Acitretin acts by modulating the proliferation of epidermal keratinocytes. In hyperproliferative tissue, such as psoriasis plaques, acitretin has an antiproliferative effect, whereas in healthy tissues it induces proliferation.24 In psoriasis, this antiproliferative action reduces desquamation, erythema, and the overall thickness of the lesion. Some authors have also attributed retinoids a role in the modulation of the T-cell response,25 the inhibition of chemotaxis, and the activation of polymorphonuclear leukocytes.26 Unlike other systemic antipsoriatic therapies, acitretin is not considered to be cytotoxic or immunosuppressive.

Acitretin binds to RAR and RXR nuclear receptors, activating all 3 subtypes (α, β, and γ) and modulating the transcription of the genes that code for various proteins involved in the pathogenesis of psoriasis.27 Although retinoids act primarily by binding to nuclear receptors, they also act indirectly by antagonizing a number of transcription factors, competing with coactivator proteins which are essential for the activation of genes on which retinoids have no direct effect (Fig. 2).10,28,29 In addition to its direct mechanism of positive transcription, acitretin also exerts an indirect effect by inhibiting certain genes that regulate proliferation, angiogenesis, and inflammation in psoriasis.12,30

Figure 2.

Mechanism of action of retinoids. Abbreviations: ADH, alcohol dehydrogenase; COUP-TFII, chicken ovalbumin upstream promoter-transcription factor II; CRABP, cellular retinoic acid-binding proteins; CRBP, cellular retinol-binding proteins; CYP, cytochrome P450, family 26; FOG2, friend of GATA; GATA4, guanine, adenine, thymine, adenine; LRAT, lecithin retinol acyltransferase; RAR, retinoic acid receptors; RARE, retinoic acid response elements; RBP, retinol binding protein; RDH, retinol dehydrogenase, RXR, retinoid X receptors; STRA6, stimulated by retinoic acid 6.

Source: Saurat31; Siegenthaler et al.145; and Napoli.146

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Although the specific action that derives from this acitretin-induced transcription and inhibition is not fully understood, various hypotheses have focused on 2 areas of action: the modification of the metabolism and action of endogenous retinoids,29,31 and the overall immune regulation of the inflammatory molecules and cells involved in psoriasis,19,31,32 particularly helper T (Th) 1 and Th17 cells.18,20,33 These theories would explain the mechanisms of action that make acitretin capable of reversing the pathological and clinical manifestations of plaque psoriasis.18,34–37

The mean absolute bioavailability of acitretin is 59% (range, 36% to 95%). Absorption is linear up to 50mg/d and nonlinear at higher doses. The rate and extent of absorption can be 2 to 5 times higher when acitretin is taken with food.38,39

Absorbed acitretin is transported bound to plasma proteins (95%)—mostly albumin—with the remainder binding to high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein.38,40 The drug is distributed rapidly throughout the body and does not accumulate in any particular tissue. It is about 50 times less lipophilic than etretinate, and does not therefore tend to accumulate in adipose tissue.41

Acitretin is metabolized primarily by the liver, giving rise to 2 metabolites: 13-cis-acitretin and etretinate. The amount of 13-cis-acitretin formed is independent of dose, formulation, and administration with food. Steady state concentrations of acitretin and 13-cis-acitretin are reached after approximately 3 weeks of daily administration of acitretin.

It has been found that etretinate is naturally produced from acitretin through a re-esterification process that varies in each individual.42 The amount of etretinate produced is very small, but this process is potentiated by the presence of ethanol through the action of a liver enzyme that catalyzes the ethyl esterification of acitretin to etretinate.17,43 Since the accumulation of etretinate in fatty tissue, and in the liver, kidney, brain, and testes, is 50 times greater than that of acitretin, retinoid activity can persist for a long time even after the patient has stopped taking acitretin.

Once it has exerted its action on the target cell, the unused acitretin and etretinate are converted to polar metabolites by the enzymatic action of the cytochrome P450 complex.10,44

Chemically, acitretin and etretinate are very similar, with the only difference being that etretinate is the ethylester form of acitretin. This small chemical difference, however, results in major differences in the pharmacokinetic profiles of the 2 drugs. Etretinate, unlike acitretin, is an uncharged molecule and therefore highly lipophilic, a characteristic that leads to considerable accumulation of the drug in body fat. Acitretin, on the other hand, has a negative ionic charge and therefore accumulates less in adipose tissue. Its higher rate of clearance and lower volume of distribution means that it has a much shorter elimination half-life than etretinate (50hours vs 120 days).45–47 In fact, this was the main reason why acitretin replaced etretinate in clinical practice.

