American Academy of Dermatology evidence-based guideline development process: responding to new challenges and establishing transparency.

BACKGROUND: Evidence-based clinical guidelines are developed to educate and inform physicians about best practices in patient care, and assist providers in the application of treatments and technologies that can improve outcomes. Clinical guidelines also aid appeal of payment decisions; serve as the basis for quality measure development, appropriateness criteria, and maintenance of certification modules; and help identify areas for further clinical research. OBJECTIVE: For guidelines to serve dermatologists effectively in these diverse roles, they must be current, varied in clinical focus, and developed with a high degree of rigor that includes attention to potential conflicts of interest. METHOD: To address these needs and keep pace with advances in medicine, the American Academy of Dermatology (AAD) recently revised the evidence-based guideline development process. RESULTS: Key changes include development of a yearly needs assessment process to determine what guidelines are most needed, the development of focused guidelines that address rapidly evolving clinical topics, a formal method of vetting guidelines produced by other societies, and a scheduled reassessment of existing guidelines to ensure they provide current and practical information. The process for identifying and managing potential conflicts of interest was also revised and expanded to meet current expectations and evolving standards. LIMITATIONS: The impact of these changes to the AAD's guideline development process will not be fully realized for several years. CONCLUSIONS: These changes will help ensure the AAD will be able to provide its members with continued evidence-based guidance to support patient care across the scope of dermatologic practice.

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.

Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology.

The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

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.

Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma.

PURPOSE: The anti-B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS: In this first-in-human study, up to 10 cycles of AMG 420 were given (4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/104 bone marrow cells by flow cytometry. RESULTS: Forty-two patients received AMG 420 at 0.2-800 µg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 µg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 µg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year. CONCLUSION: In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 µg/d, the MTD for this study.

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.

Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies.

Psoriasis is a common, chronic, inflammatory, multi-system disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this third of 6 sections of the guidelines of care for psoriasis, we discuss the use of topical medications for the treatment of psoriasis. The majority of patients with psoriasis have limited disease (<5% body surface area involvement) and can be treated with topical agents, which generally provide a high efficacy-to-safety ratio. Topical agents may also be used adjunctively for patients with more extensive psoriasis undergoing therapy with either ultraviolet light, systemic or biologic medications. However, the use of topical agents as monotherapy in the setting of extensive disease or in the setting of limited, but recalcitrant, disease is not routinely recommended. Treatment should be tailored to meet individual patients' needs. We will discuss the efficacy and safety of as well as offer recommendations for the use of topical corticosteroids, vitamin D analogues, tazarotene, tacrolimus, pimecrolimus, emollients, salicylic acid, anthralin, coal tar, as well as combination therapy.

Sinecatechins, a defined green tea extract, in the treatment of external anogenital warts: a randomized controlled trial.

OBJECTIVE: To estimate the clinical efficacy of topical sinecatechins, a defined green tea extract, in the treatment of external genital and perianal warts. METHODS: This was a randomized, double-blind, vehicle-controlled trial involving 502 male and female patients aged 18 years and older, with 2-30 anogenital warts ranging from 12 to 600 mm(2) total wart area. Patients applied sinecatechins ointment 15% or 10% or vehicle (placebo) three times daily for a maximum of 16 weeks or until complete clearance of all warts, followed by a 12-week treatment-free follow-up to assess recurrence. RESULTS: Complete clearance of all baseline and newly occurring warts was obtained in 57.2% and 56.3% of patients treated with sinecatechins ointment 15% and 10%, respectively, compared with 33.7% for vehicle (both P<.001). Significance was observed at weeks 4 and 6 and all subsequent visits. Numbers needed to treat were 4.3 and 4.4. Partial clearance rates of at least 50% were reported for 78.4% and 74.0% of patients in the sinecatechins ointment 15% and 10% groups compared with 51.5% of vehicle patients. During follow-up, recurrence of any wart was observed in 6.5%, 8.3%, and 8.8% in the sinecatechins ointment 15% group, sinecatechins ointment 10% group, and vehicle patients, respectively. A total of 3.7%, 8.3%, and 0.0% developed new warts, respectively. A total of 87.7% and 87.3% of patients in the sinecatechins ointment 15% and 10% groups, and 72.1% of vehicle patients experienced application site reactions; 49.2%, 46.2%, and 65.4% of those, respectively, were mild or moderate. CONCLUSION: Topical sinecatechins ointments 15% and 10% are effective and well-tolerated in the treatment of anogenital warts. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00449982. LEVEL OF EVIDENCE: I.

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.

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this second of 5 sections of the guidelines of care for psoriasis, we give an overview of psoriatic arthritis including its cardinal clinical features, pathogenesis, prognosis, classification, assessment tools used to evaluate psoriatic arthritis, and the approach to treatment. Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis. We will discuss the use of disease-modifying antirheumatic drugs and the biologic therapies in the treatment of patients with moderate to severe psoriatic arthritis.

Once-daily valacyclovir to reduce the risk of transmission of genital herpes.

