonadotrophins. The combination of low-dose ethinyl estradiol 35 mg with norgestimate as the progestin has been shown to be effective in treating acne13Redmond GP Olson WH Lippman JS et al.Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized placebo-controlled trial.Obstet Gynecol. 1997; 89: 615-622Crossref PubMed Scopus (220) Google Scholar ; in fact, the triphasic norgestimate oral contraceptive formulation has been approved by the FDA for this indication. Clinical trials before FDA approval established a dose response for length of remission but not a clear correlation for clinical responsiveness. Dosing of 1 mg/kg for 4 to 5 months resulted in the lowest rate of relapse, and that dose became the standard recommendation. Although no dose-response relationship was found for the prevalence of side effects, the intensity of side effects appears to be influenced by dose. My own approach has been to start slowly with 0.5 mg/kg and to raise the dose to 1.0 mg/kg if side effects are minimal. This approach is similar to that used by many dermatologists on the consensus panel. The group agreed that the goal should be a minimum total dose of 120 mg/kg, and many in the group continue treatment until a total of 150 mg/kg has been reached. The total time needed to achieve total dose is governed by side effects. Our experience suggests that this approach allows a flexibility that minimizes side effects without compromising clinical response. This cumulative total dose results in 60% of patients requiring no further treatment up to 10 years after a single course of oral therapy. Of those who experience a relapse, approximately 21% require only topical therapy, 16% require oral antibiotics, and 40% require no constant therapy. Approximately 23% of those who experience relapse require additional isotretinoin therapy.10Layton AM Knaggs H Taylor J Cunliffe WJ Isotretinoin for acne vulgaris—10 years later: a safe and successful treatment.Br J Dermatol. 1993; 129: 292-296Crossref PubMed Scopus (198) Google Scholar Commonly asked questions include how soon after a course of isotretinoin can a second course be given and how many courses of isotretinoin can a patient receive. It is rare for a patient to experience a significant relapse within 1 or 2 months of a course of isotretinoin. I have had experience with 6 patients—5 women and 1 man—who experienced a severe relapse within 2 months of a course of isotretinoin. Subsequent courses of isotretinoin, with even higher cumulative total doses of 200 mg/kg, were also followed by prompt relapses. The women had normal hormonal profiles. The basis for this prompt relapse remains obscure. My approach with the conditions of these patients was to use estrogen and/or antiandrogen therapy in the women and prolonged isotretinoin therapy in the man. Two of the women responded poorly to estrogen and antiandrogen therapy, and their conditions were subsequently controlled with prolonged low-dose isotretinoin therapy. Concerns about pregnancy limit the use of isotretinoin on a long-term basis in women. A far more typical patient is one who experiences a significant relapse many months or even years after a course of isotretinoin. My approach with those patients is to give another full course (150 mg/kg) and to repeat the treatment as needed. Over the years I have treated many patients with as many as 5 courses. In women, the option of antiandrogen therapy, such as spironolactone 100 to 200 mg/day and some of the newer oral contraceptives containing norgestimate, is an attractive alternative. The combination of ethinyl estradiol and norgestimate has been shown to increase sex hormone–binding globulin and to decrease free testosterone in healthy women.13Redmond GP Olson WH Lippman JS et al.Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized placebo-controlled trial.Obstet Gynecol. 1997; 89: 615-622Crossref PubMed Scopus (220) Google Scholar In addition, ethinyl estradiol can decrease production of ovarian androgens by suppressing the secretion of pituitary gonadotrophins. The combination of low-dose ethinyl estradiol 35 mg with norgestimate as the progestin has been shown to be effective in treating acne13Redmond GP Olson WH Lippman JS et al.Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized placebo-controlled trial.Obstet Gynecol. 