Isotretinoin is remarkably effective in curing acne, possibly because it affects—primarily or secondarily—all etiologic factors implicated in the pathogenesis of acne: sebum production, comedogenesis, and colonization with Propionibacterium acnes.16 Of all the natural and synthetic retinoids used in humans, only isotretinoin suppresses sebum excretion and reduces sebaceous gland size.
In the early 1980s, isotretinoin treatment was restricted to patients with severe nodulocystic acne. With increasing experience, however, its use has been extended to patients with less severe disease who respond unsatisfactorily to conventional therapies such as long-term antibiotics because of the increased resistance of P. acnes to many antibiotics.17,18
The retinoid of first choice for oral treatment of psoriasis is acitretin. Acitretin appears to be as effective as etretinate and can be used in the same combination regimens.19–23 The best results have been obtained in pustular psoriasis of the palmoplantar or generalized (von Zumbusch) type.19,24,25 Rebound does not usually occur after treatment is stopped, and reintroduction of the drug when it does occur produces a beneficial response.26 Although complete clearing of plaque-type psoriasis is achieved in only approximately 30% of treated patients, significant improvement is obtained in a further 50%.5,27,28 The decrease in the psoriasis area and severity index is approximately 60%–70%, depending on the dosage.5,8 Approximately 20% of patients may be considered to experience treatment failures. Combination of acitretin with other antipsoriatic agents may then be required (see Section “Dosing Regimens”).
In a 20-week treatment study,29 six of eleven patients (54%) with HIV infection who had psoriasis showed good-to-excellent responses to acitretin monotherapy (75 mg/day). Both skin and joint manifestations responded to acitretin therapy in most patients. The adverse effects were moderate and well tolerated, and measures of immune parameters did not indicate exacerbation of immunosuppression in most patients.
Isotretinoin has less effect on psoriasis than acitretin or etretinate, although some efficacy has been shown in combination with psoralen plus ultraviolet A light (PUVA) therapy.12 Nevertheless, some dermatologists use isotretinoin to treat women with psoriasis who need systemic retinoids to avoid the long postacitretin contraception period required.
Alitretinoin was recently approved in several European countries and in Canada for treatment-resistant chronic hand eczema. Between 3 and 6 months of therapy is usually required to fully appreciate the effect.30
Acitretin and etretinate have been used for many years “off-lable” to treat hyperkeratotic (tylotic) hand and foot eczema.
Cutaneous T-Cell Lymphoma
In 1999, the FDA approved bexarotene as oral therapy for the treatment of CTCL that is refractory to at least one systemic therapy. In early (IA-IIA) and advanced (IIB-IVB) stages of CTCL (see Chapter 145), oral bexarotene monotherapy produced approximately 60% and 50% response rates, respectively, at a dosage of 300 mg/m2 or more per day within the first 2 months in most patients.32,33
Older studies showed that etretinate may induce clinical improvement in patients with CTCL (e.g., mycosis fungoides or Sézary syndrome) with no internal involvement; better results were obtained when etretinate was combined with PUVA treatment or interferon-α therapy. Use of the combination of acitretin or isotretinoin with oral vitamin D3 (calcitriol) to obtain synergistic effects in the treatment of CTCL has been reported.31
Clinical Uses Not Approved by the US Food and Drug Administration
Multiple other skin disorders respond to retinoids, but for only a few of them is the effect established in controlled studies.34 In many reports the choice of etretinate/acitretin rather than isotretinoin was based not on pharmacologic considerations but on availability of the product. Bexarotene and alitretinoin have not been tested extensively for indications other than CTCL and hand eczema, respectively.
Among the different types of ichthyosis, the best results are obtained with acitretin for autosomal recessive congenital ichthyoses such as lamellar ichthyosis. Treatment of epidermolytic ichthyosis (bullous ichthyosiform erythroderma) may lead to an initial increase in bullae. Good results also have been achieved in treating recessive X-linked ichthyosis, ichthyosis vulgaris, and palmoplantar keratoderma; if they are of limited severity, these diseases often do not require retinoid therapy (see Chapters 49 and 50).
Moderate-to-severe forms of Darier disease (Darier-White disease) are good indications for retinoid therapy. Care should be taken to initiate therapy with a low dosage, such as 10 mg/day of acitretin, to prevent initial exacerbation of the disease; usually 20 mg/day is sufficient for significant improvement. Long-term treatment is usually needed to prevent relapse. Low-dose isotretinoin therapy has been used especially in women with Darier disease. Combination of retinoids with antibiotics may enhance the clinical effects, because skin lesions are frequently infected (see Chapter 51).
Early treatment with retinoids appears to offer the best chance for clearing of pityriasis rubra pilaris. In extensive cases, concomitant use of methotrexate may be advantageous, but this combination carries an increased risk for toxicity. Etretinate is considered to be superior to isotretinoin in the treatment of adult-onset pityriasis rubra pilaris (see Chapter 24).35
In severe forms or in treatment-resistant rosacea, isotretinoin therapy may be more effective for inflammatory lesions than for vascular lesions.36 A low daily dose (10 mg) is often sufficient. The best indications are severe cases of rosacea associated with significant seborrhea (see Chapter 81).
Isotretinoin has limited effect on hidradenitis suppurativa, but some investigators recommend this therapy during the weeks or months preceding surgical treatment. Prolonged therapy with acitretin/etretinate has been used with some success, especially in treating extensive, inflammatory lesions unsuitable for surgery (see Chapter 85).37,38
Premalignant and Malignant Skin Lesions
Etretinate and acitretin are effective in the treatment of premalignant skin lesions, including human papillomavirus-induced tumors and actinic keratoses. In basal cell nevus syndrome and in xeroderma pigmentosum, these drugs reduce dramatically the incidence of malignant degeneration of the skin lesions. A double-blind study demonstrated that acitretin at a dosage of 30 mg/day for 6 months prevented the development of premalignant and malignant skin lesions in renal transplant recipients (see Chapters 113, 114, 115 and 116.)39
Acitretin/etretinate is an effective treatment for severe lichen sclerosus et atrophicus of the vulva and may be recommended intermittently for patients who are intolerant of or resistant to local therapies (see Chapter 65).40
Both isotretinoin and acitretin have been used successfully in patients with various forms of lupus erythematosus. However, the lesions recur after completion of treatment as quickly as the initial improvement appeared. Acitretin and hydroxychloroquine are equally effective in the treatment of chronic discoid lupus erythematosus and subacute cutaneous lupus erythematosus (see Chapter 155).12