Leukotriene receptor antagonists as add-on therapy to antihistamines for urticaria: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The benefits and harms of adding antileukotrienes to H1-antihistamines for the management of urticaria (hives, itch, and/or angioedema) remain unclear. OBJECTIVE: We sought to systematically synthesize the treatment outcomes of antileukotrienes in combination with H1-antihistamines versus H1-antihistamines alone for acute and chronic urticaria. METHODS: As part of updating American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters urticaria guidelines, we searched MEDLINE, Embase, CENTRAL, LILACS, WPRIM, IBECS, ICTRP, CBM, CNKI, VIP, Wanfang, FDA, and EMA databases from inception to December 18th, 2023 for randomized controlled trials (RCTs) evaluating antileukotrienes and H1-antihistamines versus H1-antihistamines alone in patients with urticaria. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random effects models pooled effect estimates for urticaria activity, itch, wheal, sleep, quality of life, and harms. The GRADE approach informed certainty of evidence ratings. Open Science Framework registration: https://osf.io/h2bfx/. RESULTS: Thirty-four RCTs enrolled 3,324 children and adults. Compared to H1-antihistamines alone, the combination of a leukotriene receptor antagonist (LTRA) with H1-antihistamines probably modestly reduces urticaria activity (mean difference: -5.04, 95%CI -6.36 to -3.71; 7-day Urticaria Activity Score) with moderate certainty. We made similar findings for itch and wheal severity, and quality of life. Adverse events were probably not different between groups (moderate certainty), however, no RCT reported on neuropsychiatric adverse events. CONCLUSION: Among patients with urticaria, adding LTRAs to H1-antihistamines probably modestly improves urticaria activity with little to no increase in overall adverse events. The added risk of neuropsychiatric adverse events in this population with LTRAs is small and uncertain.

Efficacy and Safety of Systemic Corticosteroids for Urticaria: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with and without mast cell-mediated angioedema), but their benefits and harms are unclear. OBJECTIVE: To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids. METHODS: We searched the MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023, for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We performed random-effects meta-analyses of urticaria activity, itch severity, and adverse events. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach. RESULTS: We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5%-64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR], 2.17, 95% confidence interval [CI]: 1.43-3.31; number needed to treat [NNT], 7; moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95% CI: 0.87-6.83; risk difference, 9%; NNT, 11; low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95% CI: 1.00-7.62; risk difference, 15%; number needed to harm, 9; moderate certainty). CONCLUSIONS: Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine responsiveness, but also likely increase adverse effects in approximately 15% more.

The Social and Home Environment: Impacts of Determinants of Health on Atopic Dermatitis, Pathways Toward Solutions, and Unique Considerations for Rural and Remote North American Indigenous Populations.

Disparities in environmental and social determinants of health (DOH) are associated with morbidity in atopic dermatitis (AD). The socioecological model (SEM) is a framework that can be applied to better understand how such DOH impacts patients with AD. We include a case scenario of a remote Indigenous patient reflective of real-world situations of living with AD and examine relevant impact, gaps in knowledge, and further research needs. This review highlights a variety of social and environmental exposures as important DOH which must be addressed to achieve optimal management in AD. The "rainbow model" is a modified framework to help illustrate how complex environmental and social forces impact both AD presentation and therapeutic success. However, practical applications and outcome metrics for health promotion are limited. An inter- and transdisciplinary approach is paramount to address the complex challenges associated with AD care, as well as multistakeholder approach integrating culturally-competent equitable health frameworks. This review underscores the importance of expanding the focus of AD management beyond basic science and clinical trials to recognize and address health disparities and to promote optimal health and well-being in patients with AD, and contributes a working approach to mapping the complex interventions and patient-oriented research needed using a focus on remote North American Indigenous patients affected by AD.

Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations.

