The Role of VD/VDR Signaling Pathway in Autoimmune Skin Diseases.

BACKGROUND: Immune-related cutaneous diseases are a series of disorders, such as alopecia areata, psoriasis, atopic dermatitis, systemic lupus erythematosus and autoimmune bullous dermatoses. Vitamin D is a fat-soluble vitamin, which is known for its classical pleiotropic effect. Recent studies have found that vitamin D, after catalyzed into its biologically active form [1,25(OH) 2D], correlated with its receptor, vitamin D receptor, plays a vital role in multiple pathophysiological processes, including immune-related dermatoses. This review mainly summarizes evidence on the role of vitamin D/vitamin D receptor in immune-related cutaneous diseases and the potential therapeutic targets for skin disorders. METHODS: We have carried out a comprehensive literature search in PubMed and Google Scholar databases using keywords like "vitamin D", "vitamin D receptor", "immune", "psoriasis", "atopic dermatitis", "skin", "systemic lupus erythematosus", "alopecia areata" and "autoimmune bullous dermatoses". Only articles related to the topic were included in this review. Conference, patent, graduation thesis and articles without available full text were excluded. RESULTS: Vitamin D/vitamin D receptor is critical for skin in regulating the proliferation and differentiation of keratinocytes, keeping the integrity of the skin barrier as well as maintaining the homeostasis of the "skin's immune system". Vitamin D deficiency/vitamin D receptor mutations are potential risk factors for some immune-related cutaneous diseases. CONCLUSION: Vitamin D is a pleiotropic hormone, which is important in the homeostasis of human body. Many studies have revealed vitamin D deficiency in several skin diseases. Thus, vitamin D supplementation may be a useful therapeutic option for immune-related skin diseases.

Successful treatment of a case of idiopathic linear IgA bullous dermatosis with oral sulfasalazine.

Linear IgA bullous dermatosis (LABD) is a rare acquired autoimmune chronic vesiculobullous dermatosis affecting primarily young children and older adults. We report a 17-year-old Chinese boy with a 2-month history of intense itching erythema or tense vesicles on healthy skin or on an erythematous base, with parts of lesions arising a characteristic "cluster of jewels" pattern. With the characteristics of vesicles or blisters on the skin, subepidermal blisters with neutrophilic infiltrate on histology, and linear IgA deposits on the basement membrane zone and absence of other immunoglobulins on direct immunofluorescence, LABD was dignosized. Sulfapyridine has also been reported as one of the best options of systemic therapy for LABD. Our patient successfully treated with only oral sulfasalazine (alternative medicine of sulfasalazine), which is safe and effective.

Pentoxyfilline as a treatment for subcorneal pustular dermatosis.

Subcorneal pustular dermatosis (SPD) is a rare pustular neutrophilic dermatosis in which groups of sterile pustules appear in the superficial (subcorneal) skin. This chronic condition can be associated with significant morbidity and decreased quality of life. Dapsone is the first-line therapy for SPD, but some patients fail to respond or cannot tolerate it. In these instances, patients may be treated with second-line therapies such as phototherapy, topical corticosteroids, or systemic agents including glucocorticoids, acitretin, immunosuppressive, or biologic medications. These therapies may not always be efficacious and can be associated with intolerable adverse effects. Here, we report a case of a patient who sustained long-term remission and no side effects with the novel use of pentoxifylline, a tumor necrosis factor-alpha inhibitor, as monotherapy. Pentoxifylline should be considered as a possible therapy in patients with SPD intolerant to dapsone.

Subcorneal Pustular Dermatosis: A Review of 30 Years of Progress.

Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a rare, benign yet relapsing pustular dermatosis. Its incidence and prevalence have not been well studied. It characteristically presents as hypopyon pustules on the trunk and intertriginous areas of the body. SPD is similar to two other disease entities. Both SPD-type immunoglobulin (Ig)-A pemphigus and annular pustular psoriasis clinically and histologically present similarly to SPD. Immunologic studies separate SPD-type IgA pemphigus from SPD and pustular psoriasis. However, there is still an unclear designation as to whether SPD is its own entity distinct from pustular psoriasis, as the once thought characteristic histologic picture of psoriasis does not hold true for pustular psoriasis. SPD has been reported to occur in association with several neoplastic, immunologic, and inflammatory conditions. Dapsone remains the first-line treatment for SPD, although dapsone-resistant cases have been increasingly reported. Other therapies have been used singly or as adjunctive therapy with success, such as corticosteroids, immunosuppressive agents, tumor necrosis factor inhibitors, and ultraviolet light therapy. This article provides a review of the last 30 years of available literature, with a focus on successful treatment options and a suggestion for reappraisal of the classification of SPD.

Eosinophilic pustular folliculitis: A published work-based comprehensive analysis of therapeutic responsiveness.

