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Retinoid therapy for psoriasis
Dermatol Clin 22 (2004) 467 – 476
Retinoid therapy for psoriasis Paul S. Yamauchi, MD, PhDa,b, Dalia Rizk, MDa, Nicholas J. Lowe, MDa,b,* a Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USA Division of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1750, USA
b
The systemic retinoids possess a remarkable range of activities and clinical applications. They are an important form of therapy for patients with more severe and resistant types of psoriasis. In general, with plaque psoriasis, systemic retinoids are used most effectively in combination with other forms of therapy, such as phototherapy or other systemic agents. With generalized pustular psoriasis, they are effective as monotherapy and are frequently helpful for the control of exfoliative psoriasis. The Food and Drug and Administration (FDA) in the United States has approved four derivatives of systemic retinoids. Isotretinoin, whose main indication is for cystic acne, has been found to be ineffective for plaque-type psoriasis as monotherapy treatment [1]. Clinical responses, however, were observed with isotretinoin for pustular psoriasis [1] and in conjunction with phototherapy for psoriasis [2,3]. Bexarotene is approved for the treatment of cutaneous T-cell lymphoma. One report showed that bexarotene at 0.5 to 2 mg/kg/d reduced lesions in patients with moderate to severe psoriasis [4]. Topical retinoids for the treatment of psoriasis was introduced in the United States in 1997 for the treatment of plaque-type psoriasis. The only FDA-approved topical retinoid for psoriasis is tazarotene gel and cream. Topical tazarotene has remained one of the mainstay treatments for psoriasis. This article focuses on the treatment of psoriasis with acitretin, the only systemic retinoid approved for psoriasis, and also briefly discusses its predecessor, etretinate, which was replaced by acitretin in 1997
* Corresponding author. Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404. E-mail address: [email protected] (N.J. Lowe).
and is no longer available. The use of topical tazarotene is also discussed in detail. Combination therapy of retinoids, both topical and systemic, with phototherapy and other therapeutic agents is described. In addition, new retinoid analogues that are currently undergoing clinical investigation at the time of preparation of this article are mentioned. Finally, potential toxicities and adverse effects associated with retinoids are discussed.
Chemistry and pharmacology Fig. 1 shows the chemical structures of acitretin and etretinate. Acitretin is the principle active metabolite of the prodrug, etretinate. They are very similar to each other except that etretinate is the ethylester form of acitretin. Because of this modification, however, under physiologic conditions etretinate is in an uncharged state and is 50 times more lipophilic than acitretin, which carries a negative charge [5]. Consequently, etretinate is accumulated in adipose tissue because of its high lipophilicity as opposed to acitretin, which is not stored in fat. This is the main pharmacokinetic reason why acitretin has a much shorter half-life (approximately 50 hours) than etretinate (approximately 120 days). In light of the highly teratogenic effects associated with systemic retinoids (discussed later) and because of its long half-life and detection in the serum up to 2 years after discontinuing treatment, etretinate was withdrawn from the market in 1997 following the introduction of acitretin. Studies have demonstrated that the concurrent ingestion of ethanol with acitretin results in the transesterification conversion of acitretin to etretinate [6,7]. Furthermore, higher alcohol consumption was linked to higher etretinate concentrations. This is clinically significant because the ingestion of alcohol extends the
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Fig. 1. Chemical structures of etretinate (A) and acitretin (B).
half-life of acitretin to the same as that of etretinate because of the enzymatic conversion. There are no data documenting the spontaneous formation of acitretin to etretinate in the absence of alcohol consumption. It is also important to instruct patients that systemic retinoids, including acitretin, have higher absorption and improved bioavailability when ingested with food [8]. Fig. 2 illustrates the structure of tazarotene. Minimal systemic absorption of tazarotene occurs because of rapid metabolism in the skin to the active metabolite, tazarotenic acid, which is systemically absorbed and further metabolized. Tazarotenic acid is hydrophilic and is rapidly metabolized causing no apparent accumulation within body tissues. More than 99% of tazarotenic acid is bound to plasma proteins. The metabolism of tazarotene to tazarotenic acid occurs through esterase hydrolysis in skin. On conversion, tazarotenic acid exhibits a half-life of approximately 18 hours in both normal and psoriatic patients.
Mechanism of action The exact molecular mechanism by which retinoids are able to exert their effects on psoriasis is unknown. It has been demonstrated that acitretin modulates the cellular differentiation of the epidermis, which results in deceased scaling, erythema, and thickness of the plaques. There is also histologic evidence that acitretin decreases the thickness of the stratum corneum and the inflammation in the epidermis and dermis that is associated with psoriasis. Tazarotene has multiple effects on keratinocyte differentiation and proliferation, and inflammation processes that contribute to psoriasis. In animal models, topical tazarotene blocks induction of ornithine
decarboxylase activity, which is associated with cell proliferation and expression. In vitro skin models and cell cultures have demonstrated tazarotene suppresses expression of MRP8, a marker of inflammation present in high levels in the epidermis of psoriasis patients and inhibits the formation of hyperkeratotic plaques. Tazarotene also induces the expression of tazaroteneinduced gene 3, a suppressor gene that may inhibit epidermal hyperproliferation in treated plaques. There are two classes of nuclear retinoid receptors that have been identified: the retinoic acid receptor and retinoid X receptor. The retinoic acid receptors and retinoid X receptors are each composed of three different subtypes, labeled a, b, and g [9]. Nuclear retinoid receptors exist as dimers, and retinoic acid receptors are known to form heterodimers with retinoid X receptors [10]. Acitretin has been shown to activate all three subtypes of retinoic acid receptor, despite the absence of measurable binding to any of the subtypes [10]. Tazarotenic acid selectively binds to retinoic acid receptors and exhibits little affinity for retinoid X receptors [11]. The function of these retinoic acid receptor – retinoid X receptor heterodimers is unknown in the skin. Such data indicate that further studies are necessary to understand the interaction of acitretin with nuclear receptors.
Monotherapy with systemic retinoids Several studies have confirmed the efficacy of acitretin treatment for different types of psoriasis [12 – 19]. Pustular forms of psoriasis are more responsive to systemic retinoid monotherapy than plaque-type psoriasis, which responds more slowly. With plaque-type psoriasis, it is possible to enhance the response to therapy by combining retinoids with other treatments. Pustular psoriasis
Fig. 2. Chemical structure of tazarotene.
