Osteoporosis and bone health in pediatric patients with epidermolysis bullosa: A scoping review.

Nutritional compromise, low levels of vitamin D, chronic inflammation, abnormal growth, and physical inactivity affect bone metabolism and compromise long-term bone health in individuals with epidermolysis bullosa (EB). The result is a high risk for osteopenia, osteoporosis, and pathologic fractures, but this important consequence of EB has been the focus of few investigations. Our scoping review found 21 publications that assessed the current understanding and clinical practices for monitoring of osteoporosis and its treatment in EB. Recommendations summarized from 13 of these publications include early nutritional and weight assessments before 2 years of age; bloodwork every 6-12 months starting at birth; Tanner stage assessments every 6 months to detect any pubertal delay; DEXA scans starting at age 6 years with repeated scans every 1-2 years, except in mild cases; and vitamin D supplementation of 80-320 IU daily for children 0-7 years and 720 IU for patients >8 years.

Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies.

BACKGROUND: For people with atopic dermatitis (AD) refractory to topical therapies, treatment with phototherapy and systemic therapies can be considered. Multiple biologic therapies and Janus kinase (JAK)inhibitors have been approved since 2014 to treat AD. These guidelines update the 2014 recommendations for management of AD with phototherapy and systemic therapies. OBJECTIVE: To provide evidence-based recommendations on the use of phototherapy and systemic therapies for AD in adults. METHODS: A multidisciplinary workgroup conducted a systematic review and applied the GRADE approach for assessing the certainty of evidence and formulating and grading recommendations. RESULTS: The workgroup developed 11 recommendations on the management of AD in adults with phototherapy and systemic agents, including biologics, oral JAK inhibitors, and other immunomodulatory medications. LIMITATIONS: Most randomized controlled trials of phototherapy and systemic therapies for AD are of short duration with subsequent extension studies, limiting comparative long-term efficacy and safety conclusions. CONCLUSIONS: We make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib. We make conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids.

Executive summary: Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies.

BACKGROUND: The summarized guidelines update the 2014 recommendations for the management of AD with phototherapy and systemic therapies. METHODS: A multidisciplinary workgroup conducted a systematic review and applied the GRADE approach for assessing the certainty of the evidence and formulating and grading recommendations. RESULTS: The workgroup developed 11 recommendations on the management of AD in adults with phototherapy and systemic therapies, including biologics, oral Janus Kinase inhibitors, and other immunomodulatory medications. CONCLUSIONS: The evidence supported strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib and conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids.

Long-term Efficacy and Safety of Up to 108 Weeks of Ixekizumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis: The IXORA-PEDS Randomized Clinical Trial.

