Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial

BACKGROUND: Patients with severe chronic hand eczema (CHE) refractory to topical corticosteroids currently have limited treatment options suited for chronic use, and few controlled clinical studies have investigated new therapies in this setting. OBJECTIVES: To assess the efficacy and safety of oral alitretinoin (9-cis retinoic acid) taken at 10 mg or 30 mg once daily for up to 24 weeks, compared with placebo control, in the treatment of severe CHE refractory to topical corticosteroids. METHODS: A randomized, double-blind, placebo-controlled, prospective, multicentre trial was conducted in 111 dermatology outpatient clinics in Europe and Canada. A total of 1032 patients with severe refractory CHE were randomized in a 1 : 2 : 2 ratio to placebo, or 10 mg or 30 mg of oral alitretinoin once daily for up to 24 weeks. Safety was assessed for all patients during a follow-up period of 4 weeks, and responders were observed for relapse for 24 weeks after the end of therapy. The primary efficacy parameter was Physician Global Assessment of overall CHE severity, with response defined as clear or almost clear hands. RESULTS: Responses, defined as clear or almost clear hands, were achieved in up to 48% of patients treated with alitretinoin, compared with 17% for placebo (P < 0.001), with up to 75% median reduction in disease signs and symptoms. Treatment was well tolerated, with dose-dependent adverse effects comprising headache, mucocutaneous events, hyperlipidaemia, and decreased free thyroxine and thyroid-stimulating hormone. The median time to relapse, defined as recurrence of 75% of initial signs and symptoms, was 5.5-6.2 months in the absence of anti-eczema medication. CONCLUSIONS: Alitretinoin given at well-tolerated doses induced clearing of CHE in a substantial proportion of patients with severe disease refractory to standard therapy.     

Extended treatment with oral alitretinoin for patients with chronic hand eczema not fully responding to initial treatment

Background. In a previous large trial (Benefit of Alitretinoin in Chronic Hand Eczema; BACH), 47.7% of patients with severe chronic hand eczema (CHE) who received alitretinoin 30 mg achieved ‘clear’ or ‘almost clear’ hands during the initial 24‐week treatment course. Objectives. The current open‐label trial was designed to study extended treatment with a further 12‐ to 24‐week course of oral alitretinoin 30 mg in patients who did not fully respond to initial treatment in the BACH study. Methods. At the end of the BACH study, patients whose eczema was rated ‘mild’, ‘moderate’ or ‘severe’ according to the Physician’s Global Assessment (PGA) were eligible for a 24‐week, open‐label, multicentre study. Patients (n = 243) received 30 mg of alitretinoin once daily, irrespective of previous treatment in BACH; either alitretinoin 30 mg, alitretinoin 10 mg or placebo. Results. By the end of the follow‐on study, the PGA response rate to the subsequent course of alitretinoin 30 mg was 50% and 39% in patients treated previously in BACH with 10 or 30 mg per day, respectively, and 51% in patients who previously received placebo in BACH. Alitretinoin was well tolerated, and no significant late‐arising toxicities were seen. Conclusions. For a considerable number of patients with CHE who did not fully respond after an initial 24‐week treatment period, a switch from either placebo to the active compound at 30 mg or from the lower to the higher dose, or treatment prolongation at the higher dose could be beneficial. Alitretinoin remains well tolerated for overall treatment durations of up to 48 weeks.     

Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema

Summary Background Patients with severe chronic hand eczema (CHE) often respond to therapy with oral alitretinoin (9‐cis retinoic acid). However, the efficacy of alitretinoin after disease relapse has not been demonstrated. Objectives To assess the efficacy and safety of a second course of oral alitretinoin in patients with severe CHE who relapsed after achieving ‘clear’ or ‘almost clear’ hands following a previous course of alitretinoin. Methods The double‐blind study included 117 patients with CHE who had responded to therapy in an earlier clinical trial and subsequently relapsed. Patients were randomized to receive their previous treatment or placebo. Treatment was alitretinoin 30 mg or 10 mg or placebo given once daily for 12–24 weeks. Response was defined as an overall Physician’s Global Assessment rating of ‘clear’ or ‘almost clear’ hands at the end of therapy. Results Response rates were 80% in patients retreated with 30 mg alitretinoin compared with 8% for placebo (P < 0·001). In patients retreated with 10 mg alitretinoin response rates were 48%, compared with 10% in the placebo group. Alitretinoin was well tolerated. Adverse reactions comprised typical retinoid class effects, and no late‐arising side‐effects were observed during this second course of treatment. Conclusions The majority of patients with CHE who previously achieved ‘clear’ or ‘almost clear’ hands following treatment with alitretinoin 30 mg per day also responded to a second course of treatment. Retreatment was well tolerated. Intermittent treatment with alitretinoin is suitable for the long‐term management of CHE.     

Topical treatment of cutaneous lesions of acquired immunodeficiency syndrome-related Kaposi sarcoma using alitretinoin gel: results of phase 1 and 2 trials

OBJECTIVE: To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS). DESIGN: Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated. SETTING: Nine academic clinical centers. PATIENTS: One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS. MAIN OUTCOME MEASURES: AIDS Clinical Trials Group response criteria. RESULTS: Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity. CONCLUSIONS: Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.     

Alitretinoin

About 10% of Germans have chronic hand eczema (CHE). Until recently only off-label use agents existed for the treatment of severe CHE cases refractory to topical steroids. In addition, data from controlled clinical trials confirming the efficacy of known treatment strategies was inadequate. With the availability of alitretinoin, 9-cis retinoic acid, this situation may change. In two large clinical trials alitretinoin showed high response rates and a favorable safety profile in the treatment of severe and refractory CHE. Alitretinoin has an anti-inflammatory and immunomodulatory mechanism of action. Acting as a panagonist it binds to retinoic acid receptors A (RAR) and X (RXR). It directly affects cytokine production in keratinocytes and down-regulates leukocyte activity. When used for CHE with detailed patient counseling and appropriate laboratory monitoring, alitretinoin is a promising new option for systemic treatment.     

Alitretinoin and acitretin in severe chronic hand eczema; results from a retrospective daily practice study

Acitretin has been used off‐label for years to treat chronic hand eczema, but acitretin is less often prescribed as alitretinoïne was approved. This study evaluates both retinoids in a daily practice cohort of patients with severe chronic hand eczema in terms of drug survival and reasons for discontinuation. Patients using alitretinoin or acitretin between 01‐01‐1994 and 01‐08‐2015 were included in this retrospective daily practice study and analyzed by Kaplan‐Meier drug survival curves. Potential determinants were analyzed by Cox regression analyses. Ninety‐five patients were treated with alitretinoin and 109 patients with acitretin. The main reasons for discontinuation were adverse events and cleared hand eczema, 29.5 and 27.4% in alitretinoin versus 43.1 and 23.9% in acitretin. Patients with hyperkeratotic hand eczema had most often a good effect of treatment: 68.3% in alitretinoin and 50.7% in acitretin treatment. The drug survival rates of alitretinoin and acitretin after 12, 24, 36, and 52 weeks were 69.3, 45.1, 19.6, 7.0% and 74.3, 45.5, 33.8, 23.2%, respectively. Alitretinoin and acitretin are effective treatment options for patients with hand eczema. However, both treatments were more effective in patients with hyperkeratotic hand eczema. Fewer patients discontinued alitretinoin compared with acitretin due to adverse events.     

