Retinoid-induced skeletal hyperostosis in disorders of keratinization.

For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.

Grover disease: review of subtypes with a focus on management options.

Grover disease (GD) is a benign eruption that causes a papulovesicular rash on the trunk and proximal extremities. It often resolves spontaneously but can follow a more chronic and fluctuating course that may last several years. Although the etiology remains unknown, several associated triggers have been identified including heat and sweating, cool and dry air, renal failure, malignancy, and the initiation of several drugs. Since the disease tends to resolve on its own, management is aimed at disease prevention and symptomatic relief. First-line therapy includes topical steroids and vitamin D analogues with adjuvant antihistamines. In more severe cases that are refractory to less aggressive therapy, systemic corticosteroids, retinoids, and phototherapy may lead to successful resolution. Novel therapies are few and have little evidence but involve innovative use of light therapy and immune modulators. Herein, we review the literature and new trends of GD with a focus on established and novel treatments.

Vitamin D: A New Promising Therapy for Congenital Ichthyosis.

Severe vitamin D deficiency and rickets are highly prevalent among children with congenital ichthyosis. We report an incidental observation of a dramatic and excellent clinical response with regard to skin scaling and stiffness in children with congenital ichthyosis after short-term high-dose vitamin D supplementation that has not been previously described. Seven children with congenital ichthyosis (5 with autosomal recessive congenital ichthyosis; 2 with epidermolytic ichthyosis) and severe vitamin D deficiency (and/or rickets) were given 60,000 IU of oral cholecalciferol daily for 10 days under supervision. All children were subsequently put on recommended daily allowance of 400 to 600 IU of cholecalciferol. The main outcome measures observed and studied were reduction in skin scaling and stiffness of the extremities. All cases had severe vitamin D deficiency (serum 25-hydroxyvitamin D < 4 ng/mL) and secondary hyperparathyroidism. Six patients had clinical and radiologic evidence of rickets. Significant improvement in scaling was noticeable by day 5, showing further improvement by day 10, in 6 of the 7 cases. At 1 month, the skin had become near normal in all the cases of autosomal recessive congenital ichthyosis. Remarkable reduction in stiffness was also observed in all children. Supplementation with high-dose vitamin D followed by recommended daily allowance appears to be an effective form of therapy in the management of congenital ichthyosis with vitamin D deficiency.

CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy.

BACKGROUND: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. METHODS: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. RESULTS: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. CONCLUSIONS: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

Vitamin D Deficiency After Oral Retinoid Therapy for Ichthyosis.

Oral retinoids are being increasingly used to treat ichthyotic disorders in children. We report on two children with ichthyotic disorders who developed unusual manifestations after they were started on oral retinoids. The first case is a 10-year-old girl with nonbullous ichthyosiform erythroderma and the second is a 2-year-old girl with lamellar ichthyosis. The child with ichthyosiform erythroderma developed features of rickets within months of initiation of systemic retinoids. Her baseline examination before initiation of oral retinoids was normal. The second patient with lamellar ichthyosis was found to have low vitamin D levels after 6 months of retinoid therapy, and prompt supplementation reversed the levels in 2 months. These cases are being reported to bring attention to the probable need for initiation of vitamin D supplementation with systemic retinoid therapy in ichthyotic disorders in children.

Systemic retinoids in the management of ichthyoses and related skin types.

The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ~1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.

Rickets associated with ichthyosis.

Nutritional rickets in disorders of keratinisation is very rare. A 12-year-old girl with autosomal dominant ichthyosis vulgaris is reported who presented with tetany and a waddling gait. She had the classic clinical, biochemical and radiological features of rickets. She was treated with vitamin D and calcium supplements together with keratolytic and emollient agents, which was followed by biochemical and clinical remission. This appears to be the first report of rickets associated with autosomal dominant ichthyosis vulgaris.

Aloe vera in dermatology: a brief review.

Aloe vera Linne or aloe barbadensis Miller is a succulent from the Aloe family (400 different species), a tropical plant which is easily grown in hot and dry climates and widely distributed in Asia, Africa and other tropical areas. The use of aloe vera is being promoted for a large variety of conditions. The aim of this systematic review was to summarize all dermatology-oriented in vitro and in vivo experiments and clinical trials on aloe vera preparations. Extensive literature search were carried out to identify all in vitro and in vivo studies as well as clinical trials on the subject. Data were extracted from these in a predefined standardized manner. Forty studies were located. The results suggest that oral administration of aloe vera in mice is effective on wound healing, can decrease the number and size of papillomas and reduce the incidence of tumors and leishmania parasitemia by >90% in the liver, spleen, and bone marrow. Topical application of aloe vera is not an effective prevention for radiation-induced injuries and has no sunburn or suntan protection. It can be effective for genital herpes, psoriasis, human papilloma virus, seborrheic dermatitis, aphthous stomatitis, xerosis, lichen planus, frostbite, burn, wound healing and inflammation. It can also be used as a biological vehicle and an anti-microbial and antifungal agent and also as a candidate for photodynamic therapy of some kinds of cancer. Even though there are some promising results with the use of aloe vera for diverse dermatologic conditions, clinical effectiveness of oral and topical aloe vera is not sufficiently and meticulously explored as yet.

