Management of Darier disease: A review of the literature and update.

Darier disease (DD) is a rare type of inherited keratinizing disorder with no definitive therapeutic approach. The objective of this study is to provide a detailed literature review of all the available treatment modalities of Darier disease, including those that are both surgical and non surgical, to compare their efficacies and to propose a novel therapeutic approach. A complete search of the literature for all articles describing the different treatments of Darier disease, with no restrictions on patients' ages, gender or nationalities, was performed with the use of PubMed. A total of 68 articles were included in the study: 3 prospective studies, 44 case reports/case series and 21 letters/correspondences/clinical images. The treatments described were topical, oral or physical. Retinoids (isotretinoin, tazarotene and adapalene) and fluorouracil were the two most effective topical treatments. Oral retinoids were the most effective oral therapy and were prescribed in the cases of generalized Darier disease. For localized and resistant skin lesions, physical therapies including surgical excision, dermabrasion and CO2 laser ablation were the first line choices. Limitations of this article include the inability to verify the accuracy of the published data, the relatively small sample size, the absence of randomized controlled clinical trials and possible unidentified confounding factors in various studies. In every therapeutic approach to Darier disease, consideration of patient comorbidities, disease distribution, severity and treatment accessibility is essential. Large and randomized clinical trials are necessary for the comparison of the efficacy and the safety of all the treatments of Darier disease and settling a consensus for management.

Combination of tacalcitol ointment and photodynamic therapy for the treatment of follicular mucinosis of the scalp.

Follicular mucinosis (FM) is a rare inflammatory disorder histologically characterized by mucin deposition in the follicular epithelium. There is no standard therapy for FM and several treatments have been described in the literature. We present the case of a 59 year-old female affected by a recalcitrant FM with diffuse scalp alopecia, in which complete clinical remission was achieved after a combination of topical tacalcitol and photodynamic therapy.

1,25­Dihydroxyvitamin D regulates macrophage polarization and ameliorates experimental inflammatory bowel disease by suppressing miR-125b.

Macrophages are highly plastic cells. Depending on stimulation, macrophages rapidly polarize to functionally distinct phenotypes that are involved in the pathogenesis of inflammatory bowel disease (IBD). 1,25­Dihydroxyvitamin D (1,25(OH)2D3) has immunomodulatory activity, and 1,25(OH)2D3 deficiency is correlated with autoimmune diseases, especially IBD. This study aimed to explore whether 1,25(OH)2D3 modulates macrophage polarization in inflammation. Peripheral blood mononuclear cells and colitis mice were treated with 1,25(OH)2D3. Macrophages were transfected with siRNA-vitamin D receptor (VDR) or miR-125b mimic or inhibitor, and 1,25(OH)2D3-pretreated colitis mice were injected with a miR-125b agomir. The distribution of macrophage subsets and macrophage subtype characteristics was analyzed. As expected, 1,25(OH)2D3 transformed lipopolysaccharide-induced M1 macrophages to the M2 subset, downregulated tumor necrosis factor-α and interleukin (IL)-6 expression and interferon regulatory factor 5 (IRF5) phosphorylation, and upregulated IL-10, arginase-1, VDR, and IRF4 expression. SiRNA-VDR and miR-125b mimic significantly impaired 1,25(OH)2D3 activity. In colitis mice, 1,25(OH)2D3 pretreatment ameliorated disease activity, converted M1 macrophages to the M2 subtype, suppressed IRF5 phosphorylation, and increased IRF4 expression in lamina propria mononuclear cells (LPMC). miR-125b agomir injections reversed 1,25(OH)2D3 action. Collectively, the results demonstrate that 1,25(OH)2D3 downregulates miR-125b expression and promotes M1 macrophage polarization to the M2 subtype. 1,25(OH)2D3 pretreatment ameliorated colitis by restoring the LPMC macrophage subtype balance.

Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells.

The active form of vitamin D (1α,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1α,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose-dependently, in concentrations between 1 nM and 10 µM. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound-healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle-treated cells. However, they had no effect on caspase-3 and -7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.

Comparative evaluation of efficacy and safety of calcipotriol versus tacalcitol ointment, both in combination with NBUVB phototherapy in the treatment of stable plaque psoriasis.