BACKGROUND: Guidance addressing atopic dermatitis (AD) management, last issued in 2012 by the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force, requires updating as a result of new treatments and improved guideline and evidence synthesis methodology. OBJECTIVE: To produce evidence-based guidelines that support patients, clinicians, and other decision-makers in the optimal treatment of AD. METHODS: A multidisciplinary guideline panel consisting of patients and caregivers, AD experts (dermatology and allergy/immunology), primary care practitioners (family medicine, pediatrics, internal medicine), and allied health professionals (psychology, pharmacy, nursing) convened, prioritized equity, diversity, and inclusiveness, and implemented management strategies to minimize influence of conflicts of interest. The Evidence in Allergy Group supported guideline development by performing systematic evidence reviews, facilitating guideline processes, and holding focus groups with patient and family partners. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed rating the certainty of evidence and strength of recommendations. Evidence-to-decision frameworks, subjected to public comment, translated evidence to recommendations using trustworthy guideline principles. RESULTS: The panel agreed on 25 recommendations to gain and maintain control of AD for patients with mild, moderate, and severe AD. The eAppendix provides practical information and implementation considerations in 1-2 page patient-friendly handouts. CONCLUSION: These evidence-based recommendations address optimal use of (1) topical treatments (barrier moisturization devices, corticosteroids, calcineurin inhibitors, PDE4 inhibitors [crisaborole], topical JAK inhibitors, occlusive [wet wrap] therapy, adjunctive antimicrobials, application frequency, maintenance therapy), (2) dilute bleach baths, (3) dietary avoidance/elimination, (4) allergen immunotherapy, and (5) systemic treatments (biologics/monoclonal antibodies, small molecule immunosuppressants [cyclosporine, methotrexate, azathioprine, mycophenolate, JAK inhibitors], and systemic corticosteroids) and UV phototherapy (light therapy).

Topical treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD prescription topical treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT databases to September 5, 2022, for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using 7 groups-group 1 being most potent. This review is registered in the Open Science Framework (https://osf.io/q5m6s). RESULTS: The 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty evidence, pimecrolimus improved 6 of 7 outcomes-among the best for 2; high-dose tacrolimus (0.1%) improved 5-among the best for 2; low-dose tacrolimus (0.03%) improved 5-among the best for 1. With moderate- to high-certainty evidence, group 5 TCS improved 6-among the best for 3; group 4 TCS and delgocitinib improved 4-among the best for 2; ruxolitinib improved 4-among the best for 1; group 1 TCS improved 3-among the best for 2. These interventions did not increase harm. Crisaborole and difamilast were intermediately effective, but with uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus. CONCLUSIONS: For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.

Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

Measuring h-index and scholarly productivity in academic dermatology in Canada.

Promotion in academia heavily relies on research productivity. The h-index is a standardized metric used to quantify research productivity at the individual level. We evaluated factors associated with h -index in dermatology across select Canadian academic centers with special focus on sex and academic rank. Medical academic centers throughout Canada with dermatology training programs were included. For each faculty member, we extracted the following data from public sources: sex, graduate degree, academic rank, years since the Fellow of the Royal College of Physicians and Surgeons of Canada (FRCPC) certification or equivalent, recent Canadian Institutes of Health Research (CIHR) funding and H-index (based on Scopus author profile). Log-linear univariate and multivariate regression analyses were performed to evaluate the association between h-index and these factors. An ordinal logistic regression was performed to explore sex differences in academic ranking. Our results showed that out of 300 faculty members across Canada, 155 were females (51.67%) and 145 were male (48.33%). H-index was available for 279 dermatologists. The average h-index was 8.35 (SD 11.53) and the median was 4.00 (1st quartile = 2.00, 3rd quartile = 10.00). Higher h-index was associated with more years since dermatology certification, successive academic rank, graduate degree and recent CIHR funding, but not with sex. In conclusion, h-index was not associated with sex when controlling for potential confounders. These results could reflect recent demographic changes in the field with an increase in newly appointed female dermatologists. Longitudinal assessment of academic productivity in dermatology is needed to assess the impact of continued efforts to promote equal opportunities in the field.

Values and Preferences of Patients and Caregivers Regarding Treatment of Atopic Dermatitis (Eczema): A Systematic Review.