When acitretin is used as monotherapy for generalized pustular psoriasis, the initial dose is 25 to 50 mg per day, but higher doses may be required in some patients. A rapid resolution of generalized pustular psoriasis is achieved usually within 10 days
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of initiating acitretin, which is probably the drug of first choice for the treatment of this condition. One advantage with acitretin for pustular psoriasis over methotrexate is the absence of acute effects on the peripheral blood count. Methotrexate may occasionally produce acute leukopenia in patients with generalized pustular psoriasis, which can lead to a major toxicity risk in these patients. Pustular psoriasis leads to rapid proliferation of monocytes in the S-phase of the cell cycle. Methotrexate, which blocks DNA synthesis in these cells, may lead to failure of maturation of cells beyond mitosis that leads to myelosuppression [20]. This phenomena is not clinically evident with acitretin, After the clearance of pustulation, the psoriasis can continue to be controlled by reducing the dose of acitretin (eg, decreasing acitretin at 25 mg per day to 25 mg every other day or to 10 mg per day). Some patients, however, relapse and develop plaque-type psoriasis. In such patients, alternative forms of therapy, such as phototherapy, can gradually be instituted in combination with acitretin. When the psoriasis improves, the retinoid then can be tapered down. In women of childbearing age, acitretin should probably be avoided whenever possible, even for pustular psoriasis. If acitretin is required, strict birth control practices must be adhered to and alcohol must be avoided. In such situations, oral isotretinoin with its shorter half-life of 10 to 20 hours may be used as an alternative to control the pustulation. Starting doses range from 1 to 1.5 mg/kg/d. If necessary, phototherapy may be initiated to control the psoriasis. Another situation in which acitretin is effective is in the treatment of palmoplantar pustular psoriasis, particularly where there is significant hyperkeratosis or severe pustulation. Isotretinoin may be used as an alternative in women who are fertile. Retinoid therapy reduces the degree of hyperkeratosis and pustulation. If monotherapy with acitretin is not achieving the desired results, then combination with psoralen plus UVA (PUVA) phototherapy is extremely useful. Alternatively, hydroxyurea at 500 mg twice a day in conjunction with acitretin is another way of controlling palmoplantar pustular psoriasis. Exfoliative erythrodermic psoriasis In exfoliative erythrodermic psoriasis, acitretin is useful at starting doses of 25 to 50 mg per day. It is advantageous to use emollients liberally along with the application of mild topical corticosteroids (eg, triamcinolone acetonide [0.025% cream or ointment]) under occlusion to achieve more rapid resolution of psoriasis.
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Rarely, patients with severe exfoliative erythrodermic psoriasis may need to use a combination of acitretin with methotrexate. This combination should only be used rarely and, when it is, only with careful monitoring of the peripheral blood count and liver function tests. Another option for the treatment of exfoliative psoriasis is to use methotrexate or cyclosporine therapy to achieve a rapid improvement after which the methotrexate or cyclosporine dosage is reduced and low doses of acitretin (10 to 25 mg per day) are introduced.
Combination therapy for moderate to severe plaque psoriasis In patients with severe plaque psoriasis, especially if the condition is extensive with hyperkeratosis, the use of a retinoid plus other forms of treatment, particularly phototherapy, has been shown to be highly effective. The dose of the retinoid or the amount of alternative therapy required when used separately can be reduced if used in combination with each other. Acitretin and psoralen plus UVA phototherapy For combination therapy, the optimum dose for acitretin is 0.3 mg/kg/d, either 2 weeks before starting phototherapy or at the same time. The increases in ultraviolet radiation should be more gradual and cautious than in patients not taking systemic retinoids because of an increased risk of ultraviolet radiationinduced erythema. This is not a true photosensitivity, but probably represents increased epidermal transmission of the ultraviolet radiation because of altered optical properties of the stratum corneum caused by the retinoid. The concomitant use of PUVA with acitretin has been studied by several investigators [21 – 27]. Most patients receiving the combination improve more quickly than with PUVA or acitretin alone. In addition, the total number of ultraviolet radiation exposures can be reduced. Following clearance of psoriasis, various maintenance regimens may be used. Acitretin administered in low maintenance doses can be effective, or acitretin therapy can be stopped and maintenance therapy is undertaken solely with PUVA. In a double-blinded comparative study, patients with severe, widespread psoriasis were randomized to receive either PUVA alone or PUVA in combination with acitretin [21]. Eighty percent of patients with PUVA alone demonstrated marked or complete clearing of psoriasis, whereas 96% of patients who re-
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ceived adjunctive therapy with PUVA plus acitretin exhibited the same degree of improvement. The mean cumulative UVA dose given to patients who received combination therapy was 42% less than that required for patients who received PUVA alone. When patients with psoriasis were initially treated with acitretin at 50 mg per day for 2 weeks followed by decreasing the amount to 25 mg per day in conjunction with PUVA for up to 10 weeks, there was a 40.5% reduction in the total cumulative UVA dose, a decrease of the overall duration of treatment by almost 18 days, and a reduction in the number of PUVA treatments by nearly six sessions, when compared with treatment with PUVA alone [22]. Bath PUVA together with acitretin is another option for treatment of patents with pustular, plaquetype, or erythrodermic psoriasis [24]. After 4 weeks of treatment, patients had greater than a 90% response rate with no relapse after 3 months. The safety of PUVA is now of concern because of the risk of melanoma and nonmelanoma skin cancer. Whether or not acitretin alters this risk is unknown at this stage. Acitretin and UVB phototherapy Acitretin plus UVB therapy is another combination form of therapy to treat psoriasis and has been investigated [28 – 30]. This option can be used for those patients who are intolerant of side effects associated with oral psoralens, such as gastrointestinal toxicity. Treatment with UVB combined with acitretin at 50 mg per day or placebo resulted in greater clearance with fewer treatments and smaller amounts of UVB radiation when acitretin was used compared with placebo [29]. A 74% improvement in the psoriasis score was noted in patients treated with acitretin plus UVB compared with 35% with UVB only. In addition, in the same study, when only acitretin was used, there was a 42% reduction in psoriasis. There was a decrease in the total number of hours of exposure time to UVB therapy by approximately 6 hours when acitretin was used to attain clearance compared with light treatment alone. Another study demonstrated that when patients with psoriasis were initially treated with 35 mg per day of acitretin during the first 4 weeks of therapy followed by concomitant therapy with UVB radiation plus 25 mg per day of acitretin and compared with the placebo group, there was a 79% decrease in the psoriasis severity index in the acitretin and UVB group and 35% reduction in the UVB-only group [28]. In addition, the medium cumulative dose to achieve 75% clinical improvement
was 41.5% lower when acitretin was combined. Finally, the number of treatments to attain 80% to 100% clearance of psoriatic plaques was decreased by 5.6 sessions with UVB plus acitretin versus UVB only [30]. The total UVB dose and minimal erythema dose was reduced by approximately 20%. In summary, reasons for combining PUVA or UVB with systemic retinoids include the following: 1. Better clearance 2. Decreased cumulative ultraviolet doses 3. The number of treatments and duration of PUVA therapy is reduced 4. The possibility of reduction or cessation of acitretin therapy before the occurrence of side effects, such as hyperlipidemia or alopecia Combination therapy with other agents Combination therapy of acitretin with other modalities other than light therapy can be used to control psoriasis. Concomitant treatment with acitretin and topical calcipotriene may help reduce psoriatic plaques better than with either alone [31,32]. In addition, acitretin at 25 mg per day together with hydroxyurea, 500 mg twice daily, has been effective for some patients with chronic plaque psoriasis and pustular psoriasis. When using combination therapy with acitretin and hydroxyurea, the complete blood count should be carefully monitored. Combination therapy with immunomodulatory agents New-generation drugs are being developed that selectively target key cytokines and receptor molecules on T cells and antigen-presenting cells that are involved in the pathogenesis of psoriasis. These immunomodulators are in the form of monoclonal antibodies or fusion proteins that are administered as injections either subcutaneously, intramuscularly, or intravenously. One biologic agent that is currently on the market and is FDA-approved for rheumatoid arthritis and psoriatic arthritis is etanercept. Etanercept is currently undergoing clinical trials as monotherapy treatment for psoriasis. Etanercept is a fusion protein that acts as a soluble tumor necrosis factor and competitively binds to tumor necrosis factor thereby preventing tumor necrosis factor from binding to cell surface receptors on target cells. Because tumor necrosis factor is involved in the pathogenesis of psoriasis, through such inhibition, etanercept serves as an antiinflammatory agent that is beneficial in the treatment
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Fig. 3. Patient with recalcitrant plaque-type psoriasis (A) before and (B) after treatment with 25 mg acitretin each day plus etanercept, 25 mg twice a week subcutaneously for 8 weeks.
