Alitretinoin in Dermatology—An Update

Abstract

Alitretinoin is a pan retinoic acid agonist. It was initially used as 0.1% gel in the management of localized Kaposi's sarcoma. At present, the use of systemic alitretinoin has proved extremely efficacious in the management of recalcitrant chronic hand eczema. Furthermore, there have been other retinoid responsive dermatosis that have demonstrated remission post usage of systemic alitretinoin. With a better toxicity profile, compared to the other systemic retinoids, alitretinoin could be considered a valuable treatment option in the near future for the treatment of these dermatologic disorders.

What was known?

• Alitretinoin 0.1% gel is the FDA approved treatment for localized Kaposi's sarcoma.

• Alitretinoin has demonstrated to have apoptotic and anti-proliferative effects.

Introduction

Alitretinoin or 9-cis retinoic acid is an endogenous first-generation retinoid, routinely present in the skin and circulation, obtained after isomerization of tretinoin.[1] Though alitretinoin started off as the FDA-approved topical therapy for localized Kaposi's sarcoma(KS), it has now been systemically and topically utilized in the treatment of a number of dermatologic disorders. Recently, the efficacy of systemic alitretinoin witnessed, while managing patients with recalcitrant hand eczema has made it a licensed drug for the same, in many European countries.[2] With a better safety profile as compared to other retinoids, alitretinoin may prove to be a valuable alternative, while managing many other retinoid responsive dermatosis.

Mechanism of action

Alitretinoin has a distinct uniqueness among all retinoids in that, it has the ability to bind to all subclasses of retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Upon binding to these receptors a number of processes occur, the final outcome being expression of proteins that play a role in growth and regulation,[3] responsible for its therapeutic properties. Broadly the pharmacodyanamic profile of alitretinoin can be divided into:

1. anti-inflammatory and immunomodulatory effects and

2. anti-proliferative and apoptotic effects.

Anti-inflammatory and immunomodulatory effects

These effects of alitretinoin are exerted by suppression of chemokine receptor expression and halting recruitment of inflammatory cells.[4] Further, alitretinoin also markedly reduces the number of macrophages and activated dendritic cells, two major sources of TNF-alpha and hence considerably reduces the inflammation.[5] Other inflammatory chemokines, whose levels alitretinoin diminishes include IL-4, IL-1beta and IL-12p40.[6,7] Alitretinoin also inhibits the production of nitric oxide (NO), secondary to stimulation by other cytokines and lipopolysaccharides, further bringing about immunomodulation by downregulating the activity of leucocytes.[8]

Anti-proliferative and apoptotic effects

The anti-proliferative effect of alitretinoin is related to RARs, whereas RXRs mediate the apoptotic activity of alitretinoin. These properties of alitretinoin are of particular use in Kaposi's sarcoma (KS). Post binding to RARs and RXRs, alitretinoin downregulates expression of IL-6 receptors and reduces the expression of viral encoded oncogenes which populate the lesions of KS.[9,10]

Pharmacokinetics

Taken orally, alitretinoin has a variable rate of absorption. Absorption of alitretinoin is enhanced after food intake. It is strongly plasma protein bound and has a volume of distribution, which exceeds the extracellular volume. Metabolism of alitretinoin occurs in the liver with the CYP3A4 isoenzyme to form 4-oxoalitretinoin. The t_1/2 of alitretinoin is 2-10 hours. Elimination of the drug is via the renal route. Alitretinoin and its 4-oxo metabolite do not accumulate like the other systemic retinods, and therefore after 1 month of stoppage of alitretinoin pregnancy can be planned.[11] Topical alitretinoin has no extensive systemic exposure.[7]

