Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures.

Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the United States population. This guideline addresses important clinical questions that arise in psoriasis management and care and provides recommendations based on the available evidence. The treatment of psoriasis with topical agents and with alternative medicine will be reviewed, emphasizing treatment recommendations and the role of dermatologists in monitoring and educating patients regarding benefits as well as risks that may be associated. This guideline will also address the severity assessment methods of psoriasis in adults.

Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with phototherapy.

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 3.2% of the world's population. In this section of the guidelines of care for psoriasis, we will focus the discussion on ultraviolet (UV) light-based therapies, which include narrowband and broadband UVB, UVA in conjunction with photosensitizing agents, targeted UVB treatments such as with an excimer laser, and several other modalities and variations of these core phototherapies, including newer applications of pulsed dye lasers, intense pulse light, and light-emitting electrodes. We will provide an in-depth, evidence-based discussion of efficacy and safety for each treatment modality and provide recommendations and guidance for the use of these therapies alone or in conjunction with other topical and/or systemic psoriasis treatments.

The retinoid X receptor agonist, 9-cis UAB30, inhibits cutaneous T-cell lymphoma proliferation through the SKP2-p27kip1 axis.

BACKGROUND: Bexarotene (Targretin®) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects. OBJECTIVES: To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene. METHODS: With patient-derived CTCL cell lines, we evaluated UAB30 function in regulating growth, apoptosis, cell cycle check points, and cell cycle-related markers. RESULTS: Compared to bexarotene, UAB30 had lower half maximal inhibitory concentration (IC50) values and was more effective in inhibiting the G1 cell cycle checkpoint. Both rexinoids increased the stability of the cell cycle inhibitor, p27kip1 protein, in part, through targeting components involved in the ubiquitination-proteasome system: 1) decreasing SKP2, a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2) suppressing 20S proteasome activity (cell line-dependent) through downregulation of PSMA7, a component of the 20S proteolytic complex in 26S proteasome. CONCLUSIONS: UAB30 and bexarotene induce both early cell apoptosis and suppress cell proliferation. Inhibition of the G1 to S cell cycle transition by rexinoids is mediated, in part, through downregulation of SKP2 and/or 20S proteasome activity, leading to increased p27kip1 protein stability. Because UAB30 has minimal effect in elevating serum TGs and inducing hypothyroidism, it is potentially a better alternative to bexarotene for the treatment of CTCLs.

Tea polyphenols for the prevention of UVB-induced skin cancer.

Skin cancer is the most common type of cancer with increasing incidence rate and public health burden. Solar ultraviolet (UV) radiation causes an array of damaging cellular and molecular events that eventually lead to the development of skin cancer. Despite increased awareness about sun protection, the exposure rate remains high with less than 15% of men and 30% of women using sunscreen on a regular basis. Therefore, there is an imperative need for the development of novel preventive approaches. Skin cancer chemoprevention using phytochemicals either as dietary supplements or by topical applications has gained considerable attention due to their low toxicity, availability, and anticarcinogenic properties. Tea, the second most commonly consumed beverage in the world, is a rich source of promising phytochemicals known as polyphenols. In this review, we discuss the findings of various in vitro, in vivo and human studies signifying the chemopreventive effects of tea polyphenols against UVB-induced skin cancer. This is accomplished by exploring the role of tea polyphenols in DNA repair, inflammation, oxidative stress, signaling pathways, and epigenetics. Finally, this review discusses a variety of innovative delivery methods that enhance the photochemopreventive effects of tea polyphenols against skin cancer.

The impact of oral Polypodium leucotomos extract on ultraviolet B response: A human clinical study.

BACKGROUND: There is a rationale for adding systemic photoprotective agents to the current photoprotection regimen. OBJECTIVE: This study was designed to objectively evaluate the molecular and photobiologic effects of oral administration of Polypodium leucotomos extract (PLE). METHODS: In all, 22 subjects with Fitzpatrick skin phototype I to III were enrolled. On day 1, subjects were irradiated with visible light, ultraviolet (UV) A1, and UVB (using 308-nm excimer laser). Evaluation was done immediately and 24 hours after irradiation. On days 3 and 4, irradiation and evaluation process was repeated after ingestion of PLE. RESULTS: Clinical assessments and colorimetry data showed a decrease in UVB-induced changes in 17 of 22 subjects post-PLE administration; histology findings demonstrated such a decrease in all 22 subjects. LIMITATIONS: Only 2 doses of PLE were given. Furthermore, subjects with skin phototypes I to III only were studied. CONCLUSION: The results suggest that PLE can potentially be used as an adjunctive agent to lessen the negative photobiologic effects of UVB.

Phytochemicals for the Management of Melanoma.

Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.

Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.

Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.

Vitamin D and skin cancer.