of psoriasis. A recent report demonstrated that combination therapy with etanercept together with various systemic agents, such as cyclosporine, methotrexate, acitretin, or hydroxyurea, in patients with severe recalcitrant psoriasis resulted in marked improvement and reduction in the PASI score [33]. More importantly, no added toxicity was seen in these patients when etanercept was combined with a systemic agent. Fig. 3 shows a patient with refractory psoriasis who responded well to combination therapy with 25 mg per day of acitretin plus twice-weekly 25-mg subcutaneous injections of etanercept. Combination treatment with systemic agents and immunomodulators underscores the significance of treating psoriasis in the future. With the advent of new biologic agents and the existing systemics, this new approach to combination therapy may provide an impetus in controlling psoriasis that previously was difficult to treat.
In a dose escalation study, 181 patients with moderate to severe plaque psoriasis received daily doses of oral tazarotene (0.4 to 6.3 mg) or placebo (Lowe et al, submitted for publication). Optimal efficacy was seen with the 4.2-mg dose. At this dosage, the body surface area involvement was reduced by 17% at week 12 and 82% of patients were satisfied or very satisfied with oral tazarotene. Fig. 4 shows a patient who had good clearance of psoriatic plaques with oral tazarotene at 4.2 mg per day by week 12. The only significant adverse effect noted was cheilitis at doses of 2.8 mg or higher. There were no other dose-related adverse events, such as increased liver function enzymes, hyperlipidemia, or changes in the hematologic profile. The shorter half-life of oral tazarotene may potentially be a useful alternative for systemic retinoid treatment in women of childbearing age with psoriasis.
Other systemic retinoids
Toxicities and adverse reactions associated with systemic retinoids
Oral tazarotene
Teratogenicity
An oral form of tazarotene (a topical retinoid approved for plaque psoriasis and acne) has recently been developed that is currently not available on the market during the preparation of this article. Tazarotene is converted to its active metabolite, tazarotenic acid, which has a short elimination half-life of 7 to 12 hours (Allergan, unpublished data).
All systemic retinoids are highly teratogenic with a pregnancy category of X rated by the FDA. Major human fetal abnormalities associated with retinoids include meningomyelocele, meningoencephalocele, multiple bony malformations, facial dysmorphia, lowset ears, high palate, decreased cranial volume alterations, and cardiovascular malformations.
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Fig. 4. Patient with plaque psoriasis (A) before and (B) after treatment with oral tazarotene, 4.2 mg each day for 12 weeks.
In light of its teratogenicity, acitretin must not be used by women who are pregnant or who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy. In addition, acitretin must not be used by women who may not use reliable contraception while taking acitretin or for at least 3 years following cessation of treatment. In addition, the current guideline states that ethanol must not be ingested by female patients either during treatment with acitretin or for 2 months after discontinuing acitretin to avoid conversion into etretinate, which carries a much longer elimination half-life. This is caused by the transesterification of acitretin to etretinate by ethanol as previously discussed. Mucocutaneous toxicity Mucocutaneous toxicity occurs with all of the systemic retinoids [34]. The common mucocutaneous side-effects in order of frequency are cheilitis, skin peeling, alopecia, xerosis, rhinitis, nail dystrophy, epistaxis, sticky skin, retinoid dermatitis, and xerophthalmia. Hair loss may occur a few weeks after initiation of treatment and ceases 6 to 8 weeks after discontinuation of therapy. In rare cases, chronic hair loss has occurred. Patients frequently find these symptoms extremely difficult to accept. Rapid reduction in retinoid therapy is desirable to reduce the impact on patients of these toxicity problems. Some studies have suggested that 800 IU of vitamin E daily may reduce some of the mucocutaneous effects of systemic retinoids [35]. Arthralgias and myalgias Some patients develop muscle pain and myalgias with or without an elevation of creatine phosphokinase. In general, it is wise for patients to avoid
excessive muscle exercising, particularly excessive weight lifting and contact sports, because these forms of activity may increase such risks. Arthralgias occur in a small percentage of patients and disappear on discontinuation of therapy. Pseudotumor cerebri Acitretin and other systemic retinoids have been associated with cases of pseudotumor cerebri (benign intracranial hypertension). Such symptoms and signs include papilledema, severe headaches, nausea and vomiting, and visual disturbances. If pseudotumor cerebri is suspected, ophthalmologic evaluation for papilledema should be conducted and if present, the retinoid should be discontinued immediately. Oral retinoids should not be taken with tetracycline or tetracycline derivatives because of increased risk of pseudotumor cerebri. Ophthalmologic effects Ocular toxicity does not seem to be a major problem with acitretin, although rare cases of disturbances of color vision have been recorded. Most of the ocular symptoms have been mucocutaneous in nature, such as dry eyes, irritation of eyes, and loss of brow and lashes. Other side effects, such as blurred vision, cataracts, decreased night vision, and diplopia, are much less common. Skeletal toxicity There is some concern that long-term high-dose acitretin therapy is associated with changes that resemble diffuse idiopathic skeletal hyperostosis, which include anterior spinal ligamentous calcification and the formation of osteophytes and bony bridges. Disk space narrowing is not evident in diffuse idiopathic
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skeletal hyperostosis. There seems to be a cumulative threshold dose of 25 to 30 g etretinate below which skeletal toxicity is not seen radiographically. Psychiatric effects There are no recorded incidents of suicide or depression linked to patients on systemic retinoid therapy for the treatment of psoriasis. There is clearly a background of depression with some psoriasis patients but this has not been noted to be aggravated by acitretin (Lowe NJ, unpublished observations, 2002).
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enzymes; renal function tests; creatine phosphokinase; and a lipid panel including triglycerides, cholesterol, and high-density lipoproteins. In all women of childbearing age, a monthly pregnancy test must be conducted. These investigations should be performed initially every 2 weeks while on clearance doses, reducing to monthly or 2-monthly assessments depending on the maintenance dose required. There is presently no requirement for liver biopsy.
Guidelines for the use of systemic retinoids in psoriasis
Hyperlipidemia Hyperlipidemia occurs in approximately 25% to 50% of patients. Occasionally, severe levels reaching five to eight times the normal value occur, but usually levels are increased two to three times the normal. The incidence of pancreatitis or eruptive xanthomas with increased triglyceride levels is uncommon. In addition, levels of high-density lipoproteins decrease with oral retinoids. These abnormal levels are reversible on cessation of therapy. Patients with an increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake, or a familial history of these conditions. There are a number of ways to manage hyperlipidemia including low-fat diets, reduced alcohol intake, physical activity, the use of polyunsaturated fish-oil supplements, and prescribing lipid-lowering drugs. Hepatotoxicity All the systemic retinoids have the potential for liver toxicity. Elevations of aspartate transaminase (serum glutamic-oxaloacetic transaminase), alanine transaminase (serum glutamate pyruvate transaminase), g-glutamyltransferase (GGTP), low-density lipoproteins, and alkaline phosphatase have occurred in 33% of patients treated with acitretin. During the clinical trials in the United States for acitretin, 3.8% of patients had sufficient elevation of liver function tests that they were discontinued from further treatment. If hepatotoxicity is suspected with acitretin, the drug should be discontinued and a liver work-up should be conducted.
