Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1ß Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation.

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet's disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1ß were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Survival of Second-Line Biologics in Psoriasis: The British BADBIR Registry Data Informs Daily Practice.

Psoriasis is one of the most chronic diseases in dermatology. Only a small percentage of patients ever experience relapse-free survival. The constant presence of plaques and comorbidities that affect the cardiovascular system, joints, and other organs greatly impair patients' quality of life. In addition, the life expectancy of psoriatic patients is shortened by several years. Hence, long-term and ideally systemic treatment with minimal adverse effects may be warranted.

The Phytotherapeutic Fenugreek as Trigger of Toxic Epidermal Necrolysis.

We describe the case of a 32-year-old woman who presented to the hospital with generalized painful exanthema, blisters and erosions 1 month after giving birth to a healthy girl. The patient's medical history was inconspicuous for comorbidities; however, it included the incidental intake of pain killers and a herbal preparation (fenugreek), which she took regularly over the last 4 weeks to improve lactation. Based on the clinical characteristics, we suspected toxic epidermal necrolysis (TEN), a severe cutaneous adverse drug reaction, which was confirmed by skin biopsy. The patient was treated with high-dose intravenous human immunoglobulins and was discharged 2 weeks after hospital admission in good condition. The allergological workup identified fenugreek as the most likely causative agent. Given the increased self-medication of freely available phytotherapeutics by patients in industrialized countries, herbal mixtures should be taken into consideration in the diagnostic workup of TEN.

The inflammasomes in autoinflammatory diseases with skin involvement.

During the past years, significant progress in the understanding of the complexity, regulation, and relevance of innate immune responses underlying several inflammatory conditions with neutrophilic skin involvement has been made. These diseases belong to the novel class of autoinflammatory diseases, and several are caused by mutations in genes regulating the function of innate immune complexes, termed inflammasomes, leading to enhanced secretion of the proinflammatory cytokine IL-1ß. Consequently, targeting of IL-1ß has proven successful in the treatment of these diseases, and the identification of related pathogenic mechanisms in other more common skin diseases characterized by autoinflammation and neutrophilic tissue damage also provides extended opportunities for therapy by interfering with IL-1 signaling.

Phototherapy with UVB narrowband, UVA/UVBnb, and UVA1 differentially impacts serum 25-hydroxyvitamin-D3.

BACKGROUND: Ultraviolet (UV) B radiation increases serum 25-hydroxyvitamin-D3 [25(OH)D], but the influence of UVA1 and UVA/narrowband UVB (UVBnb) phototherapy on serum vitamin D is unknown. OBJECTIVE: We sought to investigate the influence of UVBnb, UVA1, and UVA/UVBnb phototherapy on serum levels of 25(OH)D and related parameters in patients with an inflammatory skin condition. METHODS: 25(OH)D, as well as calcium, parathormone, phosphate, and albumin were measured before therapy, 2 weeks after start, and after completion of the phototherapy. Diagnoses were divided in 4 groups: atopic dermatitis, psoriasis, morphea, and others. RESULTS: We surveyed 116 dermatologic patients undergoing phototherapy with UVA1 (n = 38), UVA/UVBnb (n = 30), or UVBnb (n = 48) 2 to 3 times a week for 53 to 90 days. UVBnb phototherapy increased serum 25(OH)D from 22.1 to 39.5 ng/mL after the therapy (P < .001). The lower the baseline 25(OH)D level was, the steeper the increase in 25(OH)D was upon application of UVBnb phototherapy. UVA/UVBnb therapy also increased serum 25(OH)D, from 23.9 to 50.3 ng/mL (P = .003). Conversely, in the UVA1 therapy group, 25(OH)D serum levels decreased significantly from 21.9 to 19.0 ng/mL (P < .001). LIMITATIONS: The study design was open trial without randomization. An influence of a precise skin disease cannot be excluded because of the heterogeneous diagnoses. Bias may have arisen from patient preference for treatment at our center, referral, unrecognized differences in underlying skin disease, and other factors. CONCLUSION: Phototherapy with UVBnb and UVA/UVBnb increased 25(OH)D serum level significantly. UVA1 therapy alone induced a reduction in serum 25(OH)D concentrations.

Melanoma after laser therapy of pigmented lesions--circumstances and outcome.

The use of laser therapy in the treatment of pigmented lesions is a controversial issue as it can delay melanoma diagnosis and may negatively impact mortality. Few cases of melanoma after laser therapy have been reported. It is still unknown whether melanoma can be induced by lasers. We discuss the outcomes of twelve patients presenting with melanoma subsequent to previous treatment with laser. In four patients, a skin biopsy was performed before laser treatment. Histology was re-evaluated by a panel of experienced dermatopathologists and analyzed in the context of clinical and photo-optical data. There was evidence for pathological misdiagnosis in two cases. The other two cases initially presented with non-suspicious features before laser treatment and were clearly diagnosed as melanoma thereafter, opening the possibility of melanoma induction by laser treatment. Most patients were female and presented with facial lesions. Three patients have already died of melanoma and two are in stage IV, showing progressive disease with distant metastases. Laser therapy is a common treatment for pigmented lesions, increasing the risk of delayed melanoma diagnosis. This prevents appropriate and timely therapy, and may therefore lead to a fatal outcome. A careful examination of all pigmented lesions using surface microscopy and representative biopsies in combination with a close follow-up is recommended.

New and experimental skin-directed therapies for cutaneous lymphomas.

Primary cutaneous lymphomas (CLs) originate in the skin and should be differentiated from secondary skin infiltrates, which are manifestations of lymphomas of nodal or extranodal origin. These rare diseases include various lymphoproliferative disorders: cutaneous T-cell lymphomas, cutaneous B-cell lymphomas and some rare subtypes. As definitive cure is often not possible, it is important to control the disease and alleviate symptoms. Patients with early-stage disease limited to the skin usually require skin-directed therapies using topical agents including corticosteroids, chemotherapeutic drugs, bexarotene gel, electron beam therapy and phototherapy. Each of these are effective; however, all have some disadvantages and are associated with significant adverse events. In the field of skin-directed therapies there are interesting developments using antineoplastic compounds, the retinoid tazarotene, imiquimod, gene therapy products (adenovirus vector expressing gamma-interferon), the monoclonal anti-CD20 antibody rituximab, photodynamic therapy and 308-nm excimer laser to mention a few. This review highlights some of the promising new and experimental local therapies for primary CLs and focuses on their efficacy and side effects.

Granulomatous slack skin responds to UVA1 phototherapy.

Granulomatous slack skin (GSS) is an extremely rare disorder within the group of cutaneous T cell lymphomas (CTCL). Ultraviolet A1 (UVA1) phototherapy has previously been reported to be useful in the treatment of CTCL such as mycosis fungoides. We report a 35-year-old Caucasian male with GSS treated with UVA1 phototherapy starting at 20 J/cm(2) UVA1 3 times a week and subsequently increased in increments of 5 J/cm(2) to a medium-range dose of 50 J/cm(2) per session. The patient underwent a total of 45 sessions with a cumulative dose of 1,495 J/cm(2) UVA1 without any adverse events. At the conclusion of UVA1 phototherapy, a decrease in erythema and skin thickness was observed which was most prominent in the periphery of the lesion in the right groin area. A follow-up 12 months after phototherapy showed continued treatment benefit. To our knowledge, this is the first report describing the successful use of UVA1 (340-400 nm) phototherapy in a patient with GSS.