However, the hydrolysis that occurs naturally in the human body to convert etretinate to acitretin can be reversed in the presence of heavy alcohol consumption.46 Etretinate has been detected in the plasma of patients on monotherapy with acitretin, and since etretinate accumulates in adipose tissue and has a long half-life, its presence prolongs the teratogenic potential of acitretin.

Larsen et al46 reported that maximum plasma concentrations of acitretin were reached between 0.9 and 4.6hours after oral administration, with an absorption half-life ranging from 0.2 to 1.7hours and a distribution half-life of between 1.2 and 3.5hours.46 In the same study, the elimination half-life of the drug after cessation of treatment varied between 16.5 and 111.1hours (mean [SD], 47.1hours [29.8]), while that of its metabolite (13-cis-acitretin) varied between 36.5 and 249.4hours (mean [SD], 119.4 [7.4]).

The conjugates produced by the metabolism of acitretin and its metabolite 13-cis-acitretin are eliminated by the kidney (16% to 53%) or excreted into bile and ultimately eliminated in feces (34% to 54%). Acitretin is eliminated within approximately 49hours (range, 33 to 96hours), its metabolite, 13-cis-acitretin within 63hours (range, 28 to 157hours), and etretinate within approximately 120 days (maximum up to 168 days).

Trace amounts of acitretin are excreted in human milk (30–40ng/mL),48 and it is estimated that the infant would ingest only 1.5% of the maternal dose. Traces of the drug have also been found in seminal fluid at very low concentrations (12.5ng/mL).

To date investigators have identified more than 20 genes that regulate the metabolism of retinoids, 6 genes that encode the nuclear receptors involved in signal transduction, and many others that code for regulators of this pathway.49 Further study and greater understanding of these genetic variations and isoforms will lead to a better understanding of the specific mechanism of action of the retinoids in general, and acitretin in particular.

The commercial preparation of acitretin (Neotigason) is available in 2 presentations: 10mg and 25mg capsules in boxes of 30 capsules.

The inactive excipients are glucose, sodium ascorbate, cellulose, iron oxide black (E172), iron oxide yellow (E 172), iron oxide red (E 172), titanium dioxide (E 171), and gelatin.

Acitretin is administered orally, preferably with food (to enhance absorption). The dose is not weight adjusted. Etretinate dosage was weight adjusted, which is perhaps why this information still appears in some acitretin guidelines.59 The optimal therapeutic dose in monotherapy is between 25 and 50mg/d.60,61 It can be administered in a single or twice-daily dose. Higher-doses (50–75mg/d) are more effective, but the appearance of adverse effects usually makes it necessary to reduce the dose or discontinue treatment.61–63 In fact, no clinical trials have been carried out with doses higher than 75mg/d. Doses under 25mg/d may be indicated in combination therapy.

A recent study that analyzed the findings of 2 pivotal clinical trials concluded that the differences in efficacy between a regimen of 25mg/d and one of 50mg/d do not justify the risk of the adverse effects that occur with the higher dose, and the authors recommended 25mg/d for maintenance regimens.64,65

Since the pharmacokinetics, efficacy, and adverse reaction profile of acitretin are subject to interindividual variations, it is not possible to establish a standard dose. The regimen must, therefore, be tailored on a case-by-case basis by adjusting the dose to obtain the best clinical outcome with the lowest possible occurrence of adverse events.66

Although the SPC for Neotigason continues to specify that treatment with acitretin for more than 6 months is contraindicated, neither the experience of years of use nor results from several retrospective studies indicate any substantial increase in adverse effects with longer term therapy.

The recommended starting dosage for acitretin in plaque psoriasis is 10 to 20 mg/d. This initial regimen should be continued for 4 weeks. Response to treatment should be assessed at 4 weeks, after which the dose should be gradually increased to achieve the best therapeutic effect with the fewest adverse effects (minimal effective dose). In general, the maintenance regimen in most series varies between 25 and 50mg/d. Psoriatic lesions clear faster when the starting dose is higher, but such high-dose regimens also increase the risk of mucocutaneous adverse effects and consequently the risk of the patient stopping treatment due to poor tolerance of side effects. Initiating treatment at a high dosage (1mg/kg/d) is currently only recommended for the treatment of generalized flares of pustular psoriasis.