Importance: About 1% of children and adolescents worldwide are affected by plaque psoriasis. Objective: To evaluate the long-term efficacy and safety of ixekizumab for pediatric patients with moderate to severe psoriasis. Design, Setting, and Participants: This multicenter randomized clinical trial (IXORA-PEDS) evaluated pediatric patients with plaque psoriasis. Participants were aged 6 years to younger than 18 years; had moderate to severe psoriasis, which was defined as Psoriasis Area and Severity Index (PASI) of 12 or higher, static Physician's Global Assessment (sPGA) score of 3 or higher, and psoriasis-affected body surface area of 10% or greater at screening and baseline; were candidates for phototherapy or systemic therapy; or had psoriasis that was not adequately controlled by topical therapies. Data analysis, which followed the intention-to-treat principle, was conducted from May to October 2021. Interventions: Pediatric patients were randomized 2:1 to receive either a weight-based dose of ixekizumab every 4 weeks or placebo. After a 12-week placebo-controlled period, patients entered a 48-week, open-label ixekizumab maintenance period (weeks 12-60), followed by an extension period that lasted through 108 weeks. A substudy evaluated the randomized withdrawal of ixekizumab after week 60. Main Outcomes and Measures: Efficacy outcomes at week 108 included the percentage of patients achieving 75% (PASI 75), 90% (PASI 90), or 100% (PASI 100) improvement from baseline; an sPGA score of 0 or 1 or score of 0; and improvement of 4 points or higher from baseline in the Itch Numeric Rating Scale. Safety outcomes included assessments of adverse events (AEs), including treatment-emergent AEs, serious AEs, and AEs of special interest, as well as improvement from baseline in a range of challenging body areas. Missing data for categorical outcomes were imputed using modified nonresponder imputation. Results: A total of 171 patients (mean [SD] age, 13.5 [3.04] years; 99 female children [57.9%]) were randomized to either ixekizumab (n = 115) or placebo (n = 56). Of 166 patients who entered the maintenance period, 139 (83.7%) completed week 108 of the trial. Primary and gated secondary end points were sustained through week 108, with patients achieving PASI 75 (91.7% [n = 86]), PASI 90 (79.0% [n = 74]), PASI 100 (55.1% [n = 52]), sPGA 0 or 1 (78.3% [n = 74]), and sPGA 0 (52.4% [n = 49]). Fifty-five patients (78.5%) reported an Itch Numeric Rating Scale improvement of 4 points or higher. In patients who received ixekizumab, at week 108, clearance of nail psoriasis was reported in 68.1% (n = 28), clearance of palmoplantar psoriasis was reported in 90.0% (n = 10), clearance of scalp psoriasis was reported in 76.2% (n = 83), and clearance of genital psoriasis was reported in 87.5% (n = 24). There were no new safety findings during weeks 48 to 108 of the trial, including no new cases of inflammatory bowel disease or candida infection. Conclusions and Relevance: Results of this study showed improvements across patient-reported outcomes and objective measures of complete skin clearance of psoriasis among pediatric patients who received ixekizumab, and these response rates were sustained through week 108 of the trial. Safety of ixekizumab was consistent with previously reported findings in this population and the known safety profile of this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT03073200.

Optimizing topical management of atopic dermatitis.

OBJECTIVE: Provide a review of atopic dermatitis management, focusing on optimizing topical therapy, creating a stepwise approach for treatment plans, and providing guidance on when to start systemic therapy. DATA SOURCES: PubMed search of articles in the English language regarding atopic dermatitis in all ages. STUDY SELECTION: Articles on the subject matter were selected and reviewed. RESULTS: Topical corticosteroids are the first-line treatment for managing atopic dermatitis. Topical nonsteroidal agents, calcineurin inhibitors, crisaborole, and recently, ruxolitinib, which cause no cutaneous atrophy, are options for reducing the use of topical corticosteroids, including on sensitive sites. Emerging topical agents are in clinical trials. Proactive management, with continued application 2 to 3 times weekly of a midpotency topical corticosteroid or tacrolimus, may maintain control for clear (or almost clear) localized sites of dermatitis that rapidly recur when topical anti-inflammatory medication is stopped. If topical therapy alone cannot control disease and quality of life is impacted, reevaluation to confirm the diagnosis, manage comorbid conditions, address compliance and patient-specific concerns, and optimize topical therapy must be undertaken before deciding to advance to systemic medication. Dupilumab, an interleukin-4 receptor inhibitor, has become first-line systemic therapy given its efficacy and safety, allowing long-term treatment without laboratory monitoring. Other biologics and Janus kinase inhibitors are emerging as alternatives that could eliminate the need for immunosuppressants with their higher risks. CONCLUSION: Several options are now available for topical treatment. A stepwise approach is needed to consider alternative therapies and diagnoses before advancing to systemic treatment, but the safety of newer immunomodulators will lower the threshold for more aggressive intervention.

Management of Severe Atopic Dermatitis in Pediatric Patients.