Eosinophilic pustular folliculitis (EPF) is a non-infectious inflammatory dermatosis of unknown etiology that principally affects the hair follicles. There are three variants of EPF: (i) classic EPF; (ii) immunosuppression-associated EPF, which is subdivided into HIV-associated (IS/HIV) and non-HIV-associated (IS/non-HIV); and (iii) infancy-associated EPF. Oral indomethacin is efficacious, especially for classic EPF. No comprehensive information on the efficacies of other medical management regimens is currently available. In this study, we surveyed regimens for EPF that were described in articles published between 1965 and 2013. In total, there were 1171 regimens; 874, 137, 45 and 115 of which were applied to classic, IS/HIV, IS/non-HIV and infancy-associated EPF, respectively. Classic EPF was preferentially treated with oral indomethacin with efficacy of 84% whereas topical steroids were preferred for IS/HIV, IS/non-HIV and infancy-associated EPF with efficacy of 47%, 73% and 82%, respectively. Other regimens such as oral Sairei-to (a Chinese-Japanese herbal medicine), diaminodiphenyl sulfone, cyclosporin and topical tacrolimus were effective for indomethacin-resistant cases. Although the preclusion of direct comparison among cases was one limitation, this study provides a dataset that is applicable to the construction of therapeutic algorithms for EPF.

When Rings Are Not Ringworms: Case Reports and Review of Literature.

Presented are two cases of subcorneal pustular dermatosis (SPD), one of which was initially confused with, and treated as, a fungal infection. Eventually both cases were successfully treated with dapsone. The exact etiology and pathophysiology of SPD remains unclear and so does its classification. Dapsone remains the treatment of choice but other valid therapeutic alternatives i.e., retinoids, phototherapy, or anti-TNF inhibitors also need to be explored because of the side effects associated with dapsone.

A recombinant fusion protein derived from dog hookworm inhibits autoantibody-induced dermal-epidermal separation ex vivo.

The proteins secreted by parasitic nematodes are evolutionarily optimized molecules with unique capabilities of suppressing the immune response of the host organism. Neutrophil inhibitory factor (NIF), which is secreted by the dog hookworm Ancylostoma caninum, binds to the ß2 integrin CD11b/CD18, which is expressed on human neutrophils, eosinophils, monocytes and macrophages and inhibits neutrophil-dependent lung injury and neutrophil invasion of ischaemic brain tissue. Neutrophils are key players in the pathogenesis of subepidermal autoimmune blistering diseases (sAIBDs), and their pathogenic activities are crucially dependent on ß2 integrin functionality. Based on the template of single-stranded, dimerizing antibody derivatives, which are already used in cancer treatment, we designed a novel biologic, NIF-IGHE-CH4, comprising NIF and the dimerizing but otherwise inert constant heavy subdomain 4 (CH4) of human IgE (IGHE). This molecule was evaluated in a variety of in vitro assays, demonstrating its ability to inhibit pathogenically relevant neutrophil functions such as migration, adhesion and spreading, and release of reactive oxygen species. Finally, we confirmed that NIF-IGHE-CH4 inhibits blister formation in an ex vivo assay of sAIBD. These results suggest that NIF-IGHE-CH4 is a novel potential anti-inflammatory drug for the treatment of neutrophil-mediated diseases such as sAIBDs. This study promotes the drugs from bugs concept and encourages further research and development focused on turning parasite proteins into useful anti-inflammatory biologics.

Heat shock protein 90: a pathophysiological factor and novel treatment target in autoimmune bullous skin diseases.

The chaperone heat shock protein 90 (Hsp90), a cell stress-inducible molecule that regulates activity of many client proteins responsible for cellular growth, differentiation and apoptosis, has been proposed as an important therapeutic target in patients with malignancies. More recently, its active participation in (auto)immune processes has been recognized as evidenced by amelioration of inflammatory disease pathways through pharmacological inhibition of Hsp90 in rodent models of autoimmune encephalomyelitis, rheumatoid arthritis and systemic lupus erythematosus. Based on own current research results, this viewpoint essay provides important insights that Hsp90 is also involved as a notable pathophysiological factor in autoimmune blistering dermatoses including epidermolysis bullosa acquisita, bullous pemphigoid and possibly dermatitis herpetiformis. The observed in vitro, ex vivo and in vivo efficacy of anti-Hsp90 treatment in experimental models of autoimmune bullous diseases and its underlying multimodal anti-inflammatory mechanisms of interference with key contributors to autoimmune-mediated blister formation supports the introduction of selective non-toxic Hsp90 inhibitors into the clinical setting for the treatment of patients with these disorders.

Dialysis-associated pseudoporphyria successfully treated with vitamin D. Report of two cases.