Vitamin D signaling plays a key role in many important processes, including cellular proliferation, differentiation and apoptosis, immune regulation, hormone secretion and skeletal health. Furthermore, vitamin D production and supplementation have been shown to exert protective effects via an unknown signaling mechanism involving the vitamin D receptor (VDR) in several diseases and cancer types, including skin cancer. With over 3.5 million new diagnoses in 2 million patients annually, skin cancer is the most common cancer type in the United States. While ultraviolet B (UVB) radiation is the main etiologic factor for nonmelanoma skin cancer (NMSC), UVB also induces cutaneous vitamin D production. This paradox has been the subject of contradictory findings in the literature in regards to amount of sun exposure necessary for appropriate vitamin D production, as well as any beneficial or detrimental effects of vitamin D supplementation for disease prevention. Further clinical and epidemiological studies are necessary to elucidate the role of vitamin D in skin carcinogenesis.

Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches.

Atopic dermatitis is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on use are given based on available evidence.

Photoimmunology.

The discipline that investigates the biologic effects of ultraviolet radiation on the immune system is called photoimmunology. Photoimmunology evolved from an interest in understanding the role of the immune system in skin cancer development and why immunosuppressed organ transplant recipients are at a greatly increased risk for cutaneous neoplasms. In addition to contributing to an understanding of the pathogenesis of nonmelanoma skin cancer, the knowledge acquired about the immunologic effects of ultraviolet radiation exposure has provided an understanding of its role in the pathogenesis of other photodermatologic diseases.

Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents.

Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option.

Research gaps in psoriasis: opportunities for future studies.

Over the past 2 decades, considerable progress has been made to further elucidate the complex pathogenesis of psoriasis, facilitating the development of a new armamentarium of more effective, targeted therapies. Despite these important advances, substantial deficits remain in our understanding of psoriasis and its treatment, necessitating further research in many areas. In the sixth section of the American Academy of Dermatology Psoriasis Guidelines of Care, gaps in research and care were identified. We discuss the most important gaps in research that currently exist and make suggestions for studies that should be performed to address these deficits. These encompass both basic science and clinical research studies, including large, prospective epidemiologic studies to determine the true prevalence and natural history of psoriasis; further molecular studies in patients with psoriatic and psoriatic arthritis to understand the function of psoriasis susceptibility genes and to identify novel therapeutic targets; studies to examine the role of environmental factors in the development of psoriasis; further investigation of the relationship between psoriasis and cardiometabolic disease; studies that examine the role of adjunctive therapies such as psychological interventions in appropriate patient groups; and finally, studies to identify biomarkers of disease severity and treatment response to optimize patient therapy.

Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice.

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T-cell-mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DC). Co-culture of CD4(+) T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of T-helper (TH) 1-type cytokines that was ameliorated when the DCs were obtained from GSP-fed mice, whereas DCs obtained from GSP-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4,-dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair-dependent functional activation of dendritic cells in mice. Cancer Prev Res; 6(3); 242-52. ©2013 AACR.

Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In the first 5 parts of the American Academy of Dermatology Psoriasis Guidelines of Care, we have presented evidence supporting the use of topical treatments, phototherapy, traditional systemic agents, and biological therapies for patients with psoriasis and psoriatic arthritis. In this sixth and final section of the Psoriasis Guidelines of Care, we will present cases to illustrate how to practically use these guidelines in specific clinical scenarios. We will describe the approach to treating patients with psoriasis across the entire spectrum of this fascinating disease from mild to moderate to severe, with and without psoriatic arthritis, based on the 5 prior published guidelines. Although specific therapeutic recommendations are given for each of the cases presented, it is important that treatment be tailored to meet individual patients' needs. In addition, we will update the prior 5 guidelines and address gaps in research and care that currently exist, while making suggestions for further studies that could be performed to help address these limitations in our knowledge base.

Proanthocyanidins inhibit UV-induced immunosuppression through IL-12-dependent stimulation of CD8+ effector T cells and inactivation of CD4+ T cells.

The inhibition of UVB-induced immunosuppression by dietary grape seed proanthocyanidins (GSP) has been associated with the induction of interleukin (IL)-12 in mice, and we now confirm that GSPs do not inhibit UVB-induced immunosuppression in IL-12p40 knockout (IL-12 KO) mice and that treatment of these mice with recombinant IL-12 restores the inhibitory effect. To characterize the cell population responsible for the GSP-mediated inhibition of UVB-induced immunosuppression and the role of IL-12 in this process, we used an adoptive transfer approach. Splenocytes and draining lymph nodes were harvested from mice that had been administered dietary GSPs (0.5%-1.0%, w/w), exposed to UVB, and sensitized by the application of 2,4-dinitrofluorobenzene (DNFB) onto the UVB-exposed skin. CD8(+) and CD4(+) T cells were positively selected and transferred into naive mice that were subsequently challenged by application of DNFB on the ear skin. Naive recipients that received CD8(+) T cells from GSP-treated, UVB-irradiated donors exhibited full contact hypersensitivity (CHS) response. Naive mice that received CD4(+) suppressor T cells from GSP-treated, UVB-exposed mice could mount a CHS response after sensitization and subsequent challenge with DNFB. On culture, the CD8(+) T cells from GSP-treated, UVB-exposed mice secreted higher levels (5- to 8-fold) of Th1 cytokines than CD8(+) T cells from UVB-irradiated mice not treated with GSPs. CD4(+) T cells from GSP-treated, UVB-exposed mice secreted significantly lower levels (80%-100%) of Th2 cytokines than CD4(+) T cells from UVB-exposed mice not treated with GSPs. These data suggest that GSPs inhibit UVB-induced immunosuppression by stimulating CD8(+) effector T cells and diminishing regulatory CD4(+) T cells.