BACKGROUND: Vitamin D analogues and NBUVB phototherapy are both well-established modalities of treatment in psoriasis. The objective of this open label, intraindividual, left right study was to compare two different vitamin D analogues, calcipotriol and tacalcitol, in combination with NBUVB phototherapy in chronic stable plaque psoriasis. METHODS: Thirty patients with stable plaque psoriasis were enrolled for a 12-week clinical trial. The target lesion on left side was treated topically with tacalcitol ointment once daily, while that on the right side was treated with calcipotriol ointment twice daily. NBUVB phototherapy was given thrice weekly. Efficacy was assessed by target plaque scoring. RESULTS: Both therapies resulted in statistically significant reduction in erythema, scaling, thickness and target plaque score, seen as early as 2 weeks into therapy. However, calcipotriol combination led to an earlier clearance of plaques and a lesser relapse rate than tacalcitol combination. The number of treatment sessions and cumulative NBUVB doses were significantly lower in the calcipotriol-treated group. CONCLUSION: Both vitamin D analogues appear to be safe, effective and cosmetically acceptable, calcipotriol being more efficacious, well tolerated with a rapid onset of action and a better maintenance of response.

Tacalcitol: A useful adjunct to narrow band ultraviolet B phototherapy in psoriasis.

BACKGROUND: A combination of calcipotriol and narrow-band ultraviolet B (NBUVB) has been shown to have a superior efficacy as compared to NBUVB alone in psoriasis. Very few studies have been performed using the combination of NBUVB with tacalcitol, a comparatively newer Vitamin D analogue. OBJECTIVE: Comparison of the efficacy and safety of topical tacalcitol in combination with NBUVB versus NBUVB alone in psoriasis. METHODS: Thirty patients with plaque psoriasis were taken up for a 12 week, open-label, right-left intra-individual clinical trial. NBUVB phototherapy was given thrice weekly. The target lesions on one side were treated topically with tacalcitol ointment once daily, while no topical treatment was given on the other side. Efficacy was assessed by target plaque scoring. RESULTS: Better improvement in plaques was seen with combination therapy as compared to NBUVB monotherapy, with a statistically significant difference from 2 to 8 weeks. The combination led to an earlier clearance of plaques and a better maintenance of the response than NBUVB alone. The number of treatment sessions and cumulative NBUVB doses were significantly lower in the tacalcitol-treated group. CONCLUSION: Topical tacalcitol enhances the therapeutic effects of NBUVB therapy and exerts a UVB-sparing effect, without increasing the incidence of adverse effects.

In vitro responses of neurofibroma fibroblasts, mast cells and Schwann cells obtained from patients with neurofibromatosis 1 to 308-nm excimer light and/or vitamin D3.

Fibroblasts, mast cells and Schwann cells were isolated from neurofibromas of patients with neurofibromatosis 1, and their responses to 308-nm excimer light irradiation and/or vitamin D3 or an analog (tacalcitol; 1,24-dihydroxyvitamin D3 ) were examined in vitro. Excimer light irradiation (300 mJ/cm(2) ) suppressed the growth of all three cell types. Exposure to 10(-7)  mol/L of 1α,25(OH)2 D3 (VD3 ) or tacalcitol suppressed the growth of fibroblasts and mast cells, but not Schwann cells. These results suggest that the different neurofibroma cell types show different responses to VD3 . A combination of excimer light irradiation and VD3 is necessary to suppress the growth of neurofibroma cells in vivo.

The separate daily application of tacalcitol 4 µg/g ointment and budesonide 0.25 mg/g cream is more effective than the single daily application of a two compound ointment containing calcipotriol 50 µg/g and betamethasone dipropionate 0.5 mg/g.

AIM: This pilot randomized intra-patient side to side trial was designed to assess the antipsoriatic efficacy, safety and tolerability of once daily versus the separate application of a vitamin D3 analogue and a powerful corticosteroid. METHODS: Twenty patients with plaque type psoriasis were enrolled. Two similar symmetrical lesions were randomized to be treated with an application of an ointment containing calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g once daily or the application of budesonide 0.25 mg/g cream in the morning and tacalcitol 4 µg/g ointment in the evening. RESULTS: Eighteen patients completed the study. Both treatments proved to be effective but budesonide cream and tacalcitol ointment gave a faster improvement of lesions and itching relief at t1 and were better tolerated. CONCLUSION: The separate daily regimen may represent a suitable treatment option for patients who need a faster improvement and a better moisturizing activity. Further studies which compare the efficacy and safety of these regimens need to be developed.

Calcipotriol plus betamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial.

