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.

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 addressing comparing topical corticosteroid to 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: Nineteen RCTs enrolled 379 participants with a median of mean age of 30.1 years (range 21.1 to 44.0). Compared to placebo, topical corticosteroids may reduce wheal size (ratio of means 0.47, 95%CI 0.38 to 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%CrI 172 fewer to 12 more; high certainty). CONCLUSION: Compared to placebo, topical corticosteroids may result in a reduction of wheal size, and result in 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.

Assessment of a novel ophthalmology tele-triage system during the COVID-19 pandemic.

BACKGROUND: In response to the COVID-19 pandemic, a web-based tele-triage system was created to prioritize in-person clinic visits and ensure safety at the University of Illinois at Chicago Department of Ophthalmology and Visual Sciences during a statewide shelter-in-place order. The aim of this study is to evaluate the impact of the tele-triage system on urgent visit volume and explore the characteristics of acute visit requests at a tertiary referral eye center. METHODS: This retrospective study analyzed acute visit requests between April 6, 2020 and June 6, 2020. Descriptive statistics, chi-square tests, ANOVA, and bivariate logistic regression were used to compare variables with a p-value of 0.05. RESULTS: Three hundred fifty-eight surveys were completed. Mean age was 49.7 ± 18.8 years (range 2-91). The majority of requests were determined as urgent (63.0%) or emergent (0.8%). Forty-nine patients had recent eye trauma (13.7%), and the most common reported symptoms were new onset eye pain (25.7%) and photophobia (22.9%). Most patients were self-referred (63.7%), though provider referral was more common in patients with symptoms of new onset lid swelling (p < 0.01), diplopia (p < 0.01), flashing lights (p = 0.02), or droopy eyelid (p < 0.01). Patients presenting with symptom onset within 48 h tended to be younger (45.8 years) versus those with symptom duration of 48 h to 1 week (49.6 years), or more than 1 week (52.6 years; p < 0.01). CONCLUSION: This novel tele-triage system screened out one-third of acute visit requests as non-urgent, which limited in-person visits during the initial shelter-in-place period of the pandemic. Tele-triage systems should be implemented in eye care practices for future emergency preparedness.

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.

VISUALIZATION OF CHOROIDAL NEOVASCULARIZATION USING TWO COMMERCIALLY AVAILABLE SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY DEVICES.

PURPOSE: To compare the sensitivity of detection and the measured size of choroidal neovascularization (CNV) on two commercially available spectral domain optical coherence tomography angiography (OCTA) devices, the Optovue RTVue XR Avanti with AngioVue and the Zeiss Cirrus HD-OCT with AngioPlex. METHODS: Patients with CNV lesions were imaged consecutively on both OCTA devices on the same day of their visit. 3 × 3 mm and 6 × 6 mm scans centered at the fovea were obtained. Two independent masked readers evaluated the OCTA images for CNV identification and its area measurements. RESULTS: No significant differences were observed between the 2 OCTA devices in CNV area measurements on their 3 × 3 mm and 6 × 6 mm scans. However, there was suboptimal performance of their automated segmentation algorithms as compared to manually adjusted segmentation for visualizing CNV lesions. CONCLUSION: There was no significant difference in the size of the CNV lesion as measured on either commercially available spectral domain OCTA device. Both devices were comparable in their detection of CNV lesions on manual adjustment of segmentation lines. However, their automated segmentation algorithms need improvement to allow for accurate measurement of CNV lesions for routine clinical application.

Assessing object-recognition memory in rats: Pitfalls of the existent tasks and the advantages of a new test.

Studies of object-recognition memory in lab rats began in the late 1980s, using variants of the trial-unique delayed nonmatching-to-sample (DNMS) task. By the end of the 20th century, most investigators who wanted to study object-recognition in rodents had abandoned the DNMS task in favor of the novel-object-preference (NOP) test, mainly because the latter test is relatively easy to employ, whereas conventional DNMS tasks are not. Some concerns have been raised, however, about the internal validity of the NOP test as a method of measuring object-recognition abilities. We describe two experiments using a new DNMS procedure which requires considerably less training than the DNMS tasks of the 1980s and 1990s, and which cannot be subject to the same criticisms that have been leveled at the NOP test. In Experiment 1, rats were trained on the new modified-DNMS (mDNMS) task using short delays. Rats successfully learned the nonmatching rule in fewer than 25 trials, and they made accurate choices with retention intervals of up to 10 min. Experiment 2 examined a different group of rats' performance on the mDNMS task following long retention intervals (72 h, 3 weeks, and ~45 weeks). Rats made accurate choices on all retention intervals, even the longest retention interval of ~45 weeks. Overall, the findings demonstrate some benefits of an alternative approach to assess object-recognition memory in rats.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY TO DETECT MACULAR CAPILLARY ISCHEMIA IN PATIENTS WITH INNER RETINAL CHANGES AFTER RESOLVED DIABETIC MACULAR EDEMA.