Atopic dermatitis is a common, chronic inflammatory skin disorder, present in about 12% of children worldwide. Optimizing management of severe atopic dermatitis in pediatric patients is critical to reduce signs of inflammation, alleviate pruritus and sleep disturbance, minimize the development and/or impact of comorbidities, and improve the patient and caregiver's quality of life. Evaluating the longitudinal severity of pediatric atopic dermatitis is an important component of measuring therapeutic response and long-term management, and is different in clinical practice versus clinical trials. This article describes when and how to use different treatments for pediatric patients with severe atopic dermatitis, including topical medications, phototherapy, and systemic medical therapies (traditional immunosuppressants, biologics, and small molecule inhibitors). It also provides recommendations useful in clinical practice for nonpharmacologic interventions for pediatric patients with severe atopic dermatitis.

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.

Prevalence of Psoriasis in Children and Adolescents in the United States: A Claims-Based Analysis.

IMPORTANCE: While psoriasis (Ps) is mainly characterized as an adult disease, it can also develop during childhood. However, prevalence estimates of pediatric psoriasis in the United States (US) are lacking. OBJECTIVE: To assess the 2015 annual prevalence of Ps and moderate-to-severe Ps in pediatric individuals in the US. DESIGN: This is a retrospective study based on a large administrative insurance claims database in the US. SETTING: Data were extracted from the Truven Health Analytics MarketScan® Commercial Claims and Encounters database, which covers over 60 million individuals with employer-provided health insurance across the US. PARTICIPANTS: Over 4.3 million of individuals continuously enrolled in their healthcare plan in 2015 and under 18 years of age were included in the study. Intervention(s) for Clinical Trials or Exposure(s) for Observational Studies: Not applicable. Main Outcome(s) and Measure(s): Ps was defined based on medical claims with a diagnosis of Ps (ICD-9-CM: 696.1); moderate-to-severe Ps was defined based on medical or pharmacy claims for a systemic treatment (biologic, conventional systemic, or phototherapy) for Ps. Overall and age- and gender-stratified prevalence was estimated for both Ps and moderate-to-severe Ps. RESULTS: The prevalence of Ps was estimated at 128 cases per 100,000 individuals (95% CI: 124-131), that of moderate-to-severe Ps at 16 cases per 100,000 individuals (95% CI: 15-17) in 2015. For both Ps and moderate-to-severe Ps, prevalence estimates were numerically higher in females than in males (146 per 100,000 vs. 110 per 100,000 and 17 per 100,000 vs. 15 per 100,000) and increased with age, ranging from 30 per 100,000 in the 0-3 year old group to 205 per 100,000 in the 12-17 year old group. CONCLUSION AND RELEVANCE: This study provides robust estimates of the prevalence of pediatric Ps that can inform decisions pertaining to the management of pediatric patients with Ps. J Drugs Dermatol. 2018;17(2):187-194.

Pediatric psoriasis: Evolving perspectives.

BACKGROUND/OBJECTIVES: Childhood-onset psoriasis is a common skin disorder that has recently received increasing attention, particularly because of its significant medical, social, financial, and psychological burdens and its associated comorbidities. With limited data available and lack of standardized management guidelines for pediatric psoriasis, an expert panel desired to provide an updated critical overview and practical guidance for management of the affected population. METHODS: A panel of pediatric dermatologists with extensive experience in pediatric psoriasis defined and prioritized a core set of topics, performed an English-language literature review, prepared critical evaluations and presentations of topic areas, and carried out a consensus meeting and follow-up consensus manuscript. RESULTS: The summation of evolving perspectives in pediatric psoriasis includes epidemiology and natural history of the disease, precipitating factors and comorbidities, quality of life and burden of disease, clinical features and disease presentation, differential diagnosis, pathogenesis and treatment, including topical, photo, and systemic therapies. CONCLUSION: Pediatric psoriasis is an important immune-mediated inflammatory skin disease with potential for significant impact on affected individuals and their caregivers. Current state-of-the-art care is based primarily on experience and expert consensus, but pediatric data are accumulating and therapeutic options are rapidly evolving.

Phosphodiesterase 4 inhibitors.

Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety.

Safety of Systemic Agents for the Treatment of Pediatric Psoriasis.