Pseudoporphyria refers to a rare bullous dermatosis characterized by the clinical and histological features of porfiria cutanea tarda without abnormalities in porphyrin metabolism. The pathogenesis is heterogeneous and several exogenous factors may promote the bullous lesion formation, including medications, end stage renal disease, dialysis and tanning beds. Regarding treatment of this condition, in literature different therapy have been reported, such as glutathione and his precursor N-acetylcysteine, which presents anti-oxidant properties; however even more toxic drugs, such as chloroquine, are used. Moreover, in patients with drug-induced PP discontinuation of the offending agent, if possible, is a crucial aspect of the clinical management. We report two cases of dialysis patients presenting blisters on extremities, which healed with the avoidance of UV exposure and oral Vitamin D supplementation. Interestingly Vitamin D despite the lack of antioxidant properties led to a completely resolution of PP in both our patients within 30 days. A possible explanation of this finding is that Vitamin D, playing a key role in the regulation of serum Ca2+, can modulated cadherin-cadherin interactions and led to healing of pseudoporphyria bullous lesions. Finally we highlight the prominent role of UV-exposure in PP elicitation thus a good photoprotection is essential for all patients with pseudoporphyria.

[Sneddon-Wilkinson disease: efficacy of intermittent adalimumab therapy after lost response to infliximab and etanercept]. / Maladie de Sneddon-Wilkinson échappant à l'infliximab et à l'étanercept: efficacité de l'adalimumab.

BACKGROUND: Sneddon-Wilkinson disease (SWD) is a rare chronic neutrophilic dermatosis. The first-line treatment is dapsone but resistance to treatment may sometimes pose a challenge. CASE REPORT: We report a multidrug-resistant patient who responded dramatically before gradually losing response to infliximab and then etanercept. Complete remission was again obtained with adalimumab. DISCUSSION: Our case confirms the previously reported dramatic efficacy of anti-TNF biological agents in recalcitrant SWD but highlights the possibility of subsequent loss of response. Furthermore, it illustrates the efficacy of adalimumab in this indication.

The role of nutrition in dermatologic diseases: facts and controversies.

Many dermatologic diseases are chronic with no definitive cure. For some diseases, the etiology is not completely understood, with treatment being difficult and associated with side effects. In such cases, patients may try alternative treatments to prevent onset, reduce symptom severity, or prevent reoccurrence of a disease. Dietary modification, through supplementation and exclusion, is an extremely popular treatment modality for patients with dermatologic conditions. It is, therefore, important for dermatologists to be aware of the growing body of literature pertaining to nutrition and skin disease to appropriately inform patients on benefits and harms of specific dietary interventions. We address the role of nutrition in psoriasis, atopic dermatitis, urticaria, and bullous diseases and specific dietary modifications as an adjunct or alternative to conventional therapy.

Blisters and homeopathy: case reports and differential diagnosis.

Blisters are skin lesions characterized by accumulation of fluid between the layers of the skin. Their severity varies from the common blisters caused by friction to severe autoimmune and congenital bullous disorders, some of them currently without treatment in conventional medicine or requiring drugs with potentially severe side-effects. This article reports cases of blistering diseases successfully treated with homeopathic medicines, which represent an alternative for the treatment of such disorders.

Erosive pustular dermatosis of the scalp. A chronic recalcitrant dermatosis developed upon CO2 laser treatment.

Erosive pustular dermatosis of the scalp (EPDS) is a rare, chronic inflammatory dermatosis that mostly affects elderly patients, who develop erosions, pustulation, crusting and scarring on the scalp. Its aetiology remains elusive, although the role of local trauma is being emphasized. Treatment is difficult, with several topical and systemic agents being reported to induce improvement. A 63-year-old Caucasian male had been suffering from persistent painful pustules, erosions and crusts on his scalp for 2 years. The onset of the lesions followed a CO2 laser vaporization procedure to treat multiple actinic keratoses. Different topical and systemic treatments had unsuccessfully been tried. A 4-month course of bid 0.1% tacrolimus ointment, along with strict external photoprotection, resulted in dramatic improvement, sustained after careful tapering of tacrolimus. This case is interesting in that the scalp eruption followed CO2 laser treatment. Other cases have been associated with cryosurgery, radiotherapy, surgery, and 5-FU. In fact, to our knowledge, ours is the fourth reported case of EPDS following CO2 laser treatment. Our case also strengthens previous observations as to the efficacy and safety of topical calcineurin inhibitors in this dermatosis. This is noteworthy bearing in mind the atrophic character of the skin in EPDS, which limits the usefulness of chronically administered topical steroids.

[Chronic graft-versus-host disease presenting as bullous lesions]. / Lesiones ampollosas como forma de presentación de una enfermedad de injerto contra huésped crónica.