Importance: Patient values and preferences can inform atopic dermatitis (AD) care. Systematic summaries of evidence addressing patient values and preferences have not previously been available. Objective: To inform American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma and Immunology (ACAAI) Joint Task Force on Practice Parameters AD guideline development, patient and caregiver values and preferences in the management of AD were systematically synthesized. Evidence Review: Paired reviewers independently screened MEDLINE, Embase, PsycINFO, and CINAHL databases from inception until March 20, 2022, for studies of patients with AD or their caregivers, eliciting values and preferences about treatment, rated risk of bias, and extracted data. Thematic and inductive content analysis to qualitatively synthesize the findings was used. Patients, caregivers, and clinical experts provided triangulation. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research) informed rating of the quality of evidence. Findings: A total of 7780 studies were identified, of which 62 proved eligible (n = 19 442; median age across studies [range], 15 years [3-44]; 59% female participants). High certainty evidence showed that patients and caregivers preferred to start with nonmedical treatments and to step up therapy with increasing AD severity. Moderate certainty evidence showed that adverse effects from treatment were a substantial concern. Low certainty evidence showed that patients and caregivers preferred odorless treatments that are not visible and have a minimal effect on daily life. Patients valued treatments capable of relieving itching and burning skin and preferred to apply topical corticosteroids sparingly. Patients valued a strong patient-clinician relationship. Some studies presented varied perspectives and 18 were at high risk for industry sponsorship bias. Conclusions and Relevance: In the first systematic review to address patient values and preferences in management of AD to our knowledge, 6 key themes that may inform optimal clinical care, practice guidelines, and future research have been identified.

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms.

BACKGROUND: Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. OBJECTIVE: We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD. METHODS: As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence. RESULTS: Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT's effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings. CONCLUSIONS: SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD.

Dietary Elimination for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis.

BACKGROUND: The influence of diet on atopic dermatitis (AD) is complex, and the use of dietary elimination as a treatment has conflicting views. OBJECTIVE: To systematically review the benefits and harms of dietary elimination for the treatment of AD. METHODS: We searched MEDLINE, Embase, AMED, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to January 18, 2022, without language restrictions, for randomized controlled trials (RCTs) and observational studies comparing dietary elimination and no dietary elimination for the treatment of AD. We conducted random-effects meta-analyses of eczema outcomes. We used the grading of recommendations, assessment, development, and evaluation approach to assess certainty of evidence (CRD42021237953). RESULTS: Ten RCT (n = 599; baseline median of study mean age, 1.5 years; median of study mean SCOring Atopic Dermatitis index, 20.7, range, 3.5-37.6) were included in the meta-analysis. Compared with no dietary elimination, low-certainty evidence showed that dietary elimination may slightly improve eczema severity (50% with vs 41% without dietary elimination improved the SCOring Atopic Dermatitis index by a minimally important difference of 8.7 points, risk difference of 9% [95% CI, 0-17]), pruritus (daytime itch score [range, 0-3] mean difference, -0.21 [95% CI, -0.57 to 0.15]), and sleeplessness (sleeplessness score [range, 0-3] mean difference, -0.47 [95% CI, -0.80 to -0.13]). There were no credible subgroup differences based on elimination strategy (empiric vs guided by testing) or food-specific sensitization. Insufficient data addressed harms of elimination diets among included RCTs, although indirect evidence suggests that elimination diets may increase the risk for developing IgE-mediated food allergy. CONCLUSIONS: Dietary elimination may lead to a slight, potentially unimportant improvement in eczema severity, pruritus, and sleeplessness in patients with mild to moderate AD. This must be balanced against potential risks for indiscriminate elimination diets including developing IgE-mediated food allergy and withholding more effective treatment options for AD.

Bleach baths for atopic dermatitis: A systematic review and meta-analysis including unpublished data, Bayesian interpretation, and GRADE.