In some patients, psoriasis may worsen after the start of treatment, a phenomenon that manifests as more intense erythema and a greater spread of lesions, which later resolve.61

Very few studies have evaluated the short-term efficacy of acitretin in plaque psoriasis. A study that examined efficacy at 8 weeks in patients who received an initial dose of 10, 25, or 50mg of acitretin reported a mean reduction in PASI of 61%, 79%, and 86%, respectively, in the 3 treatment groups as compared to 30% in the placebo group.54

The available studies on the efficacy of the drug have very varied designs and objectives. Overall, initial doses of between 40 and 50mg/d have achieved a 50% reduction in PASI (PASI 50) in 66% to 85% of patients and a 75% reduction (PASI 75) in 34% to 52% of patients at 8 to 12 weeks. Higher dose regimens—up to 70mg/d—were associated with adverse effects that make it difficult for patients to continue treatment.36,45,67,70

Clinical experience has shown acitretin to be an ideal choice for long-term maintenance therapy because the clinical response is sustained and there is no significant loss of efficacy over time. The authors of a study that enrolled 63 patients in which efficacy was assessed following 12 months of treatment with acitretin reported that, of the 37 patients who completed the study, 89% had a PASI 50 response and 78.4% a PASI 75 response.36

In generalized pustular psoriasis, acitretin is used at a dose of 0.5 to 1mg/kg/d and treatment generally produces a rapid clinical response with clearing of the lesions within 10 days. The dose should then be tapered slowly until a maintenance dose of 10mg/d is reached. Relapse on withdrawal of treatment is rare, and in such cases reintroduction of the drug restores the same efficacy. Acitretin is probably the first-line therapy in this form of psoriasis, with studies showing it to be effective in 84% of patients.50,71

It is also considered to be among the first-line options for palmoplantar pustulosis, either in monotherapy or in combination with phototherapy.72

Numerous isolated cases in the literature demonstrate the efficacy of acitretin in the treatment of nail psoriasis. In an open study of 36 patients with moderate to severe nail psoriasis treated with acitretin at a dose of 0.2 to 0.3mg/kg/d for 6 months, a good response was observed, with a mean reduction in the Nail Psoriasis Severity Index (NAPSI) score of 41%.73 Complete clearing of lesions was achieved in 9 patients (25%), and there was no improvement in 6 (11%). These findings prompted the authors to propose this low-dose regimen of acitretin as a therapeutic option for nail psoriasis because of its good tolerance profile and scant adverse effects. By contrast, no improvement was achieved in a recent open-label study of 30 patients with nail psoriasis treated with acitretin at 0.3mg/kg/d during the first month and 0.5mg/kg/d for a further 3 months.74

Most of the adverse effects of acitretin are dose-dependent and, in general, well tolerated at the recommended doses. Adverse clinical reactions and laboratory abnormalities occur less often with low-dose regimens (25mg/d) than with high ones (50mg/d).65,68 However, the toxic dose of acitretin is very close to the therapeutic dose, and for this reason most patients experience some adverse effects during the initial period of treatment while the dose is being adjusted. Such effects are usually reversible and disappear when the dose is reduced or treatment is interrupted, although in some cases they lead to discontinuation of treatment.

The adverse effects most often associated with the use of acitretin are shown in Table 2.

Before starting treatment, patients should be well informed about the most common side effects of the drug because these can quickly lead to poor adherence to treatment. They should also understand that the clinical response may take time to appear and the physician should explain why acitretin has been prescribed in preference to other possible treatments. Patients who are given complete information and involved in the choice of drug are more likely to adhere to treatment.

Women must be advised that they must avoid pregnancy during treatment with acitretin and for at least 2 to 3 years after cessation.

Patients must be instructed to moisturize their skin and mucous membranes regularly and to use sunscreen and sunglasses to filter out UV radiation.

They must be made aware that before taking any other medications they should inform the prescribing physician that they are taking acitretin; this precaution is essential to avoid toxicity (hepatotoxicity, hypervitaminosis A syndrome).

The need for regular follow-up and testing to ensure the safety of treatment and make long-term use of the drug possible must be discussed with patients, and they must commit to this program.