Importance: Use of systemic therapies for moderate to severe psoriasis in children is increasing, but comparative data on their use and toxicities are limited. Objective: To assess patterns of use and relative risks of systemic agents for moderate to severe psoriasis in children. Design, Setting, and Participants: A retrospective review was conducted at 20 centers in North America and Europe, and included all consecutive children with moderate to severe psoriasis who used systemic medications or phototherapy for at least 3 months from December 1, 1990, to September 16, 2014. Main Outcomes and Measures: The minimal core data set included age, sex, severity of psoriasis, systemic interventions, monitoring, adverse events (AEs), and reason for discontinuation. Results: For 390 children (203 girls and 187 boys; mean [SD] age at diagnosis, 8.4 [3.7] years) with psoriasis who used 1 or more systemic medications, the mean interval between diagnosis and starting systemic therapy was 3.0 years. Methotrexate was used by 270 patients (69.2%), biologic agents (primarily etanercept) by 106 (27.2%), acitretin by 57 (14.6%), cyclosporine by 30 (7.7%), fumaric acid esters by 19 (4.9%), and more than 1 medication was used by 73 (18.7%). Of 270 children taking methotrexate, 130 (48.1%) reported 1 or more AEs associated with methotrexate, primarily gastrointestinal (67 [24.8%]). Folic acid 6 days per week (odds ratio, 0.16; 95% CI, 0.06-0.41; P < .001) or 7 days per week (OR, 0.21; 95% CI, 0.08-0.58; P = .003) protected against gastrointestinal AEs more than once-weekly folic acid, regardless of the total weekly dosage. Methotrexate-associated hepatic transaminase elevations were associated with obesity (35 of 270 patients [13.0%]), but a folic acid regimen was not. Injection site reactions occurred in 20 of 106 patients (18.9%) treated with tumor necrosis factor inhibitors, but did not lead to discontinuation of treatment. Having 1 or more AEs related to medication, gastrointestinal AE, laboratory abnormality, or AE leading to discontinuation of the drug was more likely with methotrexate than tumor necrosis factor inhibitors, but having 1 or more infections related to medication (predominantly upper airway) was less likely. Six patients developed a serious treatment-related AE (methotrexate, 3; fumaric acid esters, 2; and adalimumab, 1), but methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. No patient developed tuberculosis or a malignant neoplasm. Conclusions and Relevance: Medication-related AEs occur less often with tumor necrosis factor inhibitors than with methotrexate. Folic acid administration 6 or 7 times per week protected more against methotrexate-induced gastrointestinal AEs than did weekly administration. A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis.

When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council.

BACKGROUND: Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking. OBJECTIVE: To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient. METHODS: A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific literature review, referred to guidelines when available, and provided interpretation and expert opinion. RESULTS: We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy. LIMITATIONS: Our work is a consensus statement, not a systematic review. CONCLUSION: The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies.

Evaluation of Treatments for Pruritus in Epidermolysis Bullosa.

Pruritus is a common complication in patients with epidermolysis bullosa (EB). There is limited published data about the treatments that individuals with EB use for pruritus. The objective of the current study was to determine quantitatively which treatments individuals with EB have used for pruritus and to evaluate the perceived effectiveness of these treatments in pruritus relief. A questionnaire was developed to evaluate the treatments and therapies used for pruritus in patients of all ages and for all types of EB. Questions about bathing products, moisturizers, topical products, oral medications, dressings, and alternative therapies were included. A 5-point Likert scale (-2 = relieves itch a lot, -1 = relieves itch a little, 0 = no change, 1 = increases itch a little, 2 = increases itch a lot) was used to evaluate perceived effectiveness. Patients from seven North American EB centers were invited to participate. Greasy ointments (53.4%), lotions (45.2%), creams (40.4%), and oral hydroxyzine (39.0%) were the most frequently used treatments for pruritus. Treatments that were used frequently and perceived to be the most effective included creams (mean = -1.1), topical prescription corticosteroids (mean = -1.0), oils (mean = -0.9), oral hydroxyzine (mean = -0.9), topical diphenhydramine (mean = -0.9), and vaporizing rub (menthol, camphor, eucalyptus) (mean = -0.9). Systemic opioids (mean = 0.3), adherent bandages (mean = 0.3), and bleach baths (mean = 0.2) slightly increased pruritus. Randomized controlled trials of therapies will be necessary to develop evidence-based recommendations for control of pruritus in individuals with EB.