Frequency of follow-up Blood investigations should include a full blood count; a complete metabolic panel including liver
The following guidelines apply for the use of systemic retinoids in psoriasis: 1. Acitretin can be prescribed for male patients or postmenopausal female patients. It is up to the clinician’s discretion to prescribe acitretin in women of childbearing age keeping in mind the strict guidelines associated with acitretin’s teratogenicity. If there is any suggestion that a woman desires pregnancy, or suspicion that adequate birth control methods will not be practiced, or abstinence from alcohol cannot be avoided, then acitretin should not be prescribed to that woman. 2. Careful pretreatment and screening should be performed to exclude the possibility of hyperlipidemia and hepatotoxicity. Risk factors for hyperlipidemia (diabetes mellitus, obesity) should be looked for and a history of alcohol use and hepatitis should be screened in every patient. 3. Retinoids should be considered as monotherapy in generalized pustular psoriasis. 4. Combination therapy of acitretin with PUVA or UVB is advised in patients with severe plaque psoriasis and localized palmoplantar psoriasis, including local pustular psoriasis of the palms and soles. 5. Combination therapy of acitretin with hydroxyurea may be beneficial in some patients with plaque or pustular psoriasis. In addition, combination therapy with the retinoids and the new immunomodulatory biologic agents may play pivotal roles in the future treatment of psoriasis. 6. New retinoids, such as oral tazarotene, seem to have a good safety profile. Longer-term studies and combination studies with this drug are eagerly awaited.
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Topical tazarotene There are four formulations for topical tazarotene: (1) 0.05% gel, (2) 0.1% gel, (3) 0.05% cream, and (4) 0.1% cream. All four vehicles and strengths can be used for plaque psoriasis. In general, gels and the more concentrated strengths tend to have a higher incidence of irritation, pruritus, erythema, stinging, and desquamation. These side effects are most apparent on initial applications but alleviate with continuous usage. In two multicentered, double-blinded, randomized, placebo-controlled studies involving 660 patients, tazarotene gels 0.05% and 0.1% applied once a day for 3 months were found to be efficacious and safe for the treatment of plaque psoriasis. The most profound effect with tazarotene gel was the improvement of plaque elevation [36]. Results of two multicenter studies showed that topical therapy once daily with tazarotene in a cream formulation at concentrations of 0.05% or 0.1% was effective in the treatment of plaque psoriasis [37]. A total of 1303 patients participated in these randomized, double-blinded, placebo-controlled trails in which tazarotene creams 0.1% and 0.05% or vehicle were applied daily to all psoriatic lesions for 12 weeks followed by a 12-week posttreatment period. Tazarotene creams 0.05% and 0.1% were significantly more effective than vehicle in terms of clinical success rates and in reducing the severity of the clinical signs of plaque psoriasis. Tazarotene cream 0.1% was generally more effective, although slightly less well tolerated, than the 0.05% cream. Both tazarotene concentrations showed good maintenance of therapeutic effect during a 12-week posttreatment period. Tazarotene creams 0.05% and 0.1% for the treatment of psoriasis were found to be safe with acceptable tolerability. To counteract potential irritation from tazarotene, topical corticosteroids may be combined to the lesions. A study showed that application of tazarotene in the evening and a mid- to high-potency topical corticosteroids in the morning achieved significantly greater reductions in scaling, erythema, and overall lesional severity, and a decreased incidence of adverse events [38]. Combination therapy by alternating tazarotene and high-potency steroids each day significantly increased the treatment success rate and lowered incidence of treatment-related adverse effects [39]. Short contact with tazarotene minimizes the local irritation on the skin. For patients who are beginning therapy with tazarotene, initial application times of 15 minutes in the evenings and then washing off the tazarotene decreases the incidence of stinging, burning, and erythema. As the patient becomes accus-
tomed and more tolerant to tazarotene, application times are prolonged incrementally until patients can leave it on overnight. Combination treatment using tazarotene with ultraviolet therapy has become very popular for the treatment of plaque psoriasis [40 – 43].The efficacy of tazarotene reported in clinical trials suggests that this drug may help to improve the efficacy of phototherapy, and perhaps reduce the ultraviolet light exposure required without introducing additional, clinically significant problems. Broad or narrow band UVB plus tazarotene combination achieves greater reductions in the elevation and scaling of difficult-totreat psoriatic plaques than UVB phototherapy alone. The tazarotene combination therapy also achieved initial treatment success in less than half the time needed with phototherapy alone. Combining UVB phototherapy with tazarotene treatment seems to offer a valuable therapeutic option that is more efficacious and faster than UVB phototherapy alone.
Summary Both systemic and topical retinoids provide an excellent alternative for the treatment of psoriasis. Retinoids are generally used as combination therapy with other treatment modalities, such as phototherapy or other topical or systemic agents, and can be combined with the newer biologic agents, such as etanercept. Newer retinoids are being developed to treat psoriasis with the hope of a less toxic side effect profile. For now, retinoids remain a mainstay for the treatment of psoriasis.