Before starting a patient on treatment with acitretin, the physician must obtain a complete medical history (past history, comorbidities, concomitant medication, physical examination, prior course of psoriasis, type of psoriasis, and prior medication. In women, pregnancy must be ruled out and a contraceptive regimen put in place that must continue for at least 2 years after cessation of treatment according to the European label and 3 years according to the US label. Baseline blood count and biochemistry should be obtained; explorations should include liver and kidney function and lipid profile.69

Liver function and lipid levels should be reassessed a few weeks after start of treatment. The exact timing of this assessment will depend on the patient's risk profile and whether he/she is taking concomitant medication that might increase hepatotoxicity or lipid abnormalities. In our opinion, the first assessment during treatment should take place between 4 and 8 weeks and the standard program of monitoring check-ups should be initiated thereafter. In standard clinical practice, alterations in liver function and lipid values are not very common and monitoring every 6 months is sufficient.

Regular radiographic investigation is not recommended except when there is evidence of bone toxicity.53

Clinical and laboratory parameters should be evaluated every 3 to 6 months (Table 5).69Figure 3 is a sample treatment monitoring form.

Figure 3.

Treatment monitoring form for acitretin.

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The decision to use acitretin in patients with cardiovascular risk must be very carefully weighed because of the associated risk of hypertriglyceridemia and the consequent increased risk of atherosclerosis. If acitretin is prescribed, it is always advisable to add lipid-lowering therapy98 and to advise the patient to begin or further enhance a lifestyle designed to reduce cardiovascular risk factors.69

The use of acitretin in patients with metabolic syndrome must be considered on a case-by-case basis because of the risk of exacerbating the syndrome and increasing cardiovascular risk, and because the liver toxicity associated with acitretin is favored by obesity and diabetes. If the patient's lipid levels are affected, the dose should be reduced and lipid-lowering treatment should be added; in some cases, withdrawal of acitretin might even be considered.

Hypertriglyceridemia and hyperglycemia can be managed by increasing physical exercise, introducing dietary changes, reducing alcohol intake, and pharmacotherapy.

Increased efficacy of acitretin treatment has been reported in patients with type 2 diabetes mellitus taking pyoglitazone.99 This may be a result of the anti-inflammatory and antiangiogenic effects of this oral hypoglycemic agent.100 Pyoglitazone is a second-line oral antidiabetic agent and a first-line treatment in obese patients who cannot be treated with metformin. The prescription of this combination in a patient with psoriasis should involve an endocrinologist. It may occasionally be useful to take advantage of this synergistic effect in selected patients who have both psoriasis and diabetes.

Since acitretin is potentially hepatotoxic, it is relatively contraindicated in patients with hepatic impairment. If acitretin is used in such patients, liver enzymes must be monitored and the dose and regimen adjusted accordingly; alanine aminotransferase values should not exceed 4 to 5 times the upper limit of normal.

Liver biopsy is never required since no association has been found between cumulative doses of acitretin and fibrosis or cirrhosis of the liver.101 Habitual alcohol consumption, obesity, and diabetes exacerbate the hepatotoxic effect of acitretin and therefore increase the risk of such toxicity. In such cases, closer monitoring of liver function is required or the use of acitretin may be clearly contraindicated.

Acitretin is also contraindicated in patients with renal impairment (Neotigason SPC). Plasma concentrations of acitretin are lower in patients with severe kidney failure. Note that acitretin is not eliminated by dialysis.

Logically, the concomitant use of acitretin with other drugs or substances having similar adverse effects can exacerbate these effects, or the action of acitretin may alter the function of other drugs taken concomitantly. Whenever acitretin is prescribed, all the drugs taken by the patient before and during treatment must be recorded.

It is important to note that alcohol intake increases the hepatotoxicity of acitretin and favors the re-esterification of acitretin to etretinate, with the increased risk of teratogenicity that this implies (Neotigason SPC).76 It is also important to note that acitretin reduces the anticontraceptive effect of drugs based on microdoses of progestogens and that these minipills should never be used to prevent pregnancy during treatment. Contraceptives that use a combination of estrogen and progesterone may be used since acitretin does not interfere with the action of these drugs.102 The most important drug interactions are shown in Table 6.

Since acitretin is not a direct immunosuppressant it can be used in patients who are going to be vaccinated, whether with toxoids or with live, attenuated vaccines.