BACKGROUND: Nucleoside analogues against herpes simplex virus (HSV) have been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces and may prevent sexual transmission of HSV. METHODS: We followed 1484 immunocompetent, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible to HSV-2. The partners with HSV-2 infection were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes. Source partners were followed for recurrences of genital herpes; 89 were enrolled in a substudy of HSV-2 mucosal shedding. Both partners were counseled on safer sex and were offered condoms at each visit. The predefined primary end point was the reduction in transmission of symptomatic genital herpes. RESULTS: Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir, as compared with 16 of 741 who were given placebo (hazard ratio, 0.25; 95 percent confidence interval, 0.08 to 0.75; P=0.008). Overall, acquisition of HSV-2 was observed in 14 of the susceptible partners who received valacyclovir (1.9 percent), as compared with 27 (3.6 percent) who received placebo (hazard ratio, 0.52; 95 percent confidence interval, 0.27 to 0.99; P=0.04). HSV DNA was detected in samples of genital secretions on 2.9 percent of the days among the HSV-2-infected (source) partners who received valacyclovir, as compared with 10.8 percent of the days among those who received placebo (P<0.001). The mean rates of recurrence were 0.11 per month and 0.40 per month, respectively (P<0.001). CONCLUSIONS: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.

Guidelines of care for acne vulgaris management.

DISCLAIMER: Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient.

An intra-individual randomized safety and efficacy comparison of clobetasol propionate 0.05% spray and its vehicle in the treatment of plaque psoriasis.

BACKGROUND: Plaque psoriasis affects about 2% of the US population. A new and unique spray formulation of clobetasol propionate (CP) 0.05% was developed to provide advantages over the currently available treatment formulations. OBJECTIVES: To evaluate the efficacy and safety of CP 0.05% spray compared to its vehicle in the treatment of moderate to severe plaque psoriasis. METHODS: A 4-week, single-center, randomized, double-blind, vehicle-controlled, intra-individual study in subjects with plaque psoriasis. Each of 2 target lesions per subject were randomized to receive either CP 0.05% spray or its vehicle twice daily over 4 weeks. Efficacy parameters included overall target plaque severity score, scaling, erythema, and plaque elevation at all visits. Adverse events were reported throughout the study. RESULTS: A total of 27 subjects were enrolled in the study. At all visits there was a significant intra-individual treatment effect for the overall target plaque severity (P < .001) in favor of CP spray. Throughout the study, results for scaling, erythema, and plaque elevation were significantly (P < .001) in favor of CP spray. After 4 weeks of treatment, all intra-individual response measures, with the exception of erythema, showed an average difference in severity scores of more than 4 points (based on a 9-point scale) between the lesions treated with CP 0.05% spray and the lesions treated with vehicle. No serious adverse event occurred during the course of the study. One local adverse event at the application site (5%) was considered probably related to study medication. CONCLUSION: CP 0.05% spray was effective and safe in reducing overall plaque severity, scaling, erythema, and plaque elevation from the first week of treatment continuing throughout the trial.

A look at the safety of metronidazole 1% gel: cumulative irritation, contact sensitization, phototoxicity, and photoallergy potential.

Rosacea is a common, recurrent, inflammatory dermatologic disorder characterized by the presence of facial erythema, visible blood vessels, papules, and pustules. The condition may cause serious psychologic morbidity and may significantly affect quality of life. The first topical rosacea therapy approved by the US Food and Drug Administration was metronidazole for the treatment of inflammatory lesions and erythema. Previously, metronidazole was available as a 0.75% gel. Improved solubility was achieved in a new, stable, aqueous gel that permitted the formulation of metronidazole 1.0%. This new formulation is highly spreadable, easy to use, cosmetically friendly, mild to the skin, nondrying, and moisturizing. The safety of metronidazole 1% gel was determined by the evaluation of its cumulative irritation, contact sensitization, phototoxicity, and photoallergy potential in healthy male and female patients. In this formulation, metronidazole was not irritating under occlusive application. Additionally, metronidazole 1% gel had a low potential for causing sensitization reactions, and no evidence suggested phototoxic or photoallergic reactions.

HLA-genotyping of clinical specimens using Ion Torrent-based NGS.

We have evaluated and validated the NXType™ workflow (One Lambda, Inc.) and the accompanying TypeStream™ software on the Ion Torrent Next Generation Sequencing (NGS) platform using a comprehensive testing panel. The panel consisted of 285 genomic DNA (gDNA) samples derived from four major ethnic populations and contained 59 PT samples and 226 clinical specimens. The total number of alleles from the six loci interrogated by NGS was 3420. This validation panel provided a wide range of HLA sequence variations including many rare alleles, new variants and homozygous alleles. The NXType™ system (reagents and software) was able to correctly genotype the vast majority of these specimens. The concordance rate between SBT-derived genotypes and those generated by TypeStream™ auto-analysis ranged from 99.5% to 99.8% for the HLA-A, B, C, DRB1 and DQB1 loci, and was 98.9% for HLA-DPB1. A strategy for data review was developed that would allow correction of most of the few remaining typing errors. The entire NGS workflow from gDNA amplification to genotype assignment could be completed within 3 working days. Through this validation study, the limitations and shortcomings of the platform, specific assay system, and software algorithm were also revealed for further evaluation and improvement.

