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

BACKGROUND: The benefits and harms of adding antileukotrienes to H1 antihistamines (AHs) 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 AHs versus AHs 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, US Food and Drug Administration, and European Medicines Agency databases from inception to December 18, 2023, for randomized controlled trials (RCTs) evaluating antileukotrienes and AHs versus AHs 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. The study was registered at the Open Science Framework (osf.io/h2bfx/). RESULTS: Thirty-four RCTs enrolled 3324 children and adults. Compared to AHs alone, the combination of a leukotriene receptor antagonist with AHs probably modestly reduces urticaria activity (mean difference, -5.04; 95% confidence interval, -6.36 to -3.71; 7-day urticaria activity score) with moderate certainty. We made similar findings for itch and wheal severity as well as 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 leukotriene receptor antagonists to AHs 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 leukotriene receptor antagonists is small and uncertain.

Topical corticosteroids for hives and itch (urticaria): Systematic review and Bayesian meta-analysis of randomized trials.

BACKGROUND: Topical corticosteroids are widely used as a treatment for itch and wheals (urticaria), but their benefits and harms are unclear. OBJECTIVE: To systematically synthesize the benefits and harms of topical corticosteroids for the treatment of urticaria. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from database inception to March 23, 2024, for randomized trials comparing topical corticosteroids with placebo for patients with urticaria (either chronic spontaneous or inducible urticaria or acute urticaria elicited from skin/intradermal allergy testing). Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects meta-analyses addressed urticaria severity, itch severity (numeric rating scale; range 0-10; higher is worse), and adverse events. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed certainty of evidence ratings. PROSPERO registration: CRD42023455182. RESULTS: A total of 19 randomized controlled trials enrolled 379 participants with a median of mean age of 30.1 (range 21.1-44.0) years. Compared with placebo, topical corticosteroids may reduce wheal size (ratio of means 0.47, 95% CI 0.38-0.59; low certainty) and itch severity (mean difference -1.30, 95% CI -5.07 to 2.46; very low certainty). Topical corticosteroids result in little to no difference in overall adverse events (94 fewer patients per 1000, 95% credible intervals 172 fewer to 12 more; high certainty). CONCLUSION: Compared with placebo, topical corticosteroids may result in a reduction of wheal size and little to no difference in overall adverse events. Topical corticosteroids may reduce itch severity, but the evidence is very uncertain. Future large, randomized trials addressing the use of topical corticosteroids would further support optimal urticaria management.

Correlation between PainDETECT Questionnaire and Quantitative Sensory Testing for the Detection of Neuropathic Pain in Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that is often severely painful due to nociceptive mechanisms (i.e., stimulation of cutaneous nociceptors). However, patient-reported pain character suggests that neuropathy may also drive HS pain in a subset of patients. Quantitative sensory testing (QST) can help identify neuropathic pain by testing for heightened and paradoxical pain responses in patients, but it is less feasible for routine clinical use compared with brief questionnaires. We therefore tested the suitability of a standardized neuropathic questionnaire (PainDETECT; PD-Q) for use as a surrogate clinical measure by directly comparing it with QST-identified neuropathic pain in HS. METHODS: This observational, cross-sectional study included 22 adults with painful HS lesions who completed the PD-Q and underwent QST. A receiver operating characteristic curve was generated and Cohen's Kappa, sensitivity, and specificity were examined at three scoring thresholds. RESULTS: Of the 22 participants, 14 (64%) exhibited dynamic mechanical allodynia and/or paradoxical thermal sensations in QST, which are characteristically found in neuropathic pain. According to the PD-Q, 8 participants (36%) were unlikely, 8 (36%) were possible, and 6 (27%) were likely to have neuropathic pain. A PD-Q Score indicating possible or likely neuropathic pain (i.e., ≥13) demonstrated 82% agreement with QST-determined neuropathic pain (Cohen's Kappa = 0.61 [p = 0.004]; sensitivity = 86%; specificity = 75%). CONCLUSION: The PD-Q demonstrates moderate agreement with QST in screening for neuropathic pain in HS and may be a helpful clinical tool.

Comparing Clinical Outcomes of Steroid-Sparing Therapy With Rituximab Versus Rituximab Alone in Pemphigus.

BACKGROUND: Previous clinical trials have demonstrated that rituximab therapy combined with conventional steroid-sparing therapy (SST) has increased rates of disease control for mucous membrane pemphigoid compared with rituximab alone. However, limited data is available regarding the role of SST with rituximab therapy in pemphigus. OBJECTIVE: This study aimed to examine clinical outcomes in pemphigus patients treated with rituximab with SST versus without the addition of SST. METHODS: A retrospective chart review was performed for adult pemphigus patients in the Southeastern US at Emory between January 1, 2011, and December 31, 2021. Primary outcomes, including time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, and time to relapse after a rituximab cycle, were compared between patients on SST and patients without SST.  Results: Following rituximab therapy, there was no difference in time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, or time to relapse for patients with or without SST. LIMITATIONS: Our study is limited by its retrospective decline, setting at a single academic center, and inclusion of a high proportion of patients with moderate disease. CONCLUSIONS: The use of SST with rituximab dosing did not improve clinical outcomes related to time to remission, reduction in prednisone dosing, or relapse. These data provide further evidence for the use of rituximab in the majority of pemphigus patients without the need for SST. J Drugs Dermatol. 2024;23(3):e97-e99    doi:10.36849/JDD.7949e.