Efficacy and Safety of Alitretinoin Therapy in Korean Elderly Patients with Chronic Hand Eczema: A Retrospective Single Center Study

BackgroundChronic hand eczema (CHE) tends to be refractory to conventional therapy. Previous clinical trials have found that alitretinoin is an effective and well-tolerated treatment for CHE. However, there is a relative lack of data on the effectiveness of alitretinoin in elderly patients.ObjectiveThe aim of this study was to investigate the efficacy and safety of oral alitretinoin in elderly patients with moderate to severe CHE in Korea.MethodsWe retrospectively investigated 46 CHE patients who were treated with either 10 mg or 30 mg of alitretinoin between June of 2016 and July of 2018. The physician''s global assessment (PGA) was used to evaluate treatment efficacy. All adverse events were retrospectively evaluated with respect to laboratory testing, including complete blood cell count, fasting blood chemistry, lipid profile, and liver and thyroid function tests.ResultsThe mean patient age in this study was 71.0±5.1 years. The treatment period was over eight weeks. A total of 38 of 46 patients (82.6%) exhibited clinical improvement with PGA ratings of ‘clear’ or ‘almost clear.’ There were 13 patients (28.3%) who experienced an adverse effect, with the most common being headache (13.0%) and gastrointestinal symptoms (8.7%) followed by xerosis (6.5%). A total of 13 patients developed or exhibited worsening hypertriglyceridemia (28.3%).ConclusionAlitretinoin can be considered a safe and effective treatment option in elderly patients with moderate to severe CHE.     

An open-label study assessing the safety and efficacy of alitretinoin in patients with severe chronic hand eczema unresponsive to topical corticosteroids

Background. Blinded, controlled studies have found that oral alitretinoin is well tolerated and effective in the treatment of severe chronic hand eczema (CHE). Aim. To assess the safety and efficacy of oral alitretinoin in patients with severe CHE in an open‐label study using flexible dosing and a new measurement of patient‐relevant benefits. Methods. In total, 249 patients aged 18–75 years with severe CHE unresponsive to treatment with topical corticosteroids received alitretinoin 30 mg once daily for up to 24 weeks. Safety assessments included adverse events (AEs) and laboratory tests. Efficacy assessments included Physician’s Global Assessment (PGA), the Modified Total Lesion Symptom Score, Patient’s Global Assessment and extent of disease, as well as intensity of pain and pruritus as determined by visual analogue scale (VAS) and a categorical scale for pruritus. Results. Alitretinoin was well tolerated when given for up to 24 weeks. Dose reduction occurred in 16.5% of patients. Dose interruption was required for 15.7% of patients, most commonly for headache. AEs and laboratory changes comprised effects typical of the retinoid class. A PGA response of ‘clear’ or ‘almost clear’ hands was reported for 46.6% of patients, similar to the response rate seen in blinded trials. Results of VAS and categorical assessments of pruritus provided supporting evidence of efficacy, and treatment was assessed as providing meaningful benefits to patients. Conclusions. Oral alitretinoin 30 mg was well tolerated and effective, and provided distinct therapeutic benefits in severe CHE, as assessed by patients.     

Treatment of Darier disease with oral alitretinoin

Darier disease (DD) is an autosomal dominant skin disease. Treatment is often difficult and unsatisfactory because of the chronic nature of the condition and the irritant potential of various therapeutic agents. Systemic vitamin A derivatives such as acitretin and isotretinoin are the treatment of choice, but their use is often limited by class‐specific side‐effects. Alitretinoin (9‐cis‐retinoic acid), has antiproliferative and anti‐inflammatory potential, and is licensed for the systemic treatment of chronic hand eczema in a number of countries. Unlike acitretin, alitrenoin requires contraception in women of childbearing age to be extended for only 1 month after the end of treatment. There is evidence that alitretinoin might be a well‐tolerated alternative for the systemic treatment of various retinoid‐responsive skin diseases. We present two cases of women with refractory DD successfully treated with alitretinoin without marked side‐effects, who both obtained near‐complete remission of their skin lesions.     