Indications

Chronic hand eczema

Hand eczemas are a group of dermatosis commonly encountered in clinical practice by all dermatologists. Lesions seen in chronic hand eczema (CHE) may range from erythema and vesiculation at one end to scaling and fissuring at the other end. Symptoms include pruritus and pain.[12] The mechanism by which alitretinoin alleviates the signs and symptoms in CHE is unclear. It has however been suggested that by activating RXRs, alitretinoin may stimulate T_H2 immune functions thus ameliorating the pathology encountered in CHE.[13,14] Various trials with alitretinoin for CHE have shown promising results. Bollag and Ott[14] conducted an exploratory open labelled study in 1999, with 38 patients who had recalcitrant CHE. The morphologic patterns of CHE encountered in this study were hyperkeratotic palmar eczema, finger-tip eczema, pompholyx and discoid eczema. Patients were administered 20-40 mg of oral alitretinoin for a period of 1-5 months. At the end of the study, 89% of the patients assessed by the treating physician showed a very good clinical response. The side effects encountered were transient headache, flushing, conjunctivitis and cheilitis. In 2004, Ruzicka et al.[15] further substantiated the finding of Bollag and Ott in a randomized double-blind placebo controlled trial with 348 patients. Only patients who were refractory or intolerant to topical glucocorticoids for at least 4 weeks were enrolled in the study. The morphologic patterns of CHE included were hyperkeratotic hand eczema, finger-tip eczema and pompholyx. Patients were administered 10, 20 and 40 mg of alitretinoin once daily along with a placebo group for the purpose of comparison. Treatment was instituted for a period of 12 weeks. At the end of the study, the physician's global assessment (PGA) scores were 27%, 39%, 41% and 53% for responders in the placebo, 10, 20 and 40 mg groups, respectively. A significant dose-dependent outcome was demonstrated by the Cochrane armitage trend test (P < 0.001) and evaluation of the total lesion/symptom score (TLSS) showed a 25%, 59%, 52% and 70.5% decrease of lesions in the placebo, 10, 20 and 40 mg doses, respectively. The results obtained showed a P < 0.001, which is significant as per the Kruskal–Wallis test. The Jonckheere Terpstra trend test further highlighted the importance of dose dependence in alleviation of symptoms and signs following alitretinoin administration. Adverse effects were encountered only with the 40 mg-dosed patients, which included flushing, headache, anemia, hyperlipidemia and reduced levels of thyroxine. In 2008, Ruzicka et al.[16] conducted the Benefit of Alitretinoin in Chronic Hand dermatitis (BACH) study. This was a larger randomized double blind placebo controlled study enrolling a total of 1032 patients. Three groups were allotted, first the placebo group and second and third groups receiving 10 and 30 mg of alitretinoin, respectively, for a period of 24 weeks. The morphologic patterns of CHE in this study were hyperkeratotic hand eczema, pompholyx and finger-tip eczema. At the end of 24 weeks, the PGA yielded an efficacy score of 17%, in the placebo group, 28% in the 10 mg group and 48% in the 30 mg group. A modified TLSS at 24 weeks was 39%, 56% and 75% in the placebo, 10 mg and 30 mg group, respectively. The result of this study was at par with the one conducted in 2004. Another study, done by Leiva et al.,[17] further demonstrated the efficacious role of alitretinoin in the management of CHE refractory to conventional treatment.

Psoriasis

Oral alitretinoin has been tried in the treatment of palmoplantar pustular psoriasis,[18] with a good result. Alitretrinoin helps in this papulosquamous disorder primarily by its immunomodulatory effects on keratinocytes,[19] fibroblasts,[20] mast cells,[21] dendritic cells[22] and T cells.[23] By suppressing the expression of chemokine receptors, alitretinoin prevents chemotaxis of inflammatory cells.[4] With its property to abrogate inflammation, alitretinoin brings about a rapid subsidence of the plaques and pustules encountered in palmoplantar psoriasis. Alitretinoin has also been combined with biologic agents like adalimumab and etanercept[24] in the management of palmoplantar hyperkeratotic psoriasis with a successful outcome. However, further controlled trials are required to check the efficacy of alitretinoin as a therapeutic agent for psoriasis.