Acitretin is a psoriasis treatment suitable for use in patients with cancer or in immunocompromised patients because it is not an immunosuppressant and because retinoids have been shown to have a chemopreventive effect in promyelocytic leukemia,103 precancerous and cancerous skin lesions,104–106 and hepatocellular carcinoma.107 Consequently, acitretin may be indicated as a first-line systemic treatment in patients with psoriasis who also have melanoma, solid tumors, or lymphoproliferative disorders,58 and in patients with human immunodeficiency virus infection.57,58

The use of acitretin during pregnancy is contraindicated because of the drug's teratogenicity and the risk that it may cause severe fetal malformations (independent of dose and timing of exposure).76

When acitretin is administered to woman of childbearing potential, contraception must start at least 1 month before start of treatment and must be maintained for 2 to 3 years after cessation of treatment. The minimum duration of contraception after cessation of treatment is specified as 2 years in the European SPC. The duration of this safety period has been calculated on the basis of evidence that 98% of the etretinate that may have been formed from the acitretin administered will be eliminated within 2 years. The 3-year contraception period after discontinuation of treatment specified in the US SPC (1 year longer than the calculation based on the half-life of the drug) has been established to increase the margin of safety, but is without pharmacologic basis.

If acitretin is prescribed to women of reproductive potential, it is essential to ensure adequate contraception from at least 1 month before start of treatment throughout the entire period of treatment, and for at least 2 years after cessation of treatment. Contraceptive measures must also be adopted if the patient receives repeated cycles of treatment. These precautions must be taken even by women who normally do not use contraception because of a history of infertility. Alcohol consumption is strictly prohibited in women of childbearing age during treatment and for 2 months following withdrawal of treatment. In such cases, convincing evidence that the patient understands and accepts the potential risks of treatment is essential and the patient must sign informed consent authorizing the use of acitretin.

Patients receiving acitretin must not donate blood during treatment or for 1 year following withdrawal of treatment to avoid all possible risk of teratogenicity in the eventual recipient of the donated blood. Nevertheless, a recent study that monitored the pregnancies of 18 women who accidentally received blood transfusions from individuals taking acitretin did not observe any fetal malformations or abnormalities during pregnancy.108

In male patients, acitretin has not been associated with abnormalities in spermatogenesis or the characteristics of spermatozoids.109 No cases of fetal malformation have been reported in pregnancies following conception while the father was taking acitretin. The presence of acitretin metabolites in the seminal fluid of men being treated with acitretin appears to entail very little risk for the fetus. However, the data available are scant and acitretin therapy is usually avoided in males planning to have children.110

The indications and regimens for the use of acitretin in older patients are the same as for adults in general. However, it should be remembered that older patients are more susceptible to cutaneous and mucosal xerosis and liver and kidney failure. Consequently, these adverse effects may appear at lower doses in these patients. The doses used should therefore be lower, particularly at the start of treatment, and these patients should be more closely monitored.

The use of acitretin is not contraindicated in patients undergoing surgery, although the physician should carefully consider the possible benefits of reducing the dose or even temporarily suspending treatment with the drug to prevent possible postoperative complications associated with its adverse effects (Table 2).

The effects of accidental or intentional overdose with acitretin are similar to the manifestations of acute vitamin A toxicity, namely, severe headache, nausea or vomiting, drowsiness, irritability, and pruritus. These symptoms subside without treatment. Owing to the variable absorption of the drug, gastric lavage may be indicated in the initial hours following an overdose (Neotigason SPC).

Approaches that seek to achieve a rapid response at start of treatment with acitretin are generally counterproductive because they lead to the appearance of adverse effects, which eventually limit the use of the drug.38 The primary aim should be to identify the dose that each patient can tolerate and to maintain this regimen while waiting for a clinical response in the long term (the therapeutic objective should be assessed 3 to 6 months after start of treatment).

Although the usual therapeutic dosage of acitretin is between 25 and 50mg/d, it is preferable to start treatment with a lower dosage (between 10 and 25mg/d)61 and then tentatively raise the dose by 10mg every 2 weeks until the adverse effects experienced by the patient make it advisable to refrain from further escalation.53,65 A useful sign is the appearance of cheilitis, which is an expression of the correct bioavailability of acitretin in each individual.16 Note that the individual variability associated with this drug means that low doses of acitretin may be effective.64 Thus, gradual dose escalation is the optimal strategy for the correct use of this drug since this approach makes it possible to obtain the best clinical response with the least adverse effects.68 The escalation approach also allows patients to gradually increase their tolerance of the potential and frequent adverse effects associated with acitretin and avoids the use of higher-than-necessary doses in some cases or doses that might lead to discontinuation of treatment in others.53,61

Gradual dose escalation strategies take time, and attempts to shorten this time generally result in discontinuation of treatment before its long-term efficacy has been demonstrated. This gradual approach, which is the key to the correct management of therapy with acitretin in clinical practice, contrasts sharply with the strategies and responses we are accustomed to with other antipsoriatic drugs, some of which achieve dramatic results in a relatively short period.