1997; 89: 615-622Crossref PubMed Scopus (220) Google Scholar ; in fact, the triphasic norgestimate oral contraceptive formulation has been approved by the FDA for this indication. ISOTRETINOIN RELAPSE AND FAILURETable IIIPatients with a high probability of relapse or failure with isotretinoinPreteens and young teenagersSinus tract lesionsExcess granulation tissueAndrogen excess Open table in a new tab Preteens and young teenagers with nodulocystic acne respond to isotretinoin therapy but have a high probability of relapse within 2 years and commonly require 2 to 4 courses of therapy before permanent remission occurs. The reasons for this difference in response remain unclear.By far the most common cause of failure to respond to therapy is the poor response of epithelial sinus tracts. Patients with a personal or family history of sinus tract disease (such as pilonidal sinus, hidradenitis, or dissecting cellulitis of the scalp) are prone to form undermining epithelial sinus tracts when sebaceous follicles are disrupted. These lesions are recognizable by their linear, angular configuration and their chromic condition. Patients often describe this as "growing." Typically a lesion has been present for months and has been injected with corticosteroids on several occasions but continues to extend. When the lesions are on the face, they can respond to isotretinoin and then relapse. Trunk lesions are less responsive. Identification of these lesions before isotretinoin therapy can help prepare a patient for the potential need for surgical removal if intralesional steroids and isotretinoin are not successful.Many patients with severe acne will have lesions that have hemorrhagic crusting and result in bleeding when subjected to minimal trauma. Isotretinoin and other retinoids stimulate granulation tissue and cause hemorrhagic or crusted lesions to erupt into pyogenic granuloma-like lesions.14Exner JH Dahod S Pochi PE Pyogenic granuloma-like acne lesions during isotretinoin therapy.Arch Dermatol. 1983; 119: 808-811Crossref PubMed Scopus (80) Google Scholar In addition, severe destructive hemorrhagic lesions with arthralgia, fever, and leukocytosis (acne fulminans) can be precipitated. No formal randomized clinical trials have been conducted to test various approaches to preventing or treating extreme granulation tissue because of the difficulties in accumulating sufficient numbers of patients. My approach is to start isotretinoin very slowly at 0.1 mg/kg/day in combination with topical therapy consisting of compresses and topical corticosteroids; the dose of isotretinoin is then raised slowly to 0.5 mg/kg. When any sign of extreme granulation tissue develops, isotretinoin is stopped until those lesions have healed.Patients who experience spontaneous development of acne fulminans are best treated with oral corticosteroids and local therapy. Once their unusual form of inflammation has subsided, isotretinoin can be used to control the basic acne process.Female patients can have acne as part of their androgen excess state. These patients will respond to a course of isotretinoin but very commonly will experience relapse within 6 months; elevated androgens appear to be a strong-enough stimulus for sebaceous gland regrowth and recurrence of acne. Estrogen and/or antiandrogen therapy is the most likely effective approach. In addition, a subset of these patients has a syndrome known as android obesity. A characteristic habitus of a large upper body with spindly legs and flat buttocks give a "Humpty-Dumpty" look. These patients frequently have diabetes, a tendency for increased triglycerides (which may rise dramatically with isotretinoin therapy), and, most importantly, a higher incidence of uterine cancer. Preteens and young teenagers with nodulocystic acne respond to isotretinoin therapy but have a high probability of relapse within 2 years and commonly require 2 to 4 courses of therapy before permanent remission occurs. The reasons for this difference in response remain unclear. By far the most common cause of failure to respond to therapy is the poor response of epithelial sinus tracts. Patients with a personal or family history of sinus tract disease (such as pilonidal sinus, hidradenitis, or dissecting cellulitis of the scalp) are prone to form undermining epithelial sinus tracts when sebaceous follicles are disrupted. These lesions are recognizable by their linear, angular configuration and their chromic condition. Patients often describe this as "growing." Typically a lesion has been present for months and has been injected with corticosteroids on several occasions but continues to extend. When the lesions are on the face, they can respond to isotretinoin and then relapse. Trunk lesions are less responsive. Identification of these lesions before isotretinoin therapy can help prepare a patient for the potential need for surgical removal if intralesional steroids and isotretinoin are not successful. Many patients with severe acne will have lesions that have hemorrhagic crusting and result in bleeding when subjected to minimal trauma. Isotretinoin and other retinoids stimulate granulation tissue and cause hemorrhagic or crusted lesions to erupt into pyogenic granuloma-like lesions.14Exner JH Dahod S Pochi PE Pyogenic granuloma-like acne lesions during isotretinoin therapy.Arch Dermatol. 