Kaposi's sarcoma

Alitretinoin available as a 0.1% gel has been an FDA-approved indication for localized cutaneous Kaposi's sarcoma (KS) since 1999. Apart from modulating keratinocyte differentiation, alitretinoin blocks neo-angiogenesis and proliferation of KS cells in vitro.[25] Further, alitretinoin reduces the cohesion between the malignant kerationcytes and reduces its propensity for malignant degeneration.[26,27,28] Systemic use of alitretinoin for KS only demonstrated a moderate improvement with an unfavourable toxic profile thus limiting its usage.[25] Alitretinoin gel application is initiated as a twice daily regimen and is gradually increased to four applications per day based upon individual tolerance.[29,30] Sufficient quantity of the drug needs to cover the lesions of KS and allowed to dry for 3-5 minutes before covering that area with clothing. The area is to be kept free from any form of occlusive dressing. There should be no contact of the drug with the surrounding normal skin or mucosal surfaces. Response may be seen as early as 2 weeks. With continued application further improvement is attained. Alitretinoin can be continued as long as patients benefit from it. Other modalities of treatment like cryotherapy can be also combined with topical alitretinoin.

Cutaneous lichen planus

Owing to its regulatory role in cell proliferation, differentiation and apoptosis, oral alitretinoin has been used in treating cutaneous lichen planus (CLP). Also, its anti-inflammatory and immunomodulatory characteristics have proven to play a role in the regression of CLP lesions. Molin and Ruzicka[31] have demonstrated the promising effects of systemic alitretinoin at a dose of 30 mg/day for the management of CLP. Along with alitretinoin, patients received topical glucorticoids and keratolytic agents. The lesions regressed within a period of 5-6 months. In addition to the good therapeutic outcome, there was also a favorable profile with respect to adverse effects. Though seen to be effective in this report of 2 cases by Molin and Ruzicka, further controlled trials would be mandatory to fully assess the role of alitretinoin in CLP.

Nail lichen planus

Lichen planus of the nails has been a difficult condition to treat. Alsenaid and colleagues[32] have depicted the benefits incurred post treatment of nail lichen planus (NLP) in two patients with end stage destructive pterygium, who showed characteristic improvement post administration of 30 mg of alitretinoin daily, for 8-9 months, with improvement being visible as early as 2-4 months after institution of treatment. These authors have concluded that early introduction of systemic treatment with alitretinoin may prevent pterygium formation and thus abrogate mutilating effects on the nail as a result of the disease.

Atopic dermatitis

An open label study with six patients by Grahovac et al.,[33] demonstrated a substantial clinical improvement in clinical lesions of atopic dermatitis (AD), evident over a period of 12 weeks. Patients received 30 mg of alitretinoin per day along with topical emollients and immunomodulators. The safety profile of alitretinoin seen in this study was acceptable. However, to employ alitretinoin for this indication, more placebo controlled trials are warranted.

Lichen simplex chronicus

D’Erme et al.[34] have demonstrated the promising role of systemic alitretinoin in a case of refractory lichen simplex chronicus (LSC), administered at a dose of 30 mg per day for a period of 12 weeks. The basis for the use of alitretinoin in LSC was its immunomodulatory and anti-inflammatory role on the cytokine profile encountered in LSC. The authors found a marked reduction in pruritus and regression of lesions with no recurrence. Thus, alitretinoin may be considered an alternate line of treatment for refractory LSC. Yet, more randomized controlled trials need to be conducted to verify the therapeutic improvement in cases of LSC with alitretinoin.

Cutaneous T-cell lymphoma

Among the retinoids, Bexarotene has been approved by the FDA for treating cutaneous t-cell lymphoma (CTCL) both systemically and topically. Bexarotene being a rexinoid acts by bringing about apoptosis of malignant cells.[35,36] Alitretinoin also has affinity for RXRs and so, may have therapeutic efficacy while treating these patients. Molin and Ruzicka[37] have demonstrated the beneficial effect of alitretinoin in two patients with CTCL who were administered 30 mg of alitretinoin daily. After a period of 4-5 months significant improvement was witnessed. Alitretinoin's favorable attributes in CTCL could be due to its ant-proliferative, immune-modulating and pro-apoptotic properties. However, more randomized controlled trials of alitretinoin in CTCL are warranted, in order to establish its use for this indication.