OBJECTIVE: To establish the efficacy and safety of once daily treatment of Daivobet®/Dovobet® gel in patients with psoriasis vulgaris, relative to tacalcitol ointment and the gel vehicle alone. METHODS: 458 patients with at least moderately severe disease were randomized in 3 treatment arms for an 8-week period. Treatment was investigator blinded, and treatment success was defined as patients with an Investigator's Global Assessment of 'clear' or 'almost clear' at week 8. RESULTS: The proportion of patients who were 'clear or almost clear' was significantly higher in the 2-compound gel group (39.9%) compared with 17.9% in the tacalcitol group and 5.5% in the gel vehicle group: p < 0.001 in both comparisons. The proportion of patients with at least 1 adverse drug reaction was significantly lower in the 2-compound gel group compared to the other 2 treatment groups. CONCLUSIONS: Once-a-day treatment with the 2-compound Daivobet/Dovobet gel is a safe and efficacious therapeutic regimen for individuals with psoriasis on the body.

Serum prolactin levels in psoriasis and correlation with cutaneous disease activity.

BACKGROUND: Prolactin (PRL), a neuropeptide secreted by the anterior pituitary gland, possesses a variety of physiological actions. It has been implicated as an important immunomodulator and exerts a proliferative effect in cultured human keratinocytes via specific receptors. Some studies have indicated an increase in serum PRL levels in psoriasis and exacerbation of psoriasis when a prolactinoma is present. AIM: To evaluate the correlation between serum PRL levels and Psoriasis Area and Severity Index (PASI). METHODS: Serum PRL levels were measured in 20 patients (10 mean, 10 women, age range 18-88 years) with plaque-type psoriasis before and after a 6-week period of topical treatment with tacalcitol ointment. Results were compared with a group of 20 healthy volunteers. RESULTS: Serum PRL levels were significantly increased in the psoriatic group compared with the control group (P < 0.001) and were significantly reduced after treatment (P = 0.001). There was a correlation between pretreatment serum PRL levels and PASI (r = 0.33; P = 0.02). CONCLUSIONS: These results indicate that serum PRL levels may serve as a biological marker of psoriatic disease activity.

Successful treatment of combination therapy with tacalcitol lotion associated with sunscreen for localized Darier's disease.

We herein report a sporadic case of Darier's disease localized to the bilateral side of the neck in a 39-year-old Japanese woman. Several clinical variants of Darier's disease have so far been recognized including unilateral Darier's disease, localized Darier's disease, segmental Darier's disease and acral Darier's disease. Few cases of Darier's disease, restricted to sun-exposed areas such as the bilateral side of the neck, have been described in the published work. It remains controversial, however, whether ultraviolet exposure can induce the onset of Darier's disease. Our patient's skin lesions, which were resistant to previous treatment with corticosteroid, improved substantially with high-concentration tacalcitol lotion and sunscreen. This is the first report on the efficacy of topical tacalcitol lotion associated with sunscreen for the treatment of localized Darier's disease.

Secondary hyperparathyroidism after kidney transplantation: a cross-sectional study.

INTRODUCTION: The purpose of the present study was to investigate the prevalence of hyperparathyroidism among a population of kidney graft recipients. PATIENTS AND METHODS: We investigated biochemical bone parameters of 509 renal transplant recipients with a mean follow-up of 113 +/- 76 months. Among these patients, 257 patients were treated with either vitamin D or calcium supplements or both. RESULTS: The mean estimated glomerular filtration rate (eGFR) was 47.2 +/- 18.4 mL/min/1.73 m(2) and the mean intact parathyroid hormone (iPTH) level was 144 +/- 149 pg/mL. A total of 70 patients (13.7%) had hypercalcemia defined by a corrected serum calcium >10.2 mg/dL. When the patients were classified according to iPTH concentrations following the Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines: 22.4% had iPTH <70 pg/mL; 30.8% between 70 and 110 pg/mL; 16.5% between 110 and 150 pg/mL; 24.3% between 150 and 300 pg/mL; and 6.9% >300 pg/mL. There were no differences in biochemical bone parameters between those that were or were not on calcium and vitamin D supplements, but there was a higher percentage of patients with normal iPTH among the treated group (28.0% vs 16.7%; P = 0.003). In patients not receiving calcium and/or vitamin D supplements, multiple linear regression demonstrated that only time on dialysis, eGFR, and serum 25-hydroxyvitamin D (25OHD) levels were significantly predictive of iPTH concentrations (R(2) = 0.21; P = .000). CONCLUSIONS: About 80% of patients displayed high iPTH concentrations. The persistence of hyperparathyroidism was associated with graft dysfunction, longer time on dialysis, and low concentrations of 25OHD. Treatment with vitamin D produced a slight improvement in the prevalence of hyperparathyroidism.