Acitretin is a second generation retinoid (a vitamin A derivative) used as an oral systemic therapy for patients with psoriasis that is too extensive and/or severe for topical treatment. Due to lack of significant immunosuppression and an ability to maintain long-term clinical response with prolonged therapy, acitretin can be a good alternative for severe psoriasis that is resistant to other forms of therapy. Acitretin is a potent teratogen, however, and should not be used in women of childbearing potential.
Acitretin’s ability to regulate keratinization makes acitretin useful for reducing scale in hyperkeratotic psoriasis and making phototherapy more effective. Localized and generalized forms of pustular psoriasis and erythrodermic psoriasis may respond well to acitretin monotherapy. Acitretin may be a good choice for patients with history of melanoma, solid tumors, lymphoproliferative malignancies or HIV because its mechanism of action does not involve significant immunosuppression.
Mechanism of Action
Acitretin functions by modulating the differentiation and proliferation of keratinocytes in the epidermis by binding to nuclear receptors responsible for gene transcription. This process reduces hyperproliferation of the rapidly dividing keratinocytes in patients with psoriasis. This helps to reduce redness, peeling and the overall thickness of skin lesions. Acitretin also has an inhibitory effect on inflammatory molecules that induces premature maturation of keratinocytes and neutrophil chemotaxis.
The therapeutic dosage of acitretin monotherapy is usually between 25 mg every other day and 50 mg per day. Because adverse effects tend to be dose related, the treatment can be initiated at a low dose (10-25 mg per day) and then raised by 10 mg biweekly. This method should be continued until adverse effects experienced by the patient make it advisable to refrain from further increasing the dosage. Since low doses of acitretin are effective in some individuals, gradual dose escalation allows for patients to receive the minimum amount of medication necessary allowing for the best clinical response to be achieved while minimizing side effects. Once an acceptable clinical response has been observed, the dose can be gradually tapered to improve tolerance. This strategy allows for maintenance of efficacy at lower doses for a very long period.
Alternatively, starting high to achieve rapid clinical improvement and then lowering the dose to avoid side effects is another approach that may be preferred by patients who are seeking rapid relief from their psoriasis (ie, in patients with pustular psoriasis.)
Acitretin is somewhat effective when used as monotherapy. In a retrospective, post hoc analysis of 4 randomized, controlled trials (RCTs) of use in generalized pustular, plaque type, severe and erythrodermic variants, 85% of patients had 50% improvement in Psoriasis Area and Severity Index (PASI 50) and 52% achieved a PASI 75 after 12 weeks. Acitretin is useful for long-term maintenance therapy for plaque psoriasis. In a long-term clinical trial, acitretin was effective for plaque psoriasis with 89% of patients achieving a PASI 50 and 78.4% attaining a PASI 75 after 12 months.
In patients with pustular psoriasis, acitretin is a first-line therapy, inducing a rapid clinical response (clearance of lesions in 10 days) in up to 84% of patients. Acitretin induced 5-fold reduction in pustules after 4 weeks in 2 RCTs in patients with palmoplantar pustulosis. Acitretin is also effective for treating nail psoriasis, with doses of 0.2 to 0.3 mg/kg attaining a mean reduction in the Nail Psoriasis Severity Index score of 41% and complete clearance in 25% of patients; acitretin can, however, cause thin, brittle nails, especially when used in high doses. In general, response to acitretin is gradual with peak efficacy usually achieved in 3 to 6 months.
Acitretin is often used in combination with phototherapy. The combination of acitretin with UVB or PUVA therapy is more effective than either phototherapy or acitretin alone. The clearance rate for acitretin with UVB therapy (Re-UVB, 75%) is greater than either acitretin (42%) or UVB (35%-41%).
In addition, combination therapy reduces the overall number of phototherapy sessions and the required dosage of acitretin. Moreover, acitretin exerts anticarcinogenic effects (including normalizing abnormal epidermal cell proliferation, inhibiting tumor cell angiogenesis and down regulating proto-oncogenes) possibly reducing the risk of skin cancer compared to monotherapy with UVB or PUVA.
When used in combination with phototherapy, it is sometimes recommended to administer acitretin at a low dose for 2 weeks before starting phototherapy; the concern is that the photosensitizing effect of acitretin will kick in when patients are getting a high UV dose resulting in a burn. Alternatively, both acitretin and UV can be started together, with the UV dose increased only very slowly. However, for patients already on phototherapy, 25 mg/day of acitretin may be prescribed, while concomitantly decreasing the dosage of phototherapy by 30% to 50% in the first week to prevent phototoxicity/burning.
The combination of calcipotriol ointment and acitretin has additive benefits on the clearance success rate. In a study, the “clear” or “almost clear” success rate with acitretin increased from 41% to 67% with the addition of calcipotriol. In a 12-week study, the complete clearance rate increased from 15% with acitretin alone to 40% with the addition of calcipotriol.