Photoaging

Baumann et al.[38] have demonstrated the efficacy and safety of 0.1% alitretinoin gel in the management of photo-damaged skin. On binding to RARs and RXRs, alitretinoin induces TGF-beta which further stimulates collagen synthesis and helps in the repair of photo-damaged skin.[39,40] Along with improvement of photo damaged skin, benign skin lesions like actinic keratosis and seborrhoeic keratosis also show marked regression.

Pyogenic granuloma

Alitretinoin gel 0.1% has been documented to have been successful in treating pyogenic granuloma (PG) by Maloney et al.[41] As PG and KS have histologic similarities, 0.1% alitretinoin gel was tried in two adult patients of PG. Out of the two cases, one showed complete clinical remission in 1 week and the other patient showed complete disappearance of lesions in 3 weeks. None of the two patients had recurrences after a year of follow up. Hence 0.1% alitretinoin gel could prove to be an effective pain free treatment modality for PG, especially in the pediatric population. However, larger clinical trials are warranted for the same.

Pityriasis rubra pilaris

Pityriasis rubra pilaris (PRP) is a papulosquamous disorder, having a chronic and relapsing course. There has been a case report of refractory PRP responding exceedingly well to a daily 30 mg dose of alitretinoin,[42] along with topical emollients for a period of 4 months. The side effects encountered were also minimal. Based on its anti-inflammatory and immune-modulating profile on keratinocytes and leukocytes, alitretinoin is able to achieve the desired results. Hence, oral alitretinoin may prove to be a worthwhile alternative in managing patients with refractory PRP.

Dariers disease

Dariers disease (DD) is an autosomal dominant disorder characterized by warty, dirty and greasy plaques distributed over the seborrhoeic areas of the body. Treatment of DD is usually unsatisfactory. Zamiri and Munro,[43] Letule et al.,[11] Anuset et al.,[44] and Barnstedt[45] have demonstrated the efficacy of oral alitretinoin in the treatment of DD. Given at a dose of 30 mg daily, improvement has been documented as early as 2 weeks after institution of therapy. Alitretinoin's positive role in DD could be explained owing to its effect on cell proliferation, differentiation, keratinization and immunomodulation. However, further clinical trials would be decisive in deciding a full-fledged role of alitretinoin in DD.

Keratitis-Ichthyosis-Deafness syndrome

The use of alitretinoin in keratitis-ichthyosis-deafness (KID) syndrome has been elaborated by Werchau et al.[46] and Prasad and Bygum.[47] Alitretinoin proves to be effective in this condition, because of its property to induce the expression of connexin.[48,49] Werchau et al. elucidated the positive role played by alitretinoin in hastening resolution of skin lesions in a case of KID syndrome. Treatment was started with 10 mg of alitretinoin for a period of 2 weeks, following which the dose was stepped to 30 mg per day for a period of 5 months. After completion of therapy, the authors witnessed a dramatic improvement in the skin lesions following alitretinoin administration. An added advantage seen here was the favorable toxicity profile. Prasad and Bygum further demonstrated benefit from alitretinoin, in a patient with KID syndrome who had dissecting cellulitis of the scalp. Hence, alitretinoin as seen in these case reports definitely appears to be a profitable treatment alternative, in these patients.

Contraindications

Absolute

• Pregnancy and lactation

• Hypersensitivity to alitretinoin

Relative

• Patients less than 18 years of age

• Patients allergic to peanuts and soya as alitretinoin capsules contain soya oil and sorbitol

• Hepatic insufficiency

• Renal insufficiency

• Uncontrolled hypercholesterolemia

• Uncontrolled hypertriglyceridemia

• Uncontrolled hypothyroidism

• Hyper-vitaminosis A

• Patients concomitantly on tetracyclines.

Special precautions while using alitretinoin

Caution must be exercised while prescribing alitretinoin in the following situations.