Childhood atopic dermatitis is associated with cognitive dysfunction: A National Health Interview Survey study from 2008 to 2018.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease in children and adults. Little is known regarding the association of childhood AD with cognitive dysfunction. OBJECTIVE: To evaluate the association of AD and cognitive dysfunction, including memory impairment, developmental delays and attention deficit (hyperactivity) disorder in US children (age <18 years). METHODS: Data was analyzed from the National Health Interview Survey 2008 to 2018, which used a multistage, clustered, cross-sectional design. RESULTS: The prevalences of cognitive dysfunction, such as memory impairment (0.87% vs 0.42%), developmental delays (6.96% vs 3.87%), and attention deficit (hyperactivity) disorder (10.78% vs 8.10%), were higher in children with vs without AD. In multivariable logistic regression models adjusting for age, sex, race, region, socioeconomic factors, allergic conditions, and mental health, childhood AD was associated with higher odds of memory impairment (adjusted odds ratio [95% confidence interval]: 1.84 [1.34-2.51]), developmental delays (1.54 [1.40-1.70]), and attention deficit (hyperactivity) disorder (1.31 [1.20-1.42]) compared with children without AD. Childhood atopic disease (defined as comorbid AD, asthma, allergic rhinitis, and food allergies) further increased the prevalence of developmental delays to 13.44% (2.10 [1.20-3.70]) in boys but not in girls. CONCLUSION: In a nationally representative sample of the US population, a statistically significant and positive association between childhood AD and atopic disease with cognitive dysfunction was identified (P < .001). Furthermore, a dimorphic relationship with developmental delays was identified between sexes.

TH2 sensitization in the skin-gut-brain axis: How early-life Th2-mediated inflammation may negatively perpetuate developmental and psychologic abnormalities.

We recently reported children with comorbid atopic dermatitis (AD), asthma, allergic rhinitis, and food allergies displaying a 2.7-fold increase in developmental delays.2 To this end, we hypothesize unregulated increases in T helper-2 (Th2)-driven inflammation, such as those seen in atopic diseases, can exert deleterious effects on the developing brain. Recognizing that available information is incomplete and that many potential associations are not firmly established, we speculate these effects underlie the association between Th2 sensitization and cognitive dysfunction in children. In this review, we explore the role of Th2 sensitization in the skin-gut-brain axis and explain how it can lead to reduced connectivity and transmission in the developing brain. With a focus on AD, we explore the association between Th2 sensitization and developmental abnormalities such as developmental delays, memory impairment, autism spectrum disorder (ASD), and epilepsy/seizures. As such, we review the available literature to examine the impact of increased IL-4 exposure in early life on the brain. We explore the possible association between Th2 sensitization and psychologic dysfunction such as attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, and suicidal ideation. We also examine the impact that increased exposure to glucocorticoids and neurotrophins in early life exerts on the developing brain. Last, we discuss future directions for the advancement of our knowledge as a scientific community including possible interventions to reduce developmental and psychologic aberrations in children.

The Effects of Surgery Type and Chemotherapy on Early-Stage Breast Cancer Patients' Quality of Life Over 2-Year Follow-up.

BACKGROUND: We examined the effects of surgery type and adjuvant chemotherapy on change in early-stage breast cancer patients' quality of life (QOL) over time. METHODS: A cohort of 549 patients (33.5% ductal carcinoma in situ, 66.5% stages I/IIA) were interviewed a mean 6.1 weeks (Time1), and 6.2 (Time2), 12.3 (Time3), and 24.4 (Time4) months following definitive breast-conserving surgery (BCS) or mastectomy. QOL was measured using the total Functional Assessment of Cancer Therapy-Breast (FACT-B). Adjusting for demographic, psychosocial, and clinical variables, multiple linear regression models estimated the associations between QOL and each of surgery type, chemotherapy, and their 2-way interaction at each interview. Adjusted generalized estimating equation (GEE) models tested Time1-Time4 change in QOL. RESULTS: At Time2, chemotherapy (P < .001) and BCS (P < .001) were independently associated with worse QOL in adjusted linear regression, and the adverse effect of chemotherapy was prominent among patients who received BCS compared with those who received mastectomy (P interaction = .031). In the GEE model, QOL significantly improved over time among patients who received BCS (P trend = .047), mastectomy (P trend = .024), and chemotherapy (P trend < .001), but not among patients who did not receive chemotherapy (P trend = .720). All patients completed adjuvant chemotherapy and radiation by Time3. Regardless of surgery type, patients receiving chemotherapy reported lower QOL following surgery, and QOL improved after completion of adjuvant treatment. CONCLUSIONS: Chemotherapy had a short-term negative impact on QOL after definitive surgical treatment regardless of surgery type. QOL rebounded after completion of adjuvant treatment.

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.