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P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476 [7] Larsen FG, Jakobsen P, Knudsen J, Weismann K, Kragballe K, Nielsen-Kudsk F. Conversion of acitretin to etretinate in psoriatic patients is influenced by ethanol. J Invest Dermatol 1993;100:623 – 7. [8] McNamara PJ, Jewell RC, Jensen BK, Brindley CJ. Food increases the bioavailability of acitretin. J Clin Pharmacol 1988;28:1051 – 5. [9] Chambon P. The retinoid signaling pathway: molecular and genetic analysis. Semin Cell Biol 1994;5:115 – 25. [10] Saurat JH. Retinoids and psoriasis: novel issues in retinoid pharmacology and implications for psoriasis treatment. J Am Acad Dermatol 1999;41:S2 – 6. [11] Chandraratna RA. Tazarotene: first of a new generation of receptor-selective retinoids. Br J Dermatol 1996;49: 18 – 25. [12] Ling MR. Acitretin: optimal dosing strategies. J Am Acad Dermatol 1999;41:S13 – 7. [13] Lowe NJ, Lazarus V, Matt L. Systemic retinoid therapy for psoriasis. J Am Acad Dermatol 1988;19:186 – 91. [14] Goldfarb MT, Ellis CN, Gupta AK, Tincoff T, Hamilton TA, Voorhees JJ. Acitretin improves psoriasis in a dose-dependent fashion. J Am Acad Dermatol 1988; 18(suppl 4, pt 1):655 – 62. [15] Olsen EA, Weed WW, Meyer CJ, Cobo LM. A double-blind, placebo-controlled trial of acitretin for the treatment of psoriasis. J Am Acad Dermatol 1989; 21(suppl 4, pt 1):681 – 6. [16] Torok L, Kadar L, Geiger JM. Acitretin treatment of severe psoriasis. Acta Dermatol Venereol Suppl (Stockh) 1989;146:104 – 6. [17] Murray HE, Anhalt AW, Lessard R, et al. A 12-month treatment of severe psoriasis with acitretin: results of a Canadian open multicenter trial. J Am Acad Dermatol 1991;24:598 – 602. [18] Geiger JM, Czarnetzki BM. Acitretin (Ro 10 – 1670, etretin): overall evaluation of clinical studies. Dermatologica 1988;176:182 – 90. [19] Lassus A, Geiger JM, Nyblom M, Virrankoski T, Kaartamaa M, Ingervo L. Treatment of severe psoriasis with etretin (Ro 10 – 1670). Br J Dermatol 1987;117: 333 – 41. [20] Hoffman TE, Watson W. Methotrexate toxicity in the treatment of generalized pustular psoriasis. Cutis 1978; 21:68 – 71. [21] Tanew A, Guggenbichler A, Ho¨nigsmann H, Geiger JM, Fritsch P. Photochemotherapy for severe psoriasis without or in combination with acitretin: a randomized, double-blind comparison study. J Am Acad Dermatol 1991;25:682 – 4. [22] Saurat J-H, Geiger J-M, Amblard P, Beani J-C, Boulanger A, Claudy A, et al. Randomized double-blind multicenter study comparing acitretin-PUVA, etretinate-PUVA, and placebo-PUVA in the treatment of severe psoriasis. Dermatologica 1988;177:218 – 24. [23] Laurahanta J, Geiger J-M. A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis. Br J Dermatol 1989;121:107 – 12. [24] Muchenberger S, Schoff E, Simon JC. The combina-
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rotene plus a topical corticosteroid for the treatment of plaque psoriasis. Br J Dermatol 1999;54:18 – 23. [40] Koo JY, Lowe NJ, Lew-Kaya DA, Vasilopoulos AI, Lue JC, Sefton J, et al. Tazarotene plus UVB phototherapy in the treatment of psoriasis. J Am Acad Dermatol 2000;43:821 – 8. [41] Lowe NJ. Optimizing therapy: tazarotene in combination with phototherapy. Br J Dermatol 1999;54:8 – 11.
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Retinoid therapy for psoriasis Paul S. Yamauchi, MD, PhDa,b, Dalia Rizk, MDa, Nicholas J. Lowe, MDa,b,* a Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USA Division of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1750, USA
b
The systemic retinoids possess a remarkable range of activities and clinical applications. They are an important form of therapy for patients with more severe and resistant types of psoriasis. In general, with plaque psoriasis, systemic retinoids are used most effectively in combination with other forms of therapy, such as phototherapy or other systemic agents. With generalized pustular psoriasis, they are effective as monotherapy and are frequently helpful for the control of exfoliative psoriasis. The Food and Drug and Administration (FDA) in the United States has approved four derivatives of systemic retinoids. Isotretinoin, whose main indication is for cystic acne, has been found to be ineffective for plaque-type psoriasis as monotherapy treatment [1]. Clinical responses, however, were observed with isotretinoin for pustular psoriasis [1] and in conjunction with phototherapy for psoriasis [2,3]. Bexarotene is approved for the treatment of cutaneous T-cell lymphoma. One report showed that bexarotene at 0.5 to 2 mg/kg/d reduced lesions in patients with moderate to severe psoriasis [4]. Topical retinoids for the treatment of psoriasis was introduced in the United States in 1997 for the treatment of plaque-type psoriasis. The only FDA-approved topical retinoid for psoriasis is tazarotene gel and cream. Topical tazarotene has remained one of the mainstay treatments for psoriasis. This article focuses on the treatment of psoriasis with acitretin, the only systemic retinoid approved for psoriasis, and also briefly discusses its predecessor, etretinate, which was replaced by acitretin in 1997
* Corresponding author. Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404. E-mail address: [email protected] (N.J. Lowe).
and is no longer available. The use of topical tazarotene is also discussed in detail. Combination therapy of retinoids, both topical and systemic, with phototherapy and other therapeutic agents is described. In addition, new retinoid analogues that are currently undergoing clinical investigation at the time of preparation of this article are mentioned. Finally, potential toxicities and adverse effects associated with retinoids are discussed.
Chemistry and pharmacology Fig. 1 shows the chemical structures of acitretin and etretinate. Acitretin is the principle active metabolite of the prodrug, etretinate. They are very similar to each other except that etretinate is the ethylester form of acitretin. Because of this modification, however, under physiologic conditions etretinate is in an uncharged state and is 50 times more lipophilic than acitretin, which carries a negative charge [5]. Consequently, etretinate is accumulated in adipose tissue because of its high lipophilicity as opposed to acitretin, which is not stored in fat. This is the main pharmacokinetic reason why acitretin has a much shorter half-life (approximately 50 hours) than etretinate (approximately 120 days). In light of the highly teratogenic effects associated with systemic retinoids (discussed later) and because of its long half-life and detection in the serum up to 2 years after discontinuing treatment, etretinate was withdrawn from the market in 1997 following the introduction of acitretin. Studies have demonstrated that the concurrent ingestion of ethanol with acitretin results in the transesterification conversion of acitretin to etretinate [6,7]. Furthermore, higher alcohol consumption was linked to higher etretinate concentrations. This is clinically significant because the ingestion of alcohol extends the
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8635(03)00126-8
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Fig. 1. Chemical structures of etretinate (A) and acitretin (B).
half-life of acitretin to the same as that of etretinate because of the enzymatic conversion. There are no data documenting the spontaneous formation of acitretin to etretinate in the absence of alcohol consumption. It is also important to instruct patients that systemic retinoids, including acitretin, have higher absorption and improved bioavailability when ingested with food [8]. Fig. 2 illustrates the structure of tazarotene. Minimal systemic absorption of tazarotene occurs because of rapid metabolism in the skin to the active metabolite, tazarotenic acid, which is systemically absorbed and further metabolized. Tazarotenic acid is hydrophilic and is rapidly metabolized causing no apparent accumulation within body tissues. More than 99% of tazarotenic acid is bound to plasma proteins. The metabolism of tazarotene to tazarotenic acid occurs through esterase hydrolysis in skin. On conversion, tazarotenic acid exhibits a half-life of approximately 18 hours in both normal and psoriatic patients.
Mechanism of action The exact molecular mechanism by which retinoids are able to exert their effects on psoriasis is unknown. It has been demonstrated that acitretin modulates the cellular differentiation of the epidermis, which results in deceased scaling, erythema, and thickness of the plaques. There is also histologic evidence that acitretin decreases the thickness of the stratum corneum and the inflammation in the epidermis and dermis that is associated with psoriasis. Tazarotene has multiple effects on keratinocyte differentiation and proliferation, and inflammation processes that contribute to psoriasis. In animal models, topical tazarotene blocks induction of ornithine
decarboxylase activity, which is associated with cell proliferation and expression. In vitro skin models and cell cultures have demonstrated tazarotene suppresses expression of MRP8, a marker of inflammation present in high levels in the epidermis of psoriasis patients and inhibits the formation of hyperkeratotic plaques. Tazarotene also induces the expression of tazaroteneinduced gene 3, a suppressor gene that may inhibit epidermal hyperproliferation in treated plaques. There are two classes of nuclear retinoid receptors that have been identified: the retinoic acid receptor and retinoid X receptor. The retinoic acid receptors and retinoid X receptors are each composed of three different subtypes, labeled a, b, and g [9]. Nuclear retinoid receptors exist as dimers, and retinoic acid receptors are known to form heterodimers with retinoid X receptors [10]. Acitretin has been shown to activate all three subtypes of retinoic acid receptor, despite the absence of measurable binding to any of the subtypes [10]. Tazarotenic acid selectively binds to retinoic acid receptors and exhibits little affinity for retinoid X receptors [11]. The function of these retinoic acid receptor – retinoid X receptor heterodimers is unknown in the skin. Such data indicate that further studies are necessary to understand the interaction of acitretin with nuclear receptors.