External genital warts: diagnosis, treatment, and prevention.

External genital warts (EGWs) are visible warts that occur in the perigenital and perianal regions. They are due primarily to non-oncogenic human papillomavirus (HPV) types, usually types 6 and 11. Physical examination assisted by bright light and magnification is the recommended approach for primary diagnosis. Biopsy is indicated when EGWs are fixed to underlying structures or discolored or when standard therapies are not effective. Recurrences are common, and there is no single treatment that is superior to others. Among women with atypical squamous cells, molecular HPV testing may be useful in determining who should be referred for colposcopy. Condoms may provide some protection against HPV-related diseases and thus are recommended in new sexual relationships and when partnerships are not mutually monogamous. Because the efficacy of cesarean section in preventing vertical transmission of HPV infection from women with EGWs to their progeny has not been proved, it is not recommended.

Validity of self-reporting of episodes of external genital warts.

To determine whether men are able to self-diagnose external genital warts (EGWs), we studied data from 1115 men with and without human immunodeficiency virus infection. Men were largely unable to accurately assess the presence of EGWs. Self-reporting of EGWs was not a sensitive tool; only 38% of men who had EGWs diagnosed by a trained examiner who used bright light and visual inspection also reported having them. When we controlled for other covariates in a multivariate model, men who had EGWs diagnosed by an examiner were 14 times less likely to show concordance between examiner findings and self-report than were men who did not have EGWs diagnosed by an examiner (odds ratio, 0.07; 95% confidence interval, 0.06-0.09). Self-diagnosis and self-assessment may not accurately reflect the presence of EGWs, and self-diagnosis should not be used in place of an examiner's findings for epidemiologic studies that seek to determine the cause of disease.

Emerging therapies for herpes viral infections (types 1 - 8).

There are eight members of the herpesviridae family: herpes simplex virus-1 (HSV-1), HSV-2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human herpes virus-6, human herpes virus-7 and human herpes virus-8. The diseases caused by viruses of the herpesviridae family are treated with and managed by systemic and topical antiviral therapies and immunomodulating drugs. Because these viruses establish a latent state in hosts, antiherpetic agents, such as nucleoside analogues, only control symptoms of disease or prevent outbreaks, and cannot cure the infections. There is a need for treatments that require less frequent dosing, can be taken even when lesions are more advanced than the first signs or symptoms, and can treat resistant strains of the viruses without the toxicities of existing therapies. Immunomodulating agents, such as resiquimod, can act on the viruses indirectly by inducing host production of cytokines, and can thereby reduce recurrences of herpes. The new helicase primase inhibitors, which are the first non-nucleoside antiviral compounds, are being investigated for treatment of HSV disease, including infections resistant to existing therapy.

Recent clinical experience with famciclovir--a "third generation" nucleoside prodrug.

The herpesviruses continue to produce considerable morbidity in man. Once infected with herpes simplex (HSV), the virus remains dormant within the nervous system and may reactivate if provoked by stress, trauma and/or other factors. To date, there is no cure, but antiviral medication can reduce duration and severity of symptoms and prophylaxis can suppress recurrent episodes of disease. The second-generation guanosine nucleosides, acyclovir and penciclovir, are effective inhibitors with low toxicity; both, however, have relatively low oral bioavailability. Subsequently, the orally bioavailable prodrugs valaciclovir and famciclovir have been introduced. These compounds offer high oral bioavailabilty and deliver acyclovir and penciclovir, respectively, to the target cells by means of more convenient dosing schedules. This short review points to recent experience with famciclovir in the management of HSV and varicella-zoster virus.

Estimating uncertainty in brain region delineations.

This paper presents a method for estimating uncertainty in MRI-based brain region delineations provided by fully-automated segmentation methods. In large data sets, the uncertainty estimates could be used to detect fully-automated method failures, identify low-quality imaging data, or endow downstream statistical analyses with per-subject uncertainty in derived morphometric measures. Region segmentation is formulated in a statistical inference framework; the probability that a given region-delineating surface accounts for observed image data is quantified by a distribution that takes into account a prior model of plausible region shape and a model of how the region appears in images. Region segmentation consists of finding the maximum a posteriori (MAP) parameters of the delineating surface under this distribution, and segmentation uncertainty is quantified in terms of how sharply peaked the distribution is in the vicinity of the maximum. Uncertainty measures are estimated through Markov Chain Monte Carlo (MCMC) sampling of the distribution in the vicinity of the MAP estimate. Experiments on real and synthetic data show that the uncertainty measures automatically detect when the delineating surface of the entire brain is unclear due to poor image quality or artifact; the experiments cover multiple appearance models to demonstrate the generality of the method. The approach is also general enough to accommodate a wide range of shape models and brain regions.