Perspectives on Isotretinoin and the Canadian Consensus Guidelines on Treatment of Acne

J. K. L. Tan, MD, FRCP

Acne Care Center, Windsor, Ontario

ABSTRACT

Treatment objectives and pharmacoeconomic considerations are important when developing guidelines that are effective and rational. Canadian Acne Treatment Guidelines were last published in 1995. New guidelines were recently developed to incorporate therapeutic advances and data from more recent studies. Isotretinoin fulfills the major objectives of acne treatment and has clear pharmacoeconomic advantages when compared to conventional rotational oral antibiotics, antiandrogens and topical therapy in the treatment of moderate-to-severe acne. It should be considered the standard of treatment for scarring acne and moderate-to-severe non-scarring acne.

Key Words:
Acne Vulgaris, Isotretinoin, guidelines

The treatment of any condition must comprise the following
objectives, either singly or in combination:

• cure
• prevention of recurrence
• limitation of structural or functional deterioration
• prevention of complications
• relief of signs and symptoms
• maintenance of comfort and dignity
• preservation of self-esteem¹

These objectives as well as pharmacoeconomic considerations are of particular importance in the development of clinical guidelines that are effective and rational. Since the publication of the last Canadian Acne Treatment Guidelines in 1995, some of these issues have been further elucidated.² The new Canadian Consensus Guidelines for Treatment of Acne Vulgaris and Prevention of Acne Scarring³ were developed to incorporate therapeutic advances and information from recent epidemiological, pharmacoeconomic, and psychometric studies of acne.

Definition of Severe Acne

Severe acne in earlier guidelines² was defined as the combined presence of numerous comedones, papules, nodules and multiple scars. In contrast, the new Canadian Consensus Guidelines are based on the Consensus Panel of Acne Classification²⁰ definition of severe acne, in which the diagnosis is based on the presence of any of the following:

• persistent or recurrent inflammatory nodules
• extensive papulopustular disease
• ongoing scarring
• persistent purulent and/or serosanguineous drainage from lesions
• presence of sinus tracts
• psychosocial and occupational impact
• inadequate therapeutic response

The presence of acne scars and the severity of inflammatory lesions are independent indicators of severe acne. The current guidelines were developed to emphasize the need for appropriate clinical sensitivity to the presence of scarring.

Relief of Signs and Symptoms

The efficacy of isotretinoin in reducing inflammatory acne lesions is presently unrivalled. In a comparative study of isotretinoin (1mg/kg/day) and minocycline (100mg daily for 4 months) the reduction in mean acne grade was approximately 90% and 50%, respectively.⁴ While no studies directly compare hormonal therapy to isotretinoin, Diane-50 (ethinyl estradiol 50ug and cyproterone acetate 2mg) was shown to be equal but not superior in efficacy to tetracycline 500mg bid after 6 months of therapy.⁵ Diane-35 (ethinyl estradiol 35ug and cyproterone acetate 2mg) has been demonstrated to result in a clinically significant reduction in lesion counts and acne grade after six treatment cycles. Rates and duration of remission were not assessed.⁶ Ortho Tricyclen (ethinyl estradiol 35ug and a triphasic regimen of norgestimate) has been shown to reduce total acne lesion counts by 47-53% after six cycles of therapy. However, the length of remission on discontinuation of therapy was not assessed in these studies.^7,8

Cure or Long-term Remission

The sole therapy with demonstrable ability to achieve cure or long-term remission is isotretinoin, given at a standard dose of 1mg/kg. In 179 patients treated with a single course of isotretinoin and follow-up at 3 years, White, et al⁹, found a longterm remission rate of 39% in those treated with a minimum cumulative dose of 100mg/kg. Recurrences requiring only topical therapy were observed in 17%. Twenty-five percent required oral antibiotics, while 19% required further courses of isotretinoin.⁹ In a 10-year study of 88 patients by Layton, et al¹⁰, 40% required no further therapy while 21% required only topical therapy. Sixteen percent required oral antibiotics while 23% required further courses of isotretinoin.¹⁰ In these studies, total cumulative doses exceeding 100mg/kg and 120mg/kg, respectively, produced significantly better results than lower dose regimens.