Monotherapy with systemic retinoids Several studies have confirmed the efficacy of acitretin treatment for different types of psoriasis [12 – 19]. Pustular forms of psoriasis are more responsive to systemic retinoid monotherapy than plaque-type psoriasis, which responds more slowly. With plaque-type psoriasis, it is possible to enhance the response to therapy by combining retinoids with other treatments. Pustular psoriasis
Fig. 2. Chemical structure of tazarotene.
When acitretin is used as monotherapy for generalized pustular psoriasis, the initial dose is 25 to 50 mg per day, but higher doses may be required in some patients. A rapid resolution of generalized pustular psoriasis is achieved usually within 10 days
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of initiating acitretin, which is probably the drug of first choice for the treatment of this condition. One advantage with acitretin for pustular psoriasis over methotrexate is the absence of acute effects on the peripheral blood count. Methotrexate may occasionally produce acute leukopenia in patients with generalized pustular psoriasis, which can lead to a major toxicity risk in these patients. Pustular psoriasis leads to rapid proliferation of monocytes in the S-phase of the cell cycle. Methotrexate, which blocks DNA synthesis in these cells, may lead to failure of maturation of cells beyond mitosis that leads to myelosuppression [20]. This phenomena is not clinically evident with acitretin, After the clearance of pustulation, the psoriasis can continue to be controlled by reducing the dose of acitretin (eg, decreasing acitretin at 25 mg per day to 25 mg every other day or to 10 mg per day). Some patients, however, relapse and develop plaque-type psoriasis. In such patients, alternative forms of therapy, such as phototherapy, can gradually be instituted in combination with acitretin. When the psoriasis improves, the retinoid then can be tapered down. In women of childbearing age, acitretin should probably be avoided whenever possible, even for pustular psoriasis. If acitretin is required, strict birth control practices must be adhered to and alcohol must be avoided. In such situations, oral isotretinoin with its shorter half-life of 10 to 20 hours may be used as an alternative to control the pustulation. Starting doses range from 1 to 1.5 mg/kg/d. If necessary, phototherapy may be initiated to control the psoriasis. Another situation in which acitretin is effective is in the treatment of palmoplantar pustular psoriasis, particularly where there is significant hyperkeratosis or severe pustulation. Isotretinoin may be used as an alternative in women who are fertile. Retinoid therapy reduces the degree of hyperkeratosis and pustulation. If monotherapy with acitretin is not achieving the desired results, then combination with psoralen plus UVA (PUVA) phototherapy is extremely useful. Alternatively, hydroxyurea at 500 mg twice a day in conjunction with acitretin is another way of controlling palmoplantar pustular psoriasis. Exfoliative erythrodermic psoriasis In exfoliative erythrodermic psoriasis, acitretin is useful at starting doses of 25 to 50 mg per day. It is advantageous to use emollients liberally along with the application of mild topical corticosteroids (eg, triamcinolone acetonide [0.025% cream or ointment]) under occlusion to achieve more rapid resolution of psoriasis.
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Rarely, patients with severe exfoliative erythrodermic psoriasis may need to use a combination of acitretin with methotrexate. This combination should only be used rarely and, when it is, only with careful monitoring of the peripheral blood count and liver function tests. Another option for the treatment of exfoliative psoriasis is to use methotrexate or cyclosporine therapy to achieve a rapid improvement after which the methotrexate or cyclosporine dosage is reduced and low doses of acitretin (10 to 25 mg per day) are introduced.
Combination therapy for moderate to severe plaque psoriasis In patients with severe plaque psoriasis, especially if the condition is extensive with hyperkeratosis, the use of a retinoid plus other forms of treatment, particularly phototherapy, has been shown to be highly effective. The dose of the retinoid or the amount of alternative therapy required when used separately can be reduced if used in combination with each other. Acitretin and psoralen plus UVA phototherapy For combination therapy, the optimum dose for acitretin is 0.3 mg/kg/d, either 2 weeks before starting phototherapy or at the same time. The increases in ultraviolet radiation should be more gradual and cautious than in patients not taking systemic retinoids because of an increased risk of ultraviolet radiationinduced erythema. This is not a true photosensitivity, but probably represents increased epidermal transmission of the ultraviolet radiation because of altered optical properties of the stratum corneum caused by the retinoid. The concomitant use of PUVA with acitretin has been studied by several investigators [21 – 27]. Most patients receiving the combination improve more quickly than with PUVA or acitretin alone. In addition, the total number of ultraviolet radiation exposures can be reduced. Following clearance of psoriasis, various maintenance regimens may be used. Acitretin administered in low maintenance doses can be effective, or acitretin therapy can be stopped and maintenance therapy is undertaken solely with PUVA. In a double-blinded comparative study, patients with severe, widespread psoriasis were randomized to receive either PUVA alone or PUVA in combination with acitretin [21]. Eighty percent of patients with PUVA alone demonstrated marked or complete clearing of psoriasis, whereas 96% of patients who re-
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ceived adjunctive therapy with PUVA plus acitretin exhibited the same degree of improvement. The mean cumulative UVA dose given to patients who received combination therapy was 42% less than that required for patients who received PUVA alone. When patients with psoriasis were initially treated with acitretin at 50 mg per day for 2 weeks followed by decreasing the amount to 25 mg per day in conjunction with PUVA for up to 10 weeks, there was a 40.5% reduction in the total cumulative UVA dose, a decrease of the overall duration of treatment by almost 18 days, and a reduction in the number of PUVA treatments by nearly six sessions, when compared with treatment with PUVA alone [22]. Bath PUVA together with acitretin is another option for treatment of patents with pustular, plaquetype, or erythrodermic psoriasis [24]. After 4 weeks of treatment, patients had greater than a 90% response rate with no relapse after 3 months. The safety of PUVA is now of concern because of the risk of melanoma and nonmelanoma skin cancer. Whether or not acitretin alters this risk is unknown at this stage. Acitretin and UVB phototherapy Acitretin plus UVB therapy is another combination form of therapy to treat psoriasis and has been investigated [28 – 30]. This option can be used for those patients who are intolerant of side effects associated with oral psoralens, such as gastrointestinal toxicity. Treatment with UVB combined with acitretin at 50 mg per day or placebo resulted in greater clearance with fewer treatments and smaller amounts of UVB radiation when acitretin was used compared with placebo [29]. A 74% improvement in the psoriasis score was noted in patients treated with acitretin plus UVB compared with 35% with UVB only. In addition, in the same study, when only acitretin was used, there was a 42% reduction in psoriasis. There was a decrease in the total number of hours of exposure time to UVB therapy by approximately 6 hours when acitretin was used to attain clearance compared with light treatment alone. Another study demonstrated that when patients with psoriasis were initially treated with 35 mg per day of acitretin during the first 4 weeks of therapy followed by concomitant therapy with UVB radiation plus 25 mg per day of acitretin and compared with the placebo group, there was a 79% decrease in the psoriasis severity index in the acitretin and UVB group and 35% reduction in the UVB-only group [28]. In addition, the medium cumulative dose to achieve 75% clinical improvement