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fifth of 6 sections of the guidelines of care for psoriasis, we discuss the use of ultraviolet (UV) light therapy for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety as well as offer recommendations for the use of phototherapy, including narrowband and broadband UVB and photochemotherapy using psoralen plus UVA, alone and in combination with topical and systemic agents. We will also discuss the available data for the use of the excimer laser in the targeted treatment of psoriasis. Finally, where available, we will summarize the available data that compare the safety and efficacy of the different forms of UV light therapy.

Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guidelines of care for psoriasis, we discuss the use of traditional systemic medications for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety, and offer recommendations for the use of the 3 most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin. We will also briefly discuss the available data for the use of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, and 6-thioguanine in psoriasis.

T4 endonuclease V: review and application to dermatology.

BACKGROUND: T4 endonuclease V was originally isolated from Escherichia coli infected with T4 bacteriophage. It has been shown to repair ultraviolet (UV)-induced cyclobutane pyrimidine dimers in DNA, which, when unrepaired, contribute to mutations that result in actinic keratoses and non-melanoma skin cancers (NMSC). This is a particular concern in patients with genetic defects in their DNA repair systems, especially those with xeroderma pigmentosum (XP). When packaged in liposomes and applied topically, T4 endonuclease V can traverse the stratum corneum and become incorporated within the cytoplasm and nucleus of epidermal keratinocytes and Langerhans cells. OBJECTIVE: To review all major studies evaluating the efficacy of T4 endonuclease V in animals and humans, the toxicity and safety profile of the topical medication and its potential clinical uses. METHODS: A literature search was performed through PubMed/Medline, using the keywords 'T4N5', 'T4 endonuclease V' and 'dimericine'. Papers found in the bibliographies of those identified in the initial search and deemed relevant were also included. CONCLUSION: This enzyme increases the repair of UV-damaged DNA and produces other beneficial effects on UV-damaged cells. In clinical trials in XP patients, topical application of liposome-encapsulated T4 endonuclease V reduced the incidence of basal cell carcinomas by 30% and of actinic keratoses by > 68%. Adverse effects were minimal, and there was no evidence of allergic or irritant contact dermatitis. Although the photoprotective effect of T4N5 has been investigated only in XP patients, the possibility exists that it may benefit others likely to develop premalignant keratoses and NMSC, such as organ transplant recipients receiving immunosuppressive therapy and individuals who have had numerous psoralen plus UVA photochemotherapy treatments. It may be also be effective for normal individuals.

Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efficacy, safety, and patient-reported outcomes.

BACKGROUND: Moderate to severe psoriasis is a significant inflammatory disease that frequently requires systemic therapies to effectively treat the underlying disorder. Etanercept and narrow-band ultraviolet light B (NB-UVB) are widely used to treat this disease. OBJECTIVE: To evaluate the effectiveness, tolerability, and patient-reported outcomes of combination etanercept plus NB-UVB phototherapy in moderate to severe plaque psoriasis. METHODS: This 12-week, single-arm, open-label study evaluated the combination of etanercept 50 mg twice weekly and NB-UVB thrice weekly in 86 patients. The primary outcome measure was > or =75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75). Other measures included PASI 90, PASI 100, and the Dermatology Life Quality Index (DLQI). RESULTS: At week 12, 26.0% achieved PASI 100, 58.1% achieved PASI 90, and 84.9% of patients achieved PASI 75. Mean improvement from baseline in DLQI was 84.4%. No unexpected, untoward adverse events were noted. CONCLUSIONS: A 12-week course of etanercept plus NB-UVB phototherapy was well tolerated and produced clinically meaningful improvements in signs and symptoms of moderate to severe plaque psoriasis and in patient-reported outcomes. Further investigation of the safety and efficacy of the use of such combination for this indication in controlled clinical trials would be of interest.

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this first of 5 sections of the guidelines of care for psoriasis, we discuss the classification of psoriasis; associated comorbidities including autoimmune diseases, cardiovascular risk, psychiatric/psychologic issues, and cancer risk; along with assessment tools for skin disease and quality-of-life issues. Finally, we will discuss the safety and efficacy of the biologic treatments used to treat patients with psoriasis.