BACKGROUND: Bleach bathing is frequently recommended to treat atopic dermatitis (AD), but its efficacy and safety are uncertain. OBJECTIVE: To systematically synthesize randomized controlled trials (RCTs) addressing bleach baths for AD. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and GREAT from inception to December 29, 2021, for RCTs assigning patients with AD to bleach vs no bleach baths. Paired reviewers independently and in duplicate screened records, extracted data, and assessed risk of bias (Cochrane version 2) and GRADE quality of evidence. We obtained unpublished data, harmonized individual patient data and did Frequentist and Bayesian random-effects meta-analyses. RESULTS: There were 10 RCTs that enrolled 307 participants (median of mean age 7.2 years, Eczema Area Severity Index baseline mean of means 27.57 [median SD, 10.74]) for a median of 6 weeks (range, 4-10). We confirmed that other trials registered globally were terminated. Bleach baths probably improve AD severity (22% vs 32% improved Eczema Area Severity Index by 50% [ratio of means 0.78, 95% credible interval 0.59-0.99]; moderate certainty) and may slightly reduce skin Staphylococcal aureus colonization (risk ratio, 0.89 [95% confidence interval, 0.73-1.09]; low certainty). Adverse events, mostly dry skin and irritation, along with itch, patient-reported disease severity, sleep quality, quality of life, and risk of AD flares were not clearly different between groups and of low to very low certainty. CONCLUSION: In patients with moderate-to-severe AD, bleach baths probably improve clinician-reported severity by a relative 22%. One in 10 will likely improve severity by 50%. Changes in other patient-important outcomes are uncertain. These findings support optimal eczema care and the need for additional large clinical trials. TRIAL REGISTRATION: PROSPERO Identifier: CRD42021238486.

Atopic dermatitis and skin infections are a poorly documented crisis in Canada's Indigenous pediatric population: It's time to start the conversation.

Canadian Indigenous youth continue to face higher rates of health disparities than their non-Indigenous counterparts. In dermatology, this includes a high burden of atopic dermatitis, as well as secondary skin and soft tissue infections. Unfortunately, numerous barriers to treatment exist, including systemic and institutional racism, poverty, crowded housing conditions on reserves, access and cost of basic skin care regimens, and clean water access. As per the Truth and Reconciliation Commission, Canadian dermatologists have been called upon to train more First Nations, Metis, and Inuit physicians to ensure we are providing high-quality, anti-racist, culturally appropriate care to Indigenous peoples.

An atypical presentation of extensive centrofacial microcystic adnexal carcinoma responding to radiation: A case report and review of the literature.

Microcystic adnexal carcinoma is a rare cutaneous neoplasm believed to arise from pluripotent keratinocytes capable of adnexal differentiation. Due to its insidious growth and appearance, diagnosis is often delayed. A deep incisional or excisional biopsy for histopathology is the gold standard for diagnosis. Different treatment modalities have been described in the literature, including the Mohs micrographic surgery, standard excision, radiation, chemotherapy, and observation. Currently, Mohs remains the treatment of choice. We present a unique case of a 12-month history of an extensive progressive centrofacial cutaneous induration diagnosed as microcystic adnexal carcinoma in an 83-year-old female. Due to the extensive nature of the tumor, she received radiation therapy and continues to receive ongoing assessment with no evidence of clinical recurrence at 2-year post-treatment including negative scouting biopsies. To date, there is no consensus on the optimal treatment for microcystic adnexal carcinoma.

Molluscum-like papules as a presentation of early papulonecrotic tuberculid in association with nodular tuberculid in a male with asymptomatic active pulmonary tuberculosis.

BACKGROUND/OBJECTIVES: The clinical and histopathologic findings of a rare simultaneous occurrence of papulonecrotic tuberculid and nodular tuberclid in a patient with active but asymptomatic pulmonary tuberculosis are presented. Papulonecrotic tuberculid was observed at a very early stage, presenting as molluscum-like lesions. This has been described once in the literature. This was observed in conjunction with lesions compatible with the rare clinicopathologic variant of nodular tuberculid. Critical to the diagnosis of active pulmonary tuberculosis was the use of induced sputum testing, which confirmed the diagnosis despite the lack of a cough and a chest x-ray negative for active tuberculosis. METHODS/RESULTS: A 40-year-old male presented with a 2-week history of fever and a skin eruption consisting of molluscum-like papules on the ears, arms, and abdomen and nodules on his legs. Biopsies from both lesions were consistent with papulonecrotic and nodular tuberculid, respectively. Despite the lack of any respiratory symptoms, induced sputum grew Mycobacterium tuberculosis, and the lesions resolved on antituberculous therapy. CONCLUSIONS AND RELEVANCE: Tuberculids are rare in Western countries but must be considered in the differential diagnosis of eruptions in patients from endemic countries. An active tuberculous focus must be sought out.