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,* aClinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USA bDivision of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1750, USA The systemic retinoids possess a remarkable range and is no longer available. The use of topical tazar- of activities and clinical applications. They are an im- portant 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 general- ized pustular psoriasis, they are effective as mono- therapy 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 indica- tion 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 conjunc- tion 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 treat- ment of plaque-type psoriasis. The only FDA-ap- proved 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 0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right doi:10.1016/S0733-8635(03)00126-8 * Corresponding author. Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404. E-mail address: [email protected] (N.J. Lowe). otene is also discussed in detail. Combination therapy of retinoids, both topical and systemic, with photo- therapy and other therapeutic agents is described. In addition, new retinoid analogues that are currently undergoing clinical investigation at the time of prep- aration of this article are mentioned. Finally, potential toxicities and adverse effects associated with reti- noids are discussed. Chemistry and pharmacology Fig. 1 shows the chemical structures of acitretin and etretinate. Acitretin is the principle active metab- olite of the prodrug, etretinate. They are very similar to each other except that etretinate is the ethylester form of acitretin. Because of this modification, how- ever, under physiologic conditions etretinate is in an uncharged state and is 50 times more lipophilic than acitretin, which carries a negative charge [5]. Conse- quently, etretinate is accumulated in adipose tissue because of its high lipophilicity as opposed to acitre- tin, which is not stored in fat. This is the main phar- macokinetic reason why acitretin has a much shorter half-life (approximately 50 hours) than etretinate (approximately 120 days). In light of the highly tera- togenic effects associated with systemic retinoids (dis- cussed later) and because of its long half-life and detection in the serum up to 2 years after discontinu- ing 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 trans- esterification 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 s reserved. Fig. 1. Chemical structures of etretinate (A) and acitretin (B). P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476468 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 sys- temic retinoids, including acitretin, have higher ab- sorption and improved bioavailability when ingested with food [8]. Fig. 2 illustrates the structure of tazarotene. Min- imal systemic absorption of tazarotene occurs because of rapid metabolism in the skin to the active metab- olite, tazarotenic acid, which is systemically absorbed and further metabolized. Tazarotenic acid is hydro- philic 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 reti- noids are able to exert their effects on psoriasis is unknown. It has been demonstrated that acitretin modulates the cellular differentiation of the epider- mis, 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 epider- mis 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 mod- els, topical tazarotene blocks induction of ornithine Fig. 2. Chemical structure of tazarotene. 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 pres- ent in high levels in the epidermis of psoriasis patients and inhibits the formation of hyperkeratotic plaques. Tazarotene also induces the expression of tazarotene- induced gene 3, a suppressor gene that may inhibit epidermal hyperproliferation in treated plaques. There are two classes of nuclear retinoid recep- tors that have been identified: the retinoic acid recep- tor 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 reti- noid 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 hetero- dimers 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 re- sponsive 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 When acitretin is used as monotherapy for gen- eralized 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 P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476 469 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 occa- sionally produce acute leukopenia in patients with generalized pustular psoriasis, which can lead to a major toxicity risk in these patients. Pustular psoria- sis 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 mye- losuppression [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 ther- apy, 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 ther- apy reduces the degree of hyperkeratosis and pustu- lation. 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 control- ling 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 oint- ment]) under occlusion to achieve more rapid resolu- tion of psoriasis. Rarely, patients with severe exfoliative erythro- dermic 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, par- ticularly 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 radiation- induced erythema. This is not a true photosensitivity, but probably represents increased epidermal trans- mission 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 addi- tion, 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 effec- tive, or acitretin therapy can be stopped and mainte- nance 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 clear- ing of psoriasis, whereas 96% of patients who re- P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476470 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 com- pared with treatment with PUVA alone [22]. Bath PUVA together with acitretin is another option for treatment of patents with pustular, plaque- type, 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 combina- tion 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 gastrointesti- nal 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 addi- tion, 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 cu- mulative 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 acit- retin therapy before the occurrence of side ef- fects, such as hyperlipidemia or alopecia Combination therapy with other agents Combination therapy of acitretin with other mo- dalities other than light therapy can be used to control psoriasis. Concomitant