Changes in skin barrier during treatment with systemic alitretinoin: focus on skin susceptibility and stratum corneum ceramides

Alitretinoin is a new drug for systemic treatment of chronic hand eczema. Previous functional tests of skin topically treated with retinoids have indicated impaired skin barrier function, but no data are available on barrier parameters after systemic alitretinoin treatment. To investigate the effect of systemic alitretinoin on skin barrier function and response to irritants, a secondary objective was to determine if changes occur in the lipid profile of stratum corneum after treatment with systemic alitretinoin. We conducted an open clinical intervention study on eight people ascribed to systemic alitretinoin treatment. The criteria for being ascribed to alitretinoin were chronic hand eczema and insufficient therapeutic response to potent topical corticosteroids. Before initiation and after 2 months of systemic treatment with 30 mg alitretinoin, a challenge with sodium lauryl sulphate (SLS) was performed on the volar forearm and evaluated by trans-epidermal water loss (TEWL), erythema, and a cyanoacrylate skin sample was obtained for lipid analysis. We found no significant changes in response to SLS irritation as evaluated by TEWL and erythema, after treatment with alitretinoin for 2 months. No significant changes in stratum corneum lipids were found after 2 months of treatment. In conclusion, systemic alitretinoin does not influence skin susceptibility to irritants or the ceramide profile of stratum corneum.     

Nail improvement during alitretinoin treatment: three case reports and review of the literature

Alitretinoin is an endogenous vitamin A derivative, 9‐cis‐retinoic acid. Its anti‐inflammatory and immunomodulatory efficacy results from controlling leukocyte activity and cytokine production in keratinocytes. We describe three patients with severe chronic hand eczema accompanied by nail dystrophy, which was treated with alitretinoin 30 mg. Clinical evaluation at 6 months showed complete or almost complete clearing of the nail lesions. We also briefly review the literature reporting on nail dystrophy and alitretinoin treatment. There is some evidence of the clinical effect of retinoids on nail formation, owing to the presence of retinoid receptors on the nail matrix. Further studies are required to better understand the impact of alitretinoin in nail diseases. Our observation supports alitretinoin as a treatment option in retinoid‐responsive dermatoses associated with nail involvement.     

Efficacy of alitretinoin depending on the concomitant use of topical corticosteroids in chronic hand eczema patients

Alitretinoin is the only systemic agent approved for the treatment of severe chronic hand eczema (CHE) unresponsive to potent topical corticosteroids. Clinical trials have shown the efficacy of oral alitretinoin with topical emollients for CHE treatment, but most studies have failed to reach a therapeutic success rate of 50%. Reasonably, we thought it would be more effective to combine topical corticosteroids with oral alitretinoin, but the concomitant use of topical corticosteroids has not been studied yet. One‐hundred and seven Korean patients diagnosed with CHE were recruited. The participants were divided into two groups depending on the concomitant use of topical corticosteroids. Comparative analysis was performed between the combined therapy (alitretinoin and topical corticosteroids) and monotherapy groups (alitretinoin only) by using physician global assessment (PGA), patient's global assessment (PaGA), modified total lesion symptom score (mTLSS), and recurrence rates. The combined therapy group showed a significantly higher treatment success rate than the alitretinoin monotherapy group for all efficacy parameters (PGA: P < 0.001, PaGA: P < 0.001, mTLSS changes: P < 0.001), but there was no significant difference in recurrence rates between the groups (P = 0.266). Combined use of topical corticosteroids is recommended for CHE patients being treated with oral alitretinoin due to clinically rapid and superior effectiveness.     