was 41.5% lower when acitretin was combined. Finally, the number of treatments to attain 80% to 100% clearance of psoriatic plaques was decreased by 5.6 sessions with UVB plus acitretin versus UVB only [30]. The total UVB dose and minimal erythema dose was reduced by approximately 20%. In summary, reasons for combining PUVA or UVB with systemic retinoids include the following: 1. Better clearance 2. Decreased cumulative ultraviolet doses 3. The number of treatments and duration of PUVA therapy is reduced 4. The possibility of reduction or cessation of acitretin therapy before the occurrence of side effects, such as hyperlipidemia or alopecia Combination therapy with other agents Combination therapy of acitretin with other modalities other than light therapy can be used to control psoriasis. Concomitant treatment with acitretin and topical calcipotriene may help reduce psoriatic plaques better than with either alone [31,32]. In addition, acitretin at 25 mg per day together with hydroxyurea, 500 mg twice daily, has been effective for some patients with chronic plaque psoriasis and pustular psoriasis. When using combination therapy with acitretin and hydroxyurea, the complete blood count should be carefully monitored. Combination therapy with immunomodulatory agents New-generation drugs are being developed that selectively target key cytokines and receptor molecules on T cells and antigen-presenting cells that are involved in the pathogenesis of psoriasis. These immunomodulators are in the form of monoclonal antibodies or fusion proteins that are administered as injections either subcutaneously, intramuscularly, or intravenously. One biologic agent that is currently on the market and is FDA-approved for rheumatoid arthritis and psoriatic arthritis is etanercept. Etanercept is currently undergoing clinical trials as monotherapy treatment for psoriasis. Etanercept is a fusion protein that acts as a soluble tumor necrosis factor and competitively binds to tumor necrosis factor thereby preventing tumor necrosis factor from binding to cell surface receptors on target cells. Because tumor necrosis factor is involved in the pathogenesis of psoriasis, through such inhibition, etanercept serves as an antiinflammatory agent that is beneficial in the treatment
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Fig. 3. Patient with recalcitrant plaque-type psoriasis (A) before and (B) after treatment with 25 mg acitretin each day plus etanercept, 25 mg twice a week subcutaneously for 8 weeks.
of psoriasis. A recent report demonstrated that combination therapy with etanercept together with various systemic agents, such as cyclosporine, methotrexate, acitretin, or hydroxyurea, in patients with severe recalcitrant psoriasis resulted in marked improvement and reduction in the PASI score [33]. More importantly, no added toxicity was seen in these patients when etanercept was combined with a systemic agent. Fig. 3 shows a patient with refractory psoriasis who responded well to combination therapy with 25 mg per day of acitretin plus twice-weekly 25-mg subcutaneous injections of etanercept. Combination treatment with systemic agents and immunomodulators underscores the significance of treating psoriasis in the future. With the advent of new biologic agents and the existing systemics, this new approach to combination therapy may provide an impetus in controlling psoriasis that previously was difficult to treat.
In a dose escalation study, 181 patients with moderate to severe plaque psoriasis received daily doses of oral tazarotene (0.4 to 6.3 mg) or placebo (Lowe et al, submitted for publication). Optimal efficacy was seen with the 4.2-mg dose. At this dosage, the body surface area involvement was reduced by 17% at week 12 and 82% of patients were satisfied or very satisfied with oral tazarotene. Fig. 4 shows a patient who had good clearance of psoriatic plaques with oral tazarotene at 4.2 mg per day by week 12. The only significant adverse effect noted was cheilitis at doses of 2.8 mg or higher. There were no other dose-related adverse events, such as increased liver function enzymes, hyperlipidemia, or changes in the hematologic profile. The shorter half-life of oral tazarotene may potentially be a useful alternative for systemic retinoid treatment in women of childbearing age with psoriasis.
Other systemic retinoids
Toxicities and adverse reactions associated with systemic retinoids
Oral tazarotene
Teratogenicity
An oral form of tazarotene (a topical retinoid approved for plaque psoriasis and acne) has recently been developed that is currently not available on the market during the preparation of this article. Tazarotene is converted to its active metabolite, tazarotenic acid, which has a short elimination half-life of 7 to 12 hours (Allergan, unpublished data).
All systemic retinoids are highly teratogenic with a pregnancy category of X rated by the FDA. Major human fetal abnormalities associated with retinoids include meningomyelocele, meningoencephalocele, multiple bony malformations, facial dysmorphia, lowset ears, high palate, decreased cranial volume alterations, and cardiovascular malformations.
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Fig. 4. Patient with plaque psoriasis (A) before and (B) after treatment with oral tazarotene, 4.2 mg each day for 12 weeks.
In light of its teratogenicity, acitretin must not be used by women who are pregnant or who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy. In addition, acitretin must not be used by women who may not use reliable contraception while taking acitretin or for at least 3 years following cessation of treatment. In addition, the current guideline states that ethanol must not be ingested by female patients either during treatment with acitretin or for 2 months after discontinuing acitretin to avoid conversion into etretinate, which carries a much longer elimination half-life. This is caused by the transesterification of acitretin to etretinate by ethanol as previously discussed. Mucocutaneous toxicity Mucocutaneous toxicity occurs with all of the systemic retinoids [34]. The common mucocutaneous side-effects in order of frequency are cheilitis, skin peeling, alopecia, xerosis, rhinitis, nail dystrophy, epistaxis, sticky skin, retinoid dermatitis, and xerophthalmia. Hair loss may occur a few weeks after initiation of treatment and ceases 6 to 8 weeks after discontinuation of therapy. In rare cases, chronic hair loss has occurred. Patients frequently find these symptoms extremely difficult to accept. Rapid reduction in retinoid therapy is desirable to reduce the impact on patients of these toxicity problems. Some studies have suggested that 800 IU of vitamin E daily may reduce some of the mucocutaneous effects of systemic retinoids [35]. Arthralgias and myalgias Some patients develop muscle pain and myalgias with or without an elevation of creatine phosphokinase. In general, it is wise for patients to avoid
excessive muscle exercising, particularly excessive weight lifting and contact sports, because these forms of activity may increase such risks. Arthralgias occur in a small percentage of patients and disappear on discontinuation of therapy. Pseudotumor cerebri Acitretin and other systemic retinoids have been associated with cases of pseudotumor cerebri (benign intracranial hypertension). Such symptoms and signs include papilledema, severe headaches, nausea and vomiting, and visual disturbances. If pseudotumor cerebri is suspected, ophthalmologic evaluation for papilledema should be conducted and if present, the retinoid should be discontinued immediately. Oral retinoids should not be taken with tetracycline or tetracycline derivatives because of increased risk of pseudotumor cerebri. Ophthalmologic effects Ocular toxicity does not seem to be a major problem with acitretin, although rare cases of disturbances of color vision have been recorded. Most of the ocular symptoms have been mucocutaneous in nature, such as dry eyes, irritation of eyes, and loss of brow and lashes. Other side effects, such as blurred vision, cataracts, decreased night vision, and diplopia, are much less common. Skeletal toxicity There is some concern that long-term high-dose acitretin therapy is associated with changes that resemble diffuse idiopathic skeletal hyperostosis, which include anterior spinal ligamentous calcification and the formation of osteophytes and bony bridges. Disk space narrowing is not evident in diffuse idiopathic
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skeletal hyperostosis. There seems to be a cumulative threshold dose of 25 to 30 g etretinate below which skeletal toxicity is not seen radiographically. Psychiatric effects There are no recorded incidents of suicide or depression linked to patients on systemic retinoid therapy for the treatment of psoriasis. There is clearly a background of depression with some psoriasis patients but this has not been noted to be aggravated by acitretin (Lowe NJ, unpublished observations, 2002).