treatment with acitretin and topical calcipotriene may help reduce psoriatic pla- ques 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 pa- tients with chronic plaque psoriasis and pustular psoriasis. When using combination therapy with aci- tretin 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 mole- cules 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 anti- inflammatory agent that is beneficial in the treatment 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. P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476 471 of psoriasis. A recent report demonstrated that com- bination 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 impor- tantly, 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 subcu- taneous 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. Other systemic retinoids Oral tazarotene 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. Tazar- otene is converted to its active metabolite, tazarotenic acid, which has a short elimination half-life of 7 to 12 hours (Allergan, unpublished data). In a dose escalation study, 181 patients with mod- erate 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 chei- litis 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 taza- rotene may potentially be a useful alternative for sys- temic retinoid treatment in women of childbearing age with psoriasis. Toxicities and adverse reactions associated with systemic retinoids Teratogenicity 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, low- set ears, high palate, decreased cranial volume alter- ations, and cardiovascular malformations. Fig. 4. Patient with plaque psoriasis (A) before and (B) after treatment with oral tazarotene, 4.2 mg each day for 12 weeks. P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476472 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 guide- line states that ethanol must not be ingested by female patients either during treatment with acitretin or for 2 months after discontinuing acitretin to avoid con- version into etretinate, which carries a much longer elimination half-life. This is caused by the trans- esterification 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 xeroph- thalmia. 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 reduc- tion 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 phospho- kinase. 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 prob- lem with acitretin, although rare cases of disturbances of color vision have been recorded. Most of the ocu- lar 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 re- semble 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 P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476 473 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 aggra- vated by acitretin (Lowe NJ, unpublished observa- tions, 2002). 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 addi- tion, levels of high-density lipoproteins decrease with oral retinoids. These abnormal levels are reversible on cessation of therapy. Patients with an increased tend- ency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol in- take, or a familial history of these conditions. There are a number of ways to manage hyperlipidemia including low-fat diets, reduced alcohol intake, physi- cal activity, the use of polyunsaturated fish-oil supple- ments, 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 transami- nase), g-glutamyltransferase (GGTP), low-density li- poproteins, 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 treat- ment. 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 enzymes; renal function tests; creatine phosphoki- nase; and a lipid panel including triglycerides, cho- lesterol, and high-density lipoproteins. In all women of childbearing age, a monthly pregnancy test must be conducted. These investigations should be per- formed 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 The following guidelines apply for the use of sys- temic 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 hyper- lipidemia and hepatotoxicity. Risk factors for hyperlipidemia (diabetes mellitus, obesity) should be looked for and a history of alco- hol use and hepatitis should be screened in every patient. 3. Retinoids should be considered as monother- apy 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 hy- droxyurea 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 ea- gerly awaited. P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476474 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 in- cidence 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, random- ized, placebo-controlled studies involving 660 pa- tients, 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 improve- ment 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 random- ized, double-blinded, placebo-controlled trails in which tazarotene creams 0.1% and 0.05% or vehi- cle were applied daily to all psoriatic lesions for 12 weeks followed by a 12-week posttreatment pe- riod. Tazarotene creams 0.05% and 0.1% were sig- nificantly 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 mainte- nance of therapeutic effect during a 12-week post- treatment 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 tazar- otene 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, burn- ing, 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 ul- traviolet 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 photo- therapy, 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-to- treat 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 com- bined with the newer biologic agents, such as eta- nercept. 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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Retinoid therapy for psoriasis Chemistry and pharmacology Mechanism of action Monotherapy with systemic retinoids Pustular psoriasis Exfoliative erythrodermic psoriasis Combination therapy for moderate to severe plaque psoriasis Acitretin and psoralen plus UVA phototherapy Acitretin and UVB phototherapy Combination therapy with other agents Combination therapy with immunomodulatory agents Other systemic retinoids Oral tazarotene Toxicities and adverse reactions associated with systemic retinoids Teratogenicity Mucocutaneous toxicity Arthralgias and myalgias Pseudotumor cerebri Ophthalmologic effects Skeletal toxicity Psychiatric effects Hyperlipidemia Hepatotoxicity Frequency of follow-up Guidelines for the use of systemic retinoids in psoriasis Topical tazarotene Summary References