In contrast, oral antibiotics are not considered to be curative, nor are they remitting agents in the treatment of acne. The 5-year relapse rate for patients taking oral antibiotics has been estimated at 83%.^11,12 In a 6-month study of 62 patients, those treated with Diane-50 alone or in combination with tetracycline 500mg bid continued to maintain improvement in acne grade and lesional counts 2 months after completion of treatment, whereas these parameters deteriorated in those treated with tetracycline alone.⁵ Minocycline, 100mg daily for 4 months, has been shown to reduce the mean acne grade by roughly 50%. However, 6 months after treatment, acne grades had deteriorated and approached pretreatment scores. This tendency to relapse has also been demonstrated with tetracycline. In contrast, isotretinoin resulted in a significantly greater degree of mean acne grade improvement that persisted 6 months after completion of therapy.4 The rates and durability of remission for patients treated with hormonal agents has not been quantified.

Limiting Structural Deterioration

The primary structural sequela of active acne is scarring. Layton, et al¹³, found that scarring affected 95% of 185 acne patients attending their clinic. They also observed that superficial inflammatory papules, not just nodular acne, might be associated with the development of scars. Furthermore, their data showed that inadequately treated acne of up to 3 years duration correlated significantly with an increased risk of scarring. In the only study assessing the effect of early medical intervention on subsequent scarring caused by acne, Layton, et al⁴, observed that the mean scarring score in patients given isotretinoin after 3 years acne duration was significantly higher than in those who had received isotretinoin less than 3 years after acne onset. This suggests that less scarring develops in those receiving isotretinoin early in their disease process.⁴

Table 1: Comparison of isotretinoin with other treatment regimes for acne vulgaris.

Psychometric Assessments

To properly assess scarring, all areas should be examined. This includes the back, shoulders, neck and chest, and the face. The effect of the scars and the active disease on the patient’s psychological status should also be assessed when determining the severity of the disease. If the scarring and/or psychosocial impact is significant, the grade and treatment of acne should be escalated accordingly. Figure 1 (page 3) depicts an algorithm to assist clinicians in determining their options.³

Maintaining Comfort and Dignity or Preserving Self-esteem

Psychometric assessments have demonstrated that treatment with isotretinoin results in significant improvement in the psychological impact of acne.^4,14 Furthermore, while improvement in clinical acne grade, and psychosocial disability can be seen in those treated with isotretinoin and minocycline after 4 months, the improvement in both parameters was significantly greater for isotretinoin.⁴

Pharmacoeconomic Analysis

Pharmacoeconomic analyses of isotretinoin have demonstrated cost-benefit, cost-effectiveness, and cost-minimization advantages compared to conventional rotational oral antibiotics, antiandrogens and topical therapy in treatment of moderate-tosevere acne.^11,12,14,15 A recent cost-minimization analysis compared costs of treatment with the following:

1. isotretinoin on diagnosis with re-treatment based on reported rates of relapse
2. rotational oral antibiotics
3. rotational oral antibiotics with females of child-bearing age also receiving Diane
4. rotational oral antibiotics with isotretinoin only after failure of two antibiotics used for 3 months each.

This study demonstrated that the time for cost equivalence to the isotretinoin regimen was 50 months for rotational oral antibiotics, 35 months for oral antibiotics and Diane, and 10 months for the group receiving isotretinoin after two courses of failed oral antibiotics.^15,16 The latter regimen is similar to that recommended by the previous Canadian Guidelines for Treatment of Acne, in which up to 3 courses of rotational antibiotics each lasting 4–6 months, was advised prior to consideration of isotretinoin.² Those recommendations would have resulted in even more costly treatment. Furthermore, delaying effective therapy for 12–18 months would likely increase the risk and costs associated with treatment of acne scarring and psychosocial disturbances.

Adverse Effects

Although these systemic agents may be associated with adverse effects, the majority of these are mild, well tolerated, and manageable by dosage adjustment or symptomatic therapy. Serious adverse events are rare and include teratogenicity and possibly depression with isotretinoin¹⁷, thromboembolic events with hormonal contraceptives¹⁸, and hypersensitivity reactions with oral antibiotics.¹⁹

The new Canadian Consensus Guidelines differ from the earlier, 1995 version by:

• emphasizing acne scarring as the primary decision point for initial therapy
• recommending early treatment with isotretinoin if acne scars are present
• advancing treatment to isotretinoin after failure of a single course of systemic antibiotics or hormonal therapy at 4 months.

The use of this drug fulfills the major objectives of acne treatment and has clear pharmacoeconomic advantages. Accordingly, it should be considered the standard of treatment for scarring acne and moderate-to-severe non-scarring acne.

References

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