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enzymes; renal function tests; creatine phosphokinase; and a lipid panel including triglycerides, cholesterol, and high-density lipoproteins. In all women of childbearing age, a monthly pregnancy test must be conducted. These investigations should be performed initially every 2 weeks while on clearance doses, reducing to monthly or 2-monthly assessments depending on the maintenance dose required. There is presently no requirement for liver biopsy.
Guidelines for the use of systemic retinoids in psoriasis
Hyperlipidemia Hyperlipidemia occurs in approximately 25% to 50% of patients. Occasionally, severe levels reaching five to eight times the normal value occur, but usually levels are increased two to three times the normal. The incidence of pancreatitis or eruptive xanthomas with increased triglyceride levels is uncommon. In addition, levels of high-density lipoproteins decrease with oral retinoids. These abnormal levels are reversible on cessation of therapy. Patients with an increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake, or a familial history of these conditions. There are a number of ways to manage hyperlipidemia including low-fat diets, reduced alcohol intake, physical activity, the use of polyunsaturated fish-oil supplements, and prescribing lipid-lowering drugs. Hepatotoxicity All the systemic retinoids have the potential for liver toxicity. Elevations of aspartate transaminase (serum glutamic-oxaloacetic transaminase), alanine transaminase (serum glutamate pyruvate transaminase), g-glutamyltransferase (GGTP), low-density lipoproteins, and alkaline phosphatase have occurred in 33% of patients treated with acitretin. During the clinical trials in the United States for acitretin, 3.8% of patients had sufficient elevation of liver function tests that they were discontinued from further treatment. If hepatotoxicity is suspected with acitretin, the drug should be discontinued and a liver work-up should be conducted.
Frequency of follow-up Blood investigations should include a full blood count; a complete metabolic panel including liver
The following guidelines apply for the use of systemic retinoids in psoriasis: 1. Acitretin can be prescribed for male patients or postmenopausal female patients. It is up to the clinician’s discretion to prescribe acitretin in women of childbearing age keeping in mind the strict guidelines associated with acitretin’s teratogenicity. If there is any suggestion that a woman desires pregnancy, or suspicion that adequate birth control methods will not be practiced, or abstinence from alcohol cannot be avoided, then acitretin should not be prescribed to that woman. 2. Careful pretreatment and screening should be performed to exclude the possibility of hyperlipidemia and hepatotoxicity. Risk factors for hyperlipidemia (diabetes mellitus, obesity) should be looked for and a history of alcohol use and hepatitis should be screened in every patient. 3. Retinoids should be considered as monotherapy in generalized pustular psoriasis. 4. Combination therapy of acitretin with PUVA or UVB is advised in patients with severe plaque psoriasis and localized palmoplantar psoriasis, including local pustular psoriasis of the palms and soles. 5. Combination therapy of acitretin with hydroxyurea may be beneficial in some patients with plaque or pustular psoriasis. In addition, combination therapy with the retinoids and the new immunomodulatory biologic agents may play pivotal roles in the future treatment of psoriasis. 6. New retinoids, such as oral tazarotene, seem to have a good safety profile. Longer-term studies and combination studies with this drug are eagerly awaited.
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Topical tazarotene There are four formulations for topical tazarotene: (1) 0.05% gel, (2) 0.1% gel, (3) 0.05% cream, and (4) 0.1% cream. All four vehicles and strengths can be used for plaque psoriasis. In general, gels and the more concentrated strengths tend to have a higher incidence of irritation, pruritus, erythema, stinging, and desquamation. These side effects are most apparent on initial applications but alleviate with continuous usage. In two multicentered, double-blinded, randomized, placebo-controlled studies involving 660 patients, tazarotene gels 0.05% and 0.1% applied once a day for 3 months were found to be efficacious and safe for the treatment of plaque psoriasis. The most profound effect with tazarotene gel was the improvement of plaque elevation [36]. Results of two multicenter studies showed that topical therapy once daily with tazarotene in a cream formulation at concentrations of 0.05% or 0.1% was effective in the treatment of plaque psoriasis [37]. A total of 1303 patients participated in these randomized, double-blinded, placebo-controlled trails in which tazarotene creams 0.1% and 0.05% or vehicle were applied daily to all psoriatic lesions for 12 weeks followed by a 12-week posttreatment period. Tazarotene creams 0.05% and 0.1% were significantly more effective than vehicle in terms of clinical success rates and in reducing the severity of the clinical signs of plaque psoriasis. Tazarotene cream 0.1% was generally more effective, although slightly less well tolerated, than the 0.05% cream. Both tazarotene concentrations showed good maintenance of therapeutic effect during a 12-week posttreatment period. Tazarotene creams 0.05% and 0.1% for the treatment of psoriasis were found to be safe with acceptable tolerability. To counteract potential irritation from tazarotene, topical corticosteroids may be combined to the lesions. A study showed that application of tazarotene in the evening and a mid- to high-potency topical corticosteroids in the morning achieved significantly greater reductions in scaling, erythema, and overall lesional severity, and a decreased incidence of adverse events [38]. Combination therapy by alternating tazarotene and high-potency steroids each day significantly increased the treatment success rate and lowered incidence of treatment-related adverse effects [39]. Short contact with tazarotene minimizes the local irritation on the skin. For patients who are beginning therapy with tazarotene, initial application times of 15 minutes in the evenings and then washing off the tazarotene decreases the incidence of stinging, burning, and erythema. As the patient becomes accus-
tomed and more tolerant to tazarotene, application times are prolonged incrementally until patients can leave it on overnight. Combination treatment using tazarotene with ultraviolet therapy has become very popular for the treatment of plaque psoriasis [40 – 43].The efficacy of tazarotene reported in clinical trials suggests that this drug may help to improve the efficacy of phototherapy, and perhaps reduce the ultraviolet light exposure required without introducing additional, clinically significant problems. Broad or narrow band UVB plus tazarotene combination achieves greater reductions in the elevation and scaling of difficult-totreat psoriatic plaques than UVB phototherapy alone. The tazarotene combination therapy also achieved initial treatment success in less than half the time needed with phototherapy alone. Combining UVB phototherapy with tazarotene treatment seems to offer a valuable therapeutic option that is more efficacious and faster than UVB phototherapy alone.
Summary Both systemic and topical retinoids provide an excellent alternative for the treatment of psoriasis. Retinoids are generally used as combination therapy with other treatment modalities, such as phototherapy or other topical or systemic agents, and can be combined with the newer biologic agents, such as etanercept. Newer retinoids are being developed to treat psoriasis with the hope of a less toxic side effect profile. For now, retinoids remain a mainstay for the treatment of psoriasis.
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