Once the optimal dose has been achieved using the escalation strategy, and if an acceptable clinical response is achieved, it is normally possible to slightly reduce the dose to improve tolerance. Once again, this requires individualized dose adjustment achieved by gradually tapering the dose. Using this strategy it is often possible to maintain efficacy with low-dose regimens (10 to 25mg/d; or 25mg/48h) for a very long period.66

There is evidence supporting the usefulness of combining acitretin with topical treatment, phototherapy, classic systemic therapies, and biologic agents, either as an initial drug to which a second treatment is added or as a second drug added to an already established regimen.112,113

A recent study that analyzed the data on the prescription of acitretin recorded in the National Ambulatory Medical Care Survey found that in 62% of cases acitretin was prescribed concomitantly with another drug: topical corticosteroids (51%), calcipotriol (31%), biologic agents (6%), ciclosporin (5%), methotrexate (5%), and tazarotene (2%).114Table 7 shows the different options for combination therapy with acitretin.

The therapeutic efficacy of acitretin increases when it is combined with topical calcipotriol70,115,116 or topical corticosteroids.112,117 The combination with calcipotriol (1,25-dihydroxyvitamin D3) is of particular interest since this drug also induces the transcription of certain genes.28,118,119

The association of oral retinoids and phototherapy is probably the most well-known and generally accepted combination therapy. The benefit of this combination was initially demonstrated with etretinate and PUVA therapy120,121 and, given the clinical equivalence of the 2 drugs, the results obtained with etretinate may be extrapolated to acitretin. Moreover, the combination of acitretin with UV-B, UV-A, or PUVA therapy has also been shown to be more effective than monotherapy with acitretin or phototherapy the use of a combination makes it possible to reduce the number of phototherapy sessions and the dose of acitretin required, thereby improving tolerance.52,66,122–124 Moreover the anticarcinogenic potential of the retinoids makes combination treatment safer than phototherapy alone.

When clearing is used as a measure of efficacy, the result achieved with acitretin in combination with UV-B therapy (74%) is good and better than that achieved by monotherapy with either acitretin (42%) or UV-B (35% to 41%).66,125,126 The acitretin–PUVA combination has also been shown to be more effective than monotherapy with either treatment.127 The acitretin–UV-B and acitretin–PUVA combinations have similar efficacy in the treatment of psoriasis.128 UV-B, and particularly narrowband UV-B, is currently preferred to PUVA in combinations with acitretin because it does not produce the adverse effects associated with psoralens.

When combination therapy is chosen from the outset, the recommended strategy is to administer acitretin at a low dose (for example 25mg/d) for 2 weeks before starting phototherapy. When the patient is already receiving UV-B phototherapy but the therapeutic objective has not been achieved, 25mg/d of acitretin may be prescribed. In such cases the dose of UV-B should be reduced by between 30% and 50% during the first week to prevent erythema. It is then gradually increased until clinical response is achieved with acceptable tolerance.69 Once the lesions have cleared, the dose of acitretin should be maintained for 1 month before reducing either the dose of acitretin or the frequency of phototherapy sessions.129

The association of acitretin and the immunosuppressive agents used to treat psoriasis is supported only by evidence from isolated case reports and series. Acitretin is the only systemic antipsoriatic agent that can be used in combination with another systemic drug without creating a regimen of 2 immunosuppressants, and consequently the only one that will not increase the risks arising from immunodeficiency.

The combination of acitretin with methotrexate is effective,130 particularly in the case of pustular psoriasis.131 If, after starting acitretin at the usual doses a therapeutic response is not achieved within the established time frame (normally 3 to 6 months), weekly administration of methotrexate may be added at the usual doses. Once clinical improvement has been achieved, 1 of the 2 drugs may be discontinued130 or the combination can be maintained at lower doses for both drugs.