PURPOSE: To compare foveal vascular anatomy between patients with and without disorganization of retinal inner layers (DRILs) after resolved diabetic macular edema using optical coherence tomography angiography (OCTA). METHODS: Twenty-four eyes of 21 age- and sex-matched patients with resolved diabetic macular edema were included in this retrospective, cross-sectional study. All eyes were imaged with enhanced high-definition line or cross-line structural B scans and 3 × 3-mm OCTA scans. Optical coherence tomography B scans were analyzed for the presence of DRIL, and based on this, eyes were classified as either DRIL present or DRIL absent. The foveal avascular zone area on OCTA was compared between patients with and without DRIL. The foveal avascular zone area was correlated with visual acuity. RESULTS: Nine eyes with DRIL and resolved diabetic macular edema were compared with 15 control eyes without DRIL and resolved diabetic macular edema. Area of ischemia on OCTA scans corresponded to the area of DRIL as determined on OCT B scans. The foveal avascular zone area in full retina as well as superficial and deep retinal plexuses OCTA slabs were significantly larger in patients with DRIL as compared to those without DRIL (P = 0.005, P < 0.001, and P = 0.004, respectively). The larger foveal avascular zone in full retinal segmentation (r = 0.72, P = 0.03) and superficial plexus (r = 0.74, P = 0.02) were positively correlated with lower visual acuity. CONCLUSION: Optical coherence tomography angiography can visualize retinal ischemia in patients with and without DRIL. Correspondence of impaired blood flow with DRIL suggests that retinal ischemia and loss of normal vasculature contributes to DRIL.

Optical Coherence Tomography Angiography in Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: Optical coherence tomography angiography (OCTA) has demonstrated good utility in qualitative analysis of retinal and choroidal vasculature and therefore may be relevant in the diagnostic and treatment efforts surrounding nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: Retrospective, cross-sectional study of 10 eyes of 9 patients with a previous or new diagnosis of NAION that received imaging with OCTA between November 2015 and February 2016. Two independent readers qualitatively analyzed the retinal peripapillary capillaries (RPC) and peripapillary choriocapillaris (PCC) for flow impairment. Findings were compared with automated visual field and structural optical coherence tomography (OCT) studies. RESULTS: Flow impairment seen on OCTA in the RPC corresponded to structural OCT deficits of the retinal nerve fiber layer (RNFL) and ganglion cell layer complex (GCC) in 80% and 100% of eyes, respectively, and to automated visual field deficits in 90% of eyes. Flow impairment seen on OCTA in the PCC corresponded to structural OCT deficits of the RNFL and GCC in 70% and 80% of eyes, respectively, and to visual field deficits in 60%-80% of eyes. CONCLUSIONS: OCTA can noninvasively visualize microvascular flow impairment in patients with NAION.

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.

Circadian time-place (or time-route) learning in rats with hippocampal lesions.

Circadian time-place learning (TPL) is the ability to remember both the place and biological time of day that a significant event occurred (e.g., food availability). This ability requires that a circadian clock provide phase information (a time tag) to cognitive systems involved in linking representations of an event with spatial reference memory. To date, it is unclear which neuronal substrates are critical in this process, but one candidate structure is the hippocampus (HPC). The HPC is essential for normal performance on tasks that require allocentric spatial memory and exhibits circadian rhythms of gene expression that are sensitive to meal timing. Using a novel TPL training procedure and enriched, multidimensional environment, we trained rats to locate a food reward that varied between two locations relative to time of day. After rats acquired the task, they received either HPC or SHAM lesions and were re-tested. Rats with HPC lesions were initially impaired on the task relative to SHAM rats, but re-attained high scores with continued testing. Probe tests revealed that the rats were not using an alternation strategy or relying on light-dark transitions to locate the food reward. We hypothesize that transient disruption and recovery reflect a switch from HPC-dependent allocentric navigation (learning places) to dorsal striatum-dependent egocentric spatial navigation (learning routes to a location). Whatever the navigation strategy, these results demonstrate that the HPC is not required for rats to find food in different locations using circadian phase as a discriminative cue.

Neurocutaneous disease: Neurocutaneous dysesthesias.

Dysesthesia is a generic term for a cutaneous symptom--such as pruritus, burning, tingling, stinging, anesthesia, hypoesthesia, tickling, crawling, cold sensation, or even pain--without a primary cutaneous condition in a well-defined location that is often caused by nerve trauma, impingement, or irritation. There are multiple types of dysesthesias depending on the body location and the nerves involved. While location, exact symptoms, and etiologies might vary, the underlying theme is that these conditions are of neurologic origin and have dermatologic consequences. For many of these conditions, the symptoms are localized to the skin, and patients frequently present to the dermatologist; it is important for dermatologists to be knowledgeable about these symptoms and their underlying causes. In part II of this continuing medical education review, the primary diagnoses associated with underlying cutaneous dysesthesias will be explored, including scalp dysesthesia, trigeminal trophic syndrome, meralgia paresthetica, notalgia paresthetica, and brachioradial pruritus. The typical demographics in terms of symptoms, location, and patient populations will be discussed in addition to the specific etiologies, workups, and possible treatment options.

CLINICAL TRIAL ENDPOINTS FOR OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To describe qualitative and quantitative optical coherence tomography (OCT) angiography (OCTA) parameters for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and their applicability as potential clinical trial endpoints. METHODS: A review of current literature related to the topic of OCTA and AMD. RESULTS: There are a number of promising OCTA parameters that can be used to diagnose the presence of CNV and to monitor the activity and progression of the lesion, pre- and post-treatment morphological characteristics, CNV dimensions, and automated quantitative parameters such as vessel density. CONCLUSION: The OCTA parameters described in this review have promise for the future development of clinical trial endpoints, but require further validation before they can be widely used.