Alitretinoin in chronic hand eczema: summary of clinical trials

After an open preliminary study, two double-blind placebo-controlled randomized studies have confirmed the value of per os alitretinoin in the management of severe chronic hand eczema (CHE). The first showed dose-dependent efficacy and a response defined as "clear" or "almost clear" by 53% of the patients receiving 10-40 mg of alitretinoin per day for 12 weeks. In the second multicenter study (the Bach study), comparing the efficacy of a 12-week alitretinoin treatment (10 mg, 30 mg) to placebo for CHE, a "clear or almost clear" result was observed in 17% (placebo group), 28% (group alitretinoin 10 mg), and 48% (group alitretinoin 30 mg). The onset of action was also significantly shorter in the group treated with 30 mg of alitretinoin compared to the group treated with 10 mg. In a study of randomized retreatment versus placebo, 80% of the patients who were initially responders to alitretinoin and whose CHE had relapsed found "clear" or "almost clear" with alitretinoin 30 mg administered for 12-24 weeks compared to 48% with alitretinoin 10 mg. In all the studies, clinical tolerance was comparable and satisfactory, with the most frequent negative side effects being headache, flushing, and mucocutaneous signs identical to those compared with other retinoids. An increase in cholesterol and/or triglycerides was the most frequent biological side effect. Central hypothyroidism, with no clinical expression, was observed more rarely. These studies confirm that alitretinoin treatment can be envisaged as second-line therapy in adults with CHE that does not respond to well-observed treatment with class potent or very potent dermocorticoids.     

Alitretinoin

? Alitretinoin is a retinoid receptor pan-agonist, which has been investigated in the treatment of Kaposi’s sarcoma (KS). Binding with high affinity to all known retinoid receptors, alitretinoin is thought to regulate proliferation, differentiation, and apoptosis of KS cells. ? Significantly more patients experienced complete or partial responses [according to the AIDS Clinical Trials Group (ACTG) criteria for topical treatment of cutaneous KS] with alitretinoin 0.1% gel 2 to 4 times daily than with vehicle gel in 2 phase III, multicenter, 12-week, randomized, double-blind clinical trials of patients with AIDS-related KS (35 vs 18%, p = 0.002 and 37 vs 7%, p = 0.00003, respectively). Responses were also observed in patients refractory to prior systemic or topical anti-KS therapies. ? In an intent-to-treat analysis in a phase II trial, 37% of patients with AIDS-related KS receiving alitretinoin capsules 60 to 100 mg/m²/day demonstrated either complete or partial responses (determined by ACTG criteria). ? The majority of adverse events associated with alitretinoin 0.1% gel were classified as either mild or moderate, occurred at the site of application and were reversible. In both phase III trials, rash was the most common adverse event. ? The most common adverse events in patients taking alitretinoin capsules included headache, dry skin, rash, alopecia, exfoliative dermatitis, and hyperlipidemia.     

Open-label pilot study of alitretinoin gel 0.1% in the treatment of photoaging

Alitretinoin (9-cis-retinoic acid) is an FDA-approved topical therapy for the treatment of Kaposi sarcoma. Alitretinoin is a naturally occurring endogenous retinoid that binds to and activates all known intracellular retinoic acid receptor (RAR) subtypes alpha, beta, and gamma and retinoic X receptor (RXR) subtypes alpha, beta, and gamma. Photoaging of the skin is the result of accumulated exposure to solar UV radiation. Several topically applied retinoids have been proven clinically effective for treating the appearance of photoaging. Tretinoin and tazarotene, which have been shown to improve photodamaged skin, bind RAR subtypes only. The theoretic benefit of alitretinoin gel 0.1% (Panretin) in the treatment of photoaged skin stems from the binding and activation of both RARs and RXRs, which promote the repair mechanisms in damaged skin. The objective of this study was to evaluate the safety and efficacy of topical alitretinoin gel 0.1% in the treatment of photodamaged skin. The treatment was well tolerated by participants (N=20) and subjectively showed improvement of benign skin lesions (eg, seborrheic keratoses) and precancerous lesions (eg, actinic keratoses). Larger, blinded, controlled trials are needed to investigate the role of this novel retinoid in the treatment of photoaging.     