1983; 119: 808-811Crossref PubMed Scopus (80) Google Scholar In addition, severe destructive hemorrhagic lesions with arthralgia, fever, and leukocytosis (acne fulminans) can be precipitated. No formal randomized clinical trials have been conducted to test various approaches to preventing or treating extreme granulation tissue because of the difficulties in accumulating sufficient numbers of patients. My approach is to start isotretinoin very slowly at 0.1 mg/kg/day in combination with topical therapy consisting of compresses and topical corticosteroids; the dose of isotretinoin is then raised slowly to 0.5 mg/kg. When any sign of extreme granulation tissue develops, isotretinoin is stopped until those lesions have healed. Patients who experience spontaneous development of acne fulminans are best treated with oral corticosteroids and local therapy. Once their unusual form of inflammation has subsided, isotretinoin can be used to control the basic acne process. Female patients can have acne as part of their androgen excess state. These patients will respond to a course of isotretinoin but very commonly will experience relapse within 6 months; elevated androgens appear to be a strong-enough stimulus for sebaceous gland regrowth and recurrence of acne. Estrogen and/or antiandrogen therapy is the most likely effective approach. In addition, a subset of these patients has a syndrome known as android obesity. A characteristic habitus of a large upper body with spindly legs and flat buttocks give a "Humpty-Dumpty" look. These patients frequently have diabetes, a tendency for increased triglycerides (which may rise dramatically with isotretinoin therapy), and, most importantly, a higher incidence of uterine cancer. SIDE EFFECTSTable IVPatient populations who may experience greater side effects with isotretinoinCompetitive ice skaters, gymnasts, and ballet studentsLong-distance runnersWeightliftersContact sportsHistory of bone injuriesContact lens wearersHistory of nose bleedingFamily history of elevated triglycerides and cholesterolHistory of atopic disease and xerosis Open table in a new tab Significant systemic side effects such as abnormal liver function appear to be rare. In the experience of the consensus group, only mild, usually transient elevated liver enzymes were found in 1000 patients, and these changes did not result in a change of dosage. Skeletal hyperostosis has been observed on radiographs of patients treated with isotretinoin. Other types of bone abnormalities have been reported, but no causal relationship has been determined. Significant systemic side effects such as abnormal liver function appear to be rare. In the experience of the consensus group, only mild, usually transient elevated liver enzymes were found in 1000 patients, and these changes did not result in a change of dosage. Skeletal hyperostosis has been observed on radiographs of patients treated with isotretinoin. Other types of bone abnormalities have been reported, but no causal relationship has been determined. DISCUSSIONIn the 15 years that isotretinoin has been available, this therapy has proved to be extraordinarily effective and safe, provided patients and physicians work together to prevent significant side effects. The consensus group felt strongly that isotretinoin should be used as a first-line therapy in patients with severe acne.12Cunliffe WJ Caputo R Cavicchini S et al.Roaccutane treatment guidelines: results of an international study.Dermatology. 1997; 194: 351-357Crossref PubMed Scopus (189) Google Scholar The increasing problem of P. acnes resistance to antibiotics is resulting in more patients with inflammatory acne who are less responsive.15Eady EA Holland KT Cunliffe WJ Should topical antibiotics be used for the treatment of acne vulgaris?.Br J Dermatol. 1982; 107: 235-246Crossref PubMed Scopus (25) Google Scholar, 16Nishijima S Akamatsu H Akamatsu M Kurokawa I Asada Y. The antibiotic susceptibility of Propionibac-terium acnes and Staphylococcus epidermidis isolated from acne patients.J Dermatol (Japan). 