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.

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.

The yin and the yang of keratin amino acid substitutions and epidermolysis bullosa simplex.

Mutations that change the same amino acid can result in different clinical phenotypes. Through in silico modeling and keratin filament assessment of genetically engineered HaCaT cells, Natsuga et al., as reported in this issue, have demonstrated how changes in charge and structure of a replacement amino acid in keratin 14 can cause disease (KRT14pA413P, EB simplex) or no clinical effect (KRT14pA413T, polymorphism).

MAS063DP is effective monotherapy for mild to moderate atopic dermatitis in infants and children: a multicenter, randomized, vehicle-controlled study.

OBJECTIVE: To examine the efficacy and safety of MAS063DP (Atopiclair) cream in the management of mild to moderate atopic dermatitis in infants and children. STUDY DESIGN: One hundred forty-two patients aged 6 months to 12 years were administered MAS063DP (n = 72) or vehicle (n = 70) cream 3 times per day to affected areas and sites prone to develop atopic dermatitis. The primary endpoint for efficacy was the Investigator's Global Assessment at day 22. Secondary endpoints included Investigator's Global Assessment at other time-points, patient's/caregiver's assessment of pruritus, onset, duration of itch relief, Eczema Area and Severity Index, subject's/caregiver's assessment of global response, and need for rescue medication in the event of an atopic dermatitis flare. RESULTS: MAS063DP cream was statistically more effective (P < .0001) than vehicle cream for the primary endpoint and all secondary endpoints. Treatment discontinuation as a result of an adverse event occurred in 9.9% of patients using MAS063DP cream and 16% of patients using vehicle cream. CONCLUSION: MAS063DP cream is effective and safe as monotherapy for the treatment of symptoms of mild to moderate atopic dermatitis in infants and children.

Ganglioside GM3 promotes carcinoma cell proliferation via urokinase plasminogen activator-induced extracellular signal-regulated kinase-independent p70S6 kinase signaling.

Overexpression of NeuAcalpha2-3Galbeta1-4Glcbeta1-Cer (GM3), a major ganglioside of cutaneous tumor cell membranes, inhibits ligand-dependent and ligand-independent activation of the epidermal growth factor (EGF) receptor in normal and neoplastic epithelial cells. This leads to the suppression of Ras/extracellular signal-regulated kinase (ERK) activation and, in the presence of EGF or fibronectin, inhibits cell proliferation. However, some tumor cells show increased levels of GM3, and vaccines that target GM3 can inhibit the growth of neoplastic cells in vivo, especially melanomas. We report that in the presence of urokinase plasminogen activator (uPA), overexpression of GM3 paradoxically increases the proliferation of carcinoma cells by augmenting ERK-independent p70S6 kinase activation. Functional blockade of uPA receptor (uPAR) or inhibition of p70S6 kinase, but not inhibition of Ras/ERK signaling, suppresses this GM3-induced stimulation of cell proliferation. The ERK-independent activation of p70S6 kinase involves phosphorylation at threonine-389, threonine-421/serine-424, and serine-411 sites with intermediate phosphatidylinositol 3 kinase and protein kinase C-zeta activation. These studies implicate gangliosides as enhancers of uPAR-related signaling and suggest that the response to GM3 depends on the local concentration of uPA. Therapeutic modalities that target or supplement gangliosides may require concomitant treatment that suppresses EGFR or uPAR signaling, respectively, to control neoplastic cell proliferation.