Given that both acitretin and methotrexate are hepatotoxic, close monitoring of liver function is essential. However, the concern about hepatotoxicity that initially motivated the formal contraindication to this combination in the Neotigason SPC is not usually a problem in clinical practice in our experience and in that of other authors,112 and tolerance is generally good.132

The combination of acitretin and ciclosporin has also been used effectively in the treatment of psoriasis, although it is debatable whether it offers any advantage over monotherapy in terms of efficacy.133,134 In our clinical experience we have not observed any such advantage. Furthermore, prolonged use of this combination increases the risk of elevating cholesterol and triglyceride levels and of potentiating the toxicity of ciclosporin because acitretin inhibits the P-450 cytochrome, which is the principal inactivation pathway of ciclosporin. The combined use of acitretin and ciclosporin is more useful as a temporary overlap in the context of a sequential strategy (see below), or in selected cases of psoriatic erythroderma.135,136

The combination of acitretin with the new selective immunosuppressants (biologics) is also a treatment option, especially in cases in which the biologic treatment has not achieved complete control of the disease and in which the antipsoriatic, but not immunosuppressive, action of acitretin may add the small degree of efficacy required to completely control the disease. Examples of such cases are patients with inflammatory bowel disease and psoriasis, patients with generalized psoriasis in whom therapy has not completely cleared lesions on the palms and soles, and patients with psoriasis previously treated with PUVA and ciclosporin who are on biologic treatment to reduce the risk of nonmelanoma skin cancer associated with immunosuppression.137–139

A series of cases have recently been published of patients who responded to combinations of biologic drugs with acitretin.137,138,140,141 In these patients, the efficacy of monotherapy with a biologic agent was suboptimal and the addition of acitretin improved efficacy. These findings suggest that efficacy can be improved with no increase in toxicity, since acitretin is not an immunosuppressant. Furthermore, by using acitretin, physicians can reduce the dose of the biologic while maintaining response, enhancing safety, and above all reducing costs.

A recent open-label retrospective study assessed the addition of a biologic agent in a series of patients who had a poor response to acitretin therapy.138 As might be expected, the regimen was shown to be effective and is an example of the role acitretin can play in the era of biologic therapy. Because of its proven efficacy and very good long-term safety profile, acitretin may be another option to consider when choosing a combination strategy when a biologic drug does not achieve optimal efficacy or when response to biologic therapy diminishes. Moreover, acitretin is distinguished from ciclosporin, methotrexate, and the biologics in that its mechanism of action is not based on immunosuppression. To date, the tendency, perhaps influenced by the practice of rheumatologists, has been to use methotrexate with biologics as the first-line combination therapy, even in the absence of arthritis.

Sequential therapy has been established as a strategy for the long-term management of psoriasis to avoid the prolonged use of immunosuppressants and drugs with cumulative, organ-specific toxicity. The approach involves using a different drug as a maintenance regimen after the therapeutic objective has been achieved with the induction treatment; it can be a drug-sparing option in the long-term.16,142

Acitretin is an ideal candidate for sequential strategies because of its capacity to maintain efficacy in the long term without direct immunosuppressive action. Moreover, in sequential approaches the slow response associated with acitretin treatment can be compensated for by starting treatment with a faster-acting and more effective antipsoriatic drug whose long-term use is limited by the risk of exceeding a maximum cumulative dose or even by financial considerations. The idea is that once improvement has been achieved with one treatment, it can be maintained using acitretin, preferably at low doses.66,143

A classic sequential strategy involves using ciclosporin to clear the patient's psoriasis (clearing phase) and then adding a gradually escalating dose of acitretin (transition phase) to establish the maximum tolerated dose. The last step (maintenance phase) is to discontinue ciclosporin and maintain long-term monotherapy with acitretin.142 Another variant of this strategy is to occasionally add UV-B or PUVA therapy in the case of a loss of response to monotherapy with acitretin (Table 8).66

Sudden interruption of acitretin therapy does not produce a rebound effect resulting in a flare.144 This means that treatment with acitretin, whether as monotherapy or combination therapy, can be suspended at any time. Sustained remission of psoriasis after a prolonged period with therapeutic response can last 2 to 6 months.

Because of these characteristics and the absence of any known antigen action or resistance, as long as a rapid clinical response is not required, acitretin is suitable for intermittent therapy, although this type of treatment regimen has not been assessed in clinical trials