1994; 21: 166-171PubMed Google Scholar, 17Oakley A Rademaker M Duffill M Leng R Shewan J. Propionibacterium : resistance of acne to antibiotics.N Z Med J. 1995; 108: 43-44PubMed Google Scholar, 18Eady EA Jones CE Tipper JL Cove JH Cunliffe WJ Layton AM Antibiotic resistant Propionibacterium : need for policies to modify antibiotic usage.Br Med J. 1993; 306: 555-556Crossref PubMed Scopus (169) Google Scholar An ongoing trial in patients with antibiotic-resistant P. acnes indicates that isotretinoin is highly effective; treatment of P. acnes may well become a new indication for this drug. The consensus group also strongly recommended isotretinoin therapy for patients with significant physical scarring and emotional distress. Likewise, a further recommendation was noted for emphasizing the psychosocial aspects of acne and including them as part of the equation for determining therapy.19Simpson N. Effect of isotretinoinon on the quality of life of patients with acne.Pharmacoeconomics. 1994; 6: 108-113Crossref PubMed Scopus (39) Google Scholar, 20Voorhees JJ Psychiatric aspects of the treatment of mild to moderate facial acne.Int J Dermatol. 1990; 29: 719-721Crossref PubMed Scopus (75) Google Scholar, 21Krowchuk DP Stancin T Keskinen R Walker R Bass J Anglin TM The psychosocial effects of acne on adolescents.Pediatr Dermatol. 1991; 8: 332-338Crossref PubMed Scopus (128) Google Scholar, 22Koo JYM Psychological impact of acne: patients perceptions.J Am Acad Dermatol. 1995; 32: S26-S30Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 23MacDonald-Hull S Cunliffe WJ Hughes BR Treatment of the depressed and dysmorphophobic acne patient.Clin Exp Dermatol. 1991; 16: 210-211Crossref PubMed Scopus (50) Google ScholarAlthough there were variations in the doses prescribed, the group agreed that a goal of a cumulative dose of 120 to 150 mg/kg was the current best recommendation.12Cunliffe WJ Caputo R Cavicchini S et al.Roaccutane treatment guidelines: results of an international study.Dermatology. 1997; 194: 351-357Crossref PubMed Scopus (189) Google Scholar In view of the profound effects of the disease and the psychological benefit for the patient and in light of the cost savings over traditional therapy,24Warren KJ Cruz PD Clinical outcome and cost analysis of oral isotretinoin versus conventional regimens in the treatment of moderate acne vulgaris in male patients [abstract].Am Acad Dermatol Washington. 1996; Google Scholar the group recommended widening the use of isotretinoin in acne. In the 15 years that isotretinoin has been available, this therapy has proved to be extraordinarily effective and safe, provided patients and physicians work together to prevent significant side effects. The consensus group felt strongly that isotretinoin should be used as a first-line therapy in patients with severe acne.12Cunliffe WJ Caputo R Cavicchini S et al.Roaccutane treatment guidelines: results of an international study.Dermatology. 1997; 194: 351-357Crossref PubMed Scopus (189) Google Scholar The increasing problem of P. acnes resistance to antibiotics is resulting in more patients with inflammatory acne who are less responsive.15Eady EA Holland KT Cunliffe WJ Should topical antibiotics be used for the treatment of acne vulgaris?.Br J Dermatol. 1982; 107: 235-246Crossref PubMed Scopus (25) Google Scholar, 16Nishijima S Akamatsu H Akamatsu M Kurokawa I Asada Y. The antibiotic susceptibility of Propionibac-terium acnes and Staphylococcus epidermidis isolated from acne patients.J Dermatol (Japan). 1994; 21: 166-171PubMed Google Scholar, 17Oakley A Rademaker M Duffill M Leng R Shewan J. Propionibacterium : resistance of acne to antibiotics.N Z Med J. 1995; 108: 43-44PubMed Google Scholar, 18Eady EA Jones CE Tipper JL Cove JH Cunliffe WJ Layton AM Antibiotic resistant Propionibacterium : need for policies to modify antibiotic usage.Br Med J. 1993; 306: 555-556Crossref PubMed Scopus (169) Google Scholar An ongoing trial in patients with antibiotic-resistant P. acnes indicates that isotretinoin is highly effective; treatment of P. acnes may well become a new indication for this drug. The consensus group also strongly recommended isotretinoin therapy for patients with significant physical scarring and emotional distress. Likewise, a further recommendation was noted for emphasizing the psychosocial aspects of acne and including them as part of the equation for determining therapy.19Simpson N. 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