Caution has been advised concerning the use of methotrexate with acitretin, however, the combination has been used safely in some patients. Close monitoring of liver function is recommended when the 2 drugs are used together. Complimentary, sequential use of acitretin and cyclosporine has been recommended. Cyclosporine is fast acting but can cause nephrotoxicity with long-term use; acitretin’s action is slow in plaque psoriasis, but acitretin is not associated with cumulative toxicity. Thus, cyclosporine can be used initially to achieve rapid control over the psoriasis, followed by transition to acitretin to maintain safe long-term control. Both drugs can elevate triglyceride and cholesterol levels.
At low doses of acitretin (less than 25 mg per day), side effects are less common, and adverse effects generally occur at doses of 25 mg or more per day. Most patients will experience some side effects at the beginning of their treatment period. During this initiation period, the most commonly reported adverse effects include cheilitis, alopecia and peeling (Table 1). Acitretin is, like isotretinoin, an oral retinoid, and the side effects of treatment are similar to those of isotretinoin (though acitretin has a longer half-life requiring much longer pregnancy prevention). These effects are often reversible or subside with adjustment of dosage or cessation of treatment, though some patients who get severe alopecia may never want to take the drug again. Avoiding high doses can help reduce side effects.
In addition, patients should be regularly monitored for elevations in liver enzymes, cholesterol and triglycerides. In the past, screening for skeletal changes was recommended but this does not appear necessary in adults being treated for psoriasis (Table 2).
The National Psoriasis Foundation’s Systemic Treatment brochure (www.psoriasis.org/Document.Doc?id=161) is a good resource for educating patients about the risks of and alternatives to acitretin treatment.
Due to the teratogenicity of acitretin and potential for toxicity, there are some contraindications (Table 3). Absolute contraindications include severe liver failure, severe kidney failure, allergy to drug components and pregnancy. Acitretin is classified as pregnancy category X due to retinoid embryopathy resulting in craniofacial dysmorphias, hip malformations and spinal cord abnormalities. Given the many alternatives now available, acitretin should not be used in women of childbearing potential. In the rare case in which acitretin were used in such a patient, 2 effective forms of contraception should begin at least 1 month prior to initiation of treatment and continue use for at least 3 years after cessation of treatment because of the drug’s long half-life. Patients on acitretin should be cautioned not to donate blood because of this teratogenic risk. Additional relative contraindications to the use of acitretin include hypercholesterolemia, bone abnormalities, leukopenia and age under 14 years.
While some guidelines caution against using in patients with alcohol consumption, use in these patients may be appropriate. There is a risk of hepatotoxicity with alcohol and with acitretin, but patients can be monitored for that by checking liver function tests at 3-month intervals. There is also concern that the combination of acitretin plus alcohol can lead to esterification of the acitretin to etretinate; etretinate has a much longer half-life. But as long as acitretin is not used in women of childbearing potential, the potential conversion to etretinate caused by concurrent use of alcohol may be of no clinical significance.
Prior to starting a patient on acitretin, obtain a medical history and perform a baseline workup, including baseline liver function tests and lipid panel (Table 2).
Educate patients of the most common side effects of the drug and preventative measures, as unexpected adverse effects can lead to poor adherence to treatment. Patients should be apprised of their other treatment options. The National Psoriasis Foundation Systemic Treatment brochure is helpful in this regard.
Tips and Tricks
- The appearance of cheilitis is a useful sign that the correct bioavailability of acitretin has been reached.
- The effects of UV radiation are enhanced by retinoids; thus, patients should avoid excessive exposure to sun lamps or sunlight.
- When adding acitretin after initiation of phototherapy, reduce phototherapy dose by 50% 1 week prior to introducing acitretin (10-25 mg/day) to avoid sudden phototoxicity; gradually increase phototherapy dose according to phototoxicity and clinical response.
- Radiological studies (ie, targeted x-rays) are not warranted in acitretin therapy unless atypical musculoskeletal pain develops.
- Patients with diabetes, obesity and alcoholism can be monitored more frequently due to increased risk of hypertriglyceridemia and hepatotoxicity.
- Acitretin is a potent teratogen and should not be used in women of childbearing potential. If acitretin use is required by a woman of childbearing potential, note that acitretin may reduce the efficacy of progestogen contraceptives (ie, mini pill); choose a combined contraceptive pill with both estrogen and progestogen.
- Ideally, for women of childbearing potential, pick another treatment that is not teratogenic. If acitretin has to be used in women of childbearing age in which pregnancy has been excluded, therapy with acitretin should be started on the second or third day of the next menstrual cycle once pregnancy has been excluded.
This article is an excerpt from the book, Practical Psoriasis Management.
Dr. Awosika is a resident physician at Mercy Medical Center in Baltimore, MD.
Mr. Farhangian is a clinical research fellow at Wake Forest Baptist Health in Winston-Salem, NC.
Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine in Winston-Salem, NC.
Disclosure: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec and Bristol-Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol-Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea and Anacor and has received stock options from Photomedex. He is owner of www.DrScore.com and a founder of Causa Research.
Disclosure: The authors report no relevant financial relationships.
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