Graft-vs-host disease is still the leading cause of morbidity and mortality in patients undergoing bone marrow transplantation. It is important to start treatment early to reduce the severity and consequences of this complication. Cutaneous lesions are often the presenting compliant of graft-vs-host disease and presage visceral involvement. We present the case of a 45-year-old woman with multiple myeloma who underwent autologous and subsequently allogeneic bone marrow transplantation with hematopoietic precursors. She developed bullous lesions with fluid elimination on the abdomen and legs. Biopsy findings were compatible with graft-vs-host disease and immunosuppressive therapy was increased. She subsequently presented oral lichenoid lesions and sicca syndrome. The bullous lesions progressed to painful ulcers that healed leaving highly sclerodermatous skin with substantial hyperpigmentation. Bullous lesions are a rare form of presentation of chronic graft-vs-host disease. In such cases, the diagnosis may not be suspected initially, particularly when the lesions are isolated and internal organs are not involved.

Bullous systemic lupus erythematosus responding to dapsone.

A 29-year-old woman with a 4-week history of systemic lupus erythematosus presented acutely with a severe generalized tense vesicular and bullous eruption with involvement of mucosal surfaces. At the time of her initial diagnosis of systemic lupus erythematosus, she had declined treatment, preferring to explore complementary medical therapies. Skin biopsy showed subepidermal blister formation with inflammation at the dermoepidermal junction. Direct immunofluorescence revealed strongly positive linear deposition of IgG and IgM, and positive linear granular deposition of IgA along the basement membrane zone. Electron microscopy showed that the level of the basement membrane split was below the lamina densa. A diagnosis of bullous systemic lupus erythematosus was made and dapsone was commenced, with a dramatic improvement in her skin eruption. The patient again declined further treatment of her systemic disease and sought complementary therapies, and subsequently presented with cerebral involvement.

Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) with absence of desmoglein 1 and 3 antibodies: case report and literature review.

Subcorneal pustular dermatosis (SPD) [Sneddon-Wilkinson disease] is a benign and uncommon disorder characterized by a chronic, relapsing vesiculopustular eruption of unknown etiology. We present a case of SPD in a young Black woman in whom ELISA was performed to test for desmoglein 1 and 3 antigens (the first reported case of evaluation for these antigens in a patient with SPD). The test revealed the absence of both antibodies. The patient was successfully treated with topical corticosteroids and narrow-band UVB phototherapy. In this report, we review both the pathophysiology of SPD, which has yet to be clarified, and its treatment. Data obtained from our case report add further support to the hypothesis that a non-antibody-mediated mechanism is operative in SPD. The treatment of choice for SPD is dapsone. However, the combination of corticosteroids and UVB phototherapy should be considered a valid therapeutic option in patients who are not appropriate candidates for dapsone therapy.

Efectividad del tratamiento tópico con esteroides en enfermedades vesículo-ampollares con signos de gingivitis descamativa: revisión de la literatura / The effectiveness of topical steroid treatment of vesiculo-bullous diseases with signs of desquamative gingivitis: a review of the literature

Existe una gran variedad de enfermedades que afectan las membranas mucosas las cuales incluyen la mucosa gingival. El signo de gingivitis descamativa constituye una condición que se caracteriza por la presencia de lesiones eritematosas, erosivas, atróficas y dolorosas en la encía marginal extendiéndose a otras localizaciones como la mucosa alveolar, palatina y yugal, entre otras. El manejo terapéutico de ésta alteración se basa principalmente en la administración de corticosteroides sistémicos y tópicos de alta potencia, al igual que el manejo dental apropiado. Es de importancia el control médico odontológico de éstos pacientes para garantizar la salud dental y sistémica del mismo. El propósito de ésta revisión es determinar, basándose en lo publicado en la literatura actual, hasta que punto es efectivo el tratamiento con corticosteroides tópicos lo que actualmente conocemos como signo de gingivitis descamativa

Pruritic urticarial papules and plaques of pregnancy.

Pruritic urticarial papules and plaques of pregnancy (PUPPP) are among the most common pruritic dermatoses observed in pregnant women. PUPPP appears most frequently in the third trimester, in primigravidas, and in multiple gestation pregnancies. The eruption of changes occurs initially on the abdomen and extends over the thighs, legs, back, buttocks, arms, and breasts. Skin changes typical for PUPPP are erythematous, urticarial plaques, and papules. Rash regression is usually observed within 6 weeks postpartum. Immunologic mechanisms, hormonal abnormalities, and abdominal skin distension have been suggested as etiologic mechanisms. PUPPP is thought to be harmless for the mother and fetus and usually requires intervention only for symptom relief. In some cases, laboratory investigation, histologic examination, and immunologic study should be performed to exclude more serious disorders of pregnancy, such as herpes gestationis or intrahepatic cholestasis of pregnancy. This article reviews the epidemiology, clinical manifestation, etiology, differential diagnosis, and treatment of PUPPP.