Quantitative Sensory Testing to Characterize Sensory Changes in Hidradenitis Suppurativa Skin Lesions.

Importance: Pain is the most impactful symptom in patients with hidradenitis suppurativa (HS). Characterization of sensory profiles may improve understanding of pain mechanisms in HS and facilitate identification of effective pain management strategies. Objective: To characterize somatosensory profiles in patients with HS at clinically affected and nonaffected sites compared with pain-free reference data. Design, Setting, and Participants: This cross-sectional study was conducted at the Emory University Dermatology Clinic. It was hypothesized (1) that patients with HS would demonstrate hypersensitivity to pain in HS lesions and (2) that some patients would have sensory profiles consistent with complex pain mechanisms. Therefore, adults with dermatologist-diagnosed HS and at least 1 painful HS lesion at the time of testing were enrolled between September 10, 2020, and March 21, 2022. Patients with other diagnoses contributing to pain or neuropathy were excluded. Data analysis was conducted between March and April 2022. Exposure: Quantitative sensory testing was performed on HS lesions and control skin according to a standardized protocol. Main Outcomes and Measures: Quantitative sensory testing outcomes included innocuous thermal and mechanical sensitivity (cold, warmth, and light touch detection thresholds), noxious thermal and mechanical sensitivity (cold, heat, pinprick, and deep pressure pain thresholds and suprathreshold pinprick sensitivity), temporal summation of pinprick, paradoxical thermal sensations, and dynamic mechanical allodynia (pain upon light stroking of the skin). Sensitivity in HS lesions was compared with sensitivity in a control location (the hand) and in pain-free controls using t tests. Results: This study included 20 participants with a median age of 35.5 (IQR, 30.0-46.5) years, the majority of whom were women (15 [75%]). In terms of race and ethnicity, 2 participants (10%) self-identified as Asian, 11 (55%) as Black, 6 (30%) as White, and 1 (5%) as more than 1 race or ethnicity. Compared with site-specific reference values from healthy, pain-free control participants, HS lesions were insensitive to innocuous cold and warmth, noxious heat, and light touch (t = -5.69, -10.20, -3.84, and 4.46, respectively; all P < .001). In contrast, HS lesions also demonstrated significant hypersensitivity to deep pressure pain (t = 8.36; P < .001) and cutaneous pinprick (t = 2.07; P = .046). Hypersensitivity to deep pressure pain was also observed in the control site (t = 5.85; P < .001). A subset of patients with HS displayed changes in pain processing that are often seen in neuropathic and nociplastic pain conditions, including hypersensitivity to repetitive pinprick (5 [26%]), paradoxical thermal sensations (3 [15%]), and pain upon light stroking of the skin (10 [50%]). Conclusions and Relevance: The findings of this cross-sectional study suggest that HS involves local changes in the skin or its free nerve endings, possibly leading to peripheral neuropathy and alterations in the transduction of innocuous and noxious thermal and mechanical stimuli. For some patients, central nervous system changes in somatosensory processing may also occur, but confirmatory evidence is needed. Better understanding of neuropathic and nociplastic mechanisms in HS pain could lead to individually tailored treatments.

Assessing Disease Outcome Measures in Bullous Pemphigoid on Standard-Of-Care Therapies.

Bullous pemphigoid (BP) is an autoimmune blistering disease resulting in pruritus and cutaneous blistering. Longitudinal studies characterizing the disease course of patients with BP on conventional therapy are lacking. We sought to characterize the changes in disease activity and pruritus of patients with BP on standard-of-care treatments. We conducted a retrospective cohort study on patients with BP on standard-of-care therapy. Generalized Estimating Equations were used to estimate the mean and standard errors for Bullous Pemphigoid Disease Activity Index (BPDAI) total activity score, BPDAI pruritus component score, and anti-BP180 autoantibody levels (BP180) over time. A total of 80 patients with BP showed consistent reductions in BPDAI total activity score and BPDAI pruritus component score, with a nadir at 4 months. BP180 decreased over time, with the largest reductions at 6 and 9 months. Median partial/complete remission was at 6.7 months, with relapses at a median time of 15.9 months. Receiving operating characteristic analysis determined an optimal BPDAI total activity score cutoff of 3.3 to discriminate partial/complete remission incidence (area under the curve = 0.895, sensitivity = 0.844, specificity = 0.78). In conclusion, in patients with BP on standard-of-care therapy, a natural course of BPDAI total activity score and BPDAI pruritus component score over time was comprehensively projected. BPDAI ≤ 3.3 was associated with partial/complete remission. These results provide reference data to guide future clinical trial design for BP.

Updates on diagnosis and management of autoimmune blistering diseases.

Over the last several decades, advances in the understanding of the pathogenesis of autoimmune blistering diseases has resulted in significant improvements in diagnosis and management. These improvements include new diagnostic assays and therapies targeted at specific disease mediators. Furthermore, the abundance of new therapies in clinic trials for autoimmune blistering diseases will translate to an enhanced therapeutic armamentarium for clinicians. The aim of this article is to review new developments in the understanding of autoimmune blistering diseases and to summarize advancements in their diagnosis and management.