Women of child-bearing age

Alitretinoin, being a teratogenic drug, the prescribing dermatologist must be extremely careful while using the drug in this category of patients. The usage of a reliable form of contraception is mandatory, which should be continued for a month even after cessation of therapy.[30]

Sun exposure

Owing to the photo-sensitive properties of alitretinoin gel, it is recommended to minimize ultra violet light exposure to the treated sites, and usage of a sunblock of spf 15 or more.[30]

Dietary vitamin A intake

The dietary intake of vitamin A should not exceed the recommended dietary intake value, because of the risk of hypervitaminosis A.

Drug interactions

N,N-diethyl-m-toluamide (DEET), a component of insect repellent products, should not be used concomitantly with alitretinoin gel. Toxicology studies in animals demonstrated increased DEET toxicity when it was a part of the gel formulation.[29] Systemically, alitretinoin interacts, only with the CYP3A4 enzyme. There have been no reported interactions with other CYP enzymes like CYP1A2, 2C9, 2C19 or 2D6. Owing to alitretinoin's strong ability to bind with plasma proteins, the potential of alitretinoin's interactions with substrates of the enzyme CYP3A4 is considerably low. The interaction of alitretinoin with cyclosporine A and ketoconazole did not demonstrate any alteration in their pharmacokinetic properties. However, the levels of simvastatin were significantly reduced with simultaneous alitretinoin administration, and therefore dose adjustments were required to obtain adequate therapeutic responses from simvastatin. On the other hand, the pharmacokinetic profile of alitretinoin was not affected by cyclosporine A or simvastatin, but ketoconazole brought about a significant increase in the plasma concentrations of alitretinoin when both the drugs were administered together.[50] Similarly, no relevant interactions were associated with ethinylestradiol/norgestimate oral contraceptive pills and alitretinoin, with no effect on the pharmacokinetic profile for either of the two drugs. Therefore, these pills could be safely used for contraception in patients receiving alitretinoin.[51] Though there is no pharmacokinetic interaction of alitretinoin and tetracycline, benign intracranial hypertension is a likely complication when the two drugs are concomitantly administered and therefore should be avoided.[52] Vitamin A and other retinoids should not be taken along with alitretinoin because of the risk of hypervitaminosis A.[53] Systemic alitretinoin may increase the hepatotoxicity of methotrexate when given together and so must be avoided.

Preliminary investigations to be undertaken prior to starting alitretinoin

• Serum pregnancy test (in women of child bearing potential)

• Complete blood count with platelets

• Liver function tests

• Fasting lipid profile

• Renal function tests.

Adverse effects

The major side effects seen with oral alitretinoin include headache, dry skin, alopecia, exfoliative dermatitis and hyperlipidemia. Other side effects include myalgia, facial flushing, dyspnea, hypertriglyceridemia, hypercalcemia and a decrease in the levels of thyroid-stimulating hormone.[53] Topical alitretinoin is associated with erythema and edema at application sites and rarely complications like vesiculation, burning, exfoliation and pareasthesias may develop.[7] Alitretinoin like other retinoids is also a teratogenic drug. However, owing to its very short t_1/2, after stopping the drug for a period of 1 month, pregnancy can be contemplated upon, thus proving to be advantageous over other retinoids in this regard.

Availability

Alitretinoin is available as soft capsules under the brand name Toctino (Basilea Medical Ltd, Guildford, England). Strengths available are 10 and 30 mg. Along with the drug, the capsule contains soya bean oil and sorbitol. The 10 mg capsule is brown in color, whereas the 30 mg capsule has red-brown hue.

Conclusion

To conclude, we can clearly identify so many other dermatologic indications in which alitretinoin can be employed. As it has a very short t_1/2, it may prove advantageous in women who are in the child-bearing age group. Further because of its better safety profile, compared to isotretinoin and acitretin, it could prove to be a much better first-line drug for the above-mentioned indications, in the near future.

What is new?

• Alitretinoin has also demonstrated to have anti-inflammatory and immunomodulatory effects making it a licensed drug for the treatment of recalcitrant chronic hand eczema.

• Topical 0.1% alitretinoin gel has also been found to be useful in the treatment of pyogenic granuloma.

• A number of retinoid responsive dermatosis as mentioned in this review have shown a good therapeutic outcome with systemic administration of alitretinoin.