Alitretinoin abrogates innate inflammation in palmoplantar pustular psoriasis

Background Palmoplantar pustular psoriasis is often recalcitrant to therapy. Here we evaluated the therapeutic effect of alitretinoin in patients with recalcitrant palmoplantar pustular psoriasis and investigated subsequent immunopathological alterations. Methods Seven patients with palmoplantar pustular psoriasis were treated with oral alitretinoin 30 mg once daily for 12 weeks. Efficacy was assessed by palmoplantar pustular psoriasis area and severity index (PPPASI), visual analogue scales (VAS) on intensity of pain and pruritus and an overall patient assessment. Immunohistochemical staining for neutrophil elastase, CD3, CD4, CD8, CD1a CD11c, CD303,CD68, CD69, CD208 and HLA‐DR was on lesional skin biopsies obtained before and after 12 weeks of treatment. Results PPPASI and VAS for pruritus and pain decreased significantly after 12 weeks of treatment with alitretinoin. The overall patient assessment ranged from 60% to 90% clinical improvement. In correlation with clinical improvement a significant reduction, particularly of neutrophils, macrophages and dendritic cells, was also observed in the skin sections. Alitretinoin was well tolerated except for headache during the first month of treatment in two patients. Limitations of the study are a missing control group and the concomitant usage of topical therapy. Discussion Our findings suggest that alitretinoin may represent a new and promising therapy for recalcitrant palmo‐plantar psoriasis and warrants further controlled studies to confirm efficacy and safety of alitretinoin in this disease.     

Alitretinoin treatment of lichen amyloidosis

Lichen amyloidosis (LA) is characterized by the deposition of amyloid that may respond to chronic scratching that may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Despite the development of several therapeutic strategies, including topical steroids, oral antihistamines, cyclosporine, and retinoids, an effective treatment for LA has not been established. A 49‐year‐old woman who has been treated irregularly for atopic dermatitis for 7 years presented with localized brownish papules on the left forearm and right elbow. They developed 3 months prior and were becoming more prominent despite of treatment with cyclosporine, oral antihistamines, and topical steroids for 5 months prior to presentation. A skin biopsy revealed amyloid deposition in the dermal papillae and the patient was diagnosed with LA associated with atopic dermatitis. A 6‐month course of daily oral alitretinoin 30 mg produced marked improvement in the thickness and color of the hyperkeratotic papules without aggravation of the patient's atopic dermatitis. Histologic evaluation showed clearance of amyloid deposition and almost normalization of the epidermal changes. Herein, we report a case of LA treated with alitretinoin and suggest that it could be a potential treatment option for LA, especially in patients with inflammatory skin diseases including atopic dermatitis.     

Novel treatment of chronic severe hand dermatitis with bexarotene gel

BACKGROUND: Hand dermatitis is an eczematous inflammation of the hands that is related to occupation or to routine activities. It often becomes chronic, and in some patients may become severe and disabling. Topical corticosteroids are effective treatment, particularly for milder forms, but they often lose effectiveness with time and can produce skin atrophy. OBJECTIVES: To evaluate bexarotene gel topical therapy for safety, tolerability and efficacy in patients with chronic hand dermatitis. METHODS: A phase I-II open-label randomized clinical study of bexarotene gel, alone and in combination with a low- and a mid-potency steroid, was conducted in 55 patients with chronic severe hand dermatitis at two academic clinics. RESULTS: Patients using bexarotene gel monotherapy reached a 79% response rate for > or = 50% clinical improvement and a 39% response rate for > or = 90% clearance of hands. Adverse events possibly related to treatment in all patients were stinging or burning (15%), flare of dermatitis (16%) and irritation (29%). Thirteen patients (24%) withdrew early, including two for related adverse events and five for inadequate response. CONCLUSIONS: Bexarotene gel appears to be safe, tolerated by most patients, with useful therapeutic activity in chronic severe hand dermatitis.     

Alitretinoin und Off-label-Use

Oral alitretinoin (9-cis retinoic acid) is an endogenous retinoid related to vitamin A. Studies have shown that oral alitretinoin is effective and well-tolerated in the treatment of severe chronic hand eczema, so that it is approved for this indication. This review summarizes new studies and clinical experience on the off-label use of alitretinoin.