Ichthyosiform mycosis fungoides.

Malignancy-associated acquired ichthyosis is well known, but the ichthyosiform subset of mycosis fungoides (MF) is rarely reported. We report on two patients with a clinical presentation for whom diagnosis of mycosis fungoides was established on histological grounds. In both cases, long term remission was obtained with non aggressive therapies. This rare condition must be added to newly described forms of MF with epidermal hyperplasia such as keratosis lichenoides chronica like MF and pilotropic MF.

Kava-induced dermopathy: a niacin deficiency?

Heavy chronic consumption of kava (Piper methysticum) is associated with a pellagroid dermopathy that has been attributed to niacin deficiency. Over 200 male kava drinkers in the Tonga Islands were interviewed and examined regarding the characteristic skin changes. A scaly rash suggestive of ichthyosis and eye irritation were present in some heavy kava drinkers. 29 kava drinkers with prominent skin changes were randomised to receive either 100 mg oral nicotinamide or placebo daily for three weeks. Skin examinations and photographs showed clinical improvement in 5/15 of the nicotinamide group and 5/14 of the placebo group. These data, along with history and physical examination findings, suggest that niacin deficiency is not responsible for the rash, which is more characteristic of an acquired ichthyosis.

Long-term radiographic follow-up after isotretinoin therapy.

We evaluated the effects of long- and short-term isotretinoin therapy on the skeletons of patients. Eight patients who were treated with isotretinoin for disorders of keratinization received frequent radiographic evaluations for 4 to 9 years. Seven patients developed multiple hyperostoses at the spine and extremities. Hyperostoses increased in size and number over the course of therapy, although relatively few sites were symptomatic. Hyperostoses typically developed first in the spine and later in the extremities, where both bilaterally symmetric and asymmetric involvement was observed. After 5 years of therapy one patient did not develop hyperostosis. In a group of nine patients who received a relatively high dose of isotretinoin in 1982 for the treatment of acne, two patients developed tiny, asymptomatic hyperostoses. One patient had hyperostoses 1 year after isotretinoin therapy, which remained unchanged 3 years later, whereas the other patient had one hyperostosis 4 years after therapy had been stopped. Although we suspect that these hyperostoses were retinoid induced, they should not be of concern for the patient needing routine isotretinoin therapy for the treatment of cystic acne.

Topical retinoids: in vivo predictive assays.

Vitamin A is important for epithelial cell proliferation and differentiation and therefore has been used as a therapy for a variety of skin diseases. Synthetic vitamin A derivatives, called retinoids, have been used to treat a number of clinical skin conditions, including cystic acne and various forms of ichthyosis, Darier's disease, and psoriasis. Because of the toxicity of existing retinoids, newer vitamin A derivatives have been synthesized and must be evaluated in preclinical assays. Retinoids have profoundly differing biologic properties that can be evaluated selectively by studying their efficacy in different in vivo animal assays. This review will discuss some of the assays that may be useful predictors of retinoid efficacy.

[Retinoids]. / Les rétinoïdes.

Retinoids are natural and synthetic analogues of vitamin A. They have a marked influence on the differentiation of epithelial tissues by modifying membrane glycoconjugates and by acting through cytosolic and nuclear mechanisms like steroid hormones. Their clinical and biological toxic effects are numerous, but they are usually benign and reversible. However the possibility of teratogenic effects requires close monitoring of female patients. Etretinate is particularly effective in disorders of keratinisation (psoriasis, ichthyosis) whereas isotretinoin is the best known therapy of severe acne. Moreover the possible role of retinoids in the prevention and treatment of certain cancers gives hopeful prospects.

[The Netherton syndrome: clinical characteristics, differential diagnosis and new ways of therapy]. / Das Netherton-Syndrom: Klinische Charakteristik, differential-diagnostische Abgrenzung und neue Wege der Therapie.

The Netherton-syndrome is a rare disease which is probably inherited through an autosomal recessive trait. It is defined by a triad of symptoms: congenital ichthyosiform erythrodermia , trichorrhexis invaginata et nodosa ("bamboo hair") and atopy. Additional disorders affect the immune system, the metabolism of amino acids and the physical development. On the basis of a new case, the cellular immune defect and the genetic background of the disease are more clearly defined. A new form of treatment--a combination of photochemotherapy (PUVA) and systematic application of aromatic retinoid--has so far proved to be successful. In order to establish an accurate diagnosis--a prerequisite for this promising therapeutic approach--diseases with similar symptoms are discussed for comparison.

Evaluation of 13-cis retinoic acid in lamellar ichthyosis, pityriasis rubra pilaris and Darier's disease.

A new synthetic oral retinoid, 13-cis retinoic acid, is fairly well tolerated in patients and appears to be effective in those with Darier's disease and lamellar ichthyosis. It is less effective in those with pityriasis rubra pilaris. The mechanism of action of 13-cis retinoic acid in disorders of keratinization is unknown at the present time; however, it does not appear to cause lysosomal proliferation in therapeutic doses.