Itch: Epidemiology, clinical presentation, and diagnostic workup.

Itch, or pruritus, is the uncomfortable sensation underlying the desire to scratch. Itch is a very common complaint in the general population that can result from dermatologic, systemic (eg, renal, hepatobiliary, endocrine), paraneoplastic, neuropathic, and psychogenic etiologies. Chronic itch is associated with significant sleep disturbances and profoundly reduces overall quality of life. Certain populations, including elderly and African Americans, are at increased risk of experiencing heightened burden of itch. Because of the variable clinical presentation and wide-ranging etiologies, itch presents a challenge for clinicians. The initial evaluation should include a complete blood count, with differential, hepatic, renal, and thyroid function testing along with diabetes screening. Further testing should be guided by history and physical examination findings. There should be a heightened concern for underlying malignancy in individuals older than 60 years of age who have a history of liver disease and diffuse itch less than 12 months of duration. For individuals with chronic pruritus of unknown origin, increased blood eosinophils may serve as a biomarker of T helper cell type 2 polarization and response to immunomodulator therapies. In this first part of a 2-part continuing medical education series, we describe the broader epidemiology and specific conditions associated with itch and the clinical presentation and diagnostic workup for patients with itch.

Itch: Pathogenesis and treatment.

Itch pathogenesis is broadly characterized into histaminergic and nonhistaminergic pathways and transmitted via 2 main receptor families: G protein-coupled receptors and transient receptor potential channels. In the skin, itch is primarily transmitted by unmyelinated type C and thinly myelinated type Aδ nerve fibers. Crosstalk between the immune and neural systems modulates itch transmission at the skin, spinal cord, and brain. Among the many known pruritogens, Th2 cytokines, such as interleukin-4, interleukin-13, interleukin-31, and thymic stromal lymphopoietin, are particularly important mediators that signal through shared Janus kinase pathways, representing novel targets for novel itch therapeutics. Emerging evidence has also revealed that the opioidergic system is a potent modulator of itch transmission, with increased µ-opioid activity and decreased κ-opioid activity contributing to itch pathogenesis. Optimal management of itch requires that treatment approaches be tailored to specific etiologic itch subtypes. When the etiology is unknown and patients are given a diagnosis of chronic pruritus of unknown origin, treatment should be guided by the presence of Th2 polarization, often reflected by increased blood eosinophils. In the second article of this 2-part series, we outline our current understanding of itch pathogenesis and discuss available and emerging treatments for itch.

Real-world comorbidities of atopic dermatitis in the US adult ambulatory population.

BACKGROUND: Atopic dermatitis (AD) is a pruritic, inflammatory skin disease associated with various comorbidities. However, comprehensive analyses of real-world comorbidities in adult patients with AD are limited. OBJECTIVE: To characterize the real-world comorbidities associated with adult AD in an ambulatory population. METHODS: We queried the MarketScan Commercial Claims and Encounters database from January 1, 2017 to December 31, 2017. Multivariable logistic regressions were performed to compare comorbidities in adult patients with AD versus age- and sex-matched controls. RESULTS: A total of 39,779 patients with AD and 353,743 controls were identified. Increased odds of psychiatric conditions, including anxiety (odds ratio [OR] 1.44) and mood disorders (OR 1.31), were observed in patients with AD. Patients with AD had higher likelihoods of autoimmune diseases, including vitiligo (OR 4.44) and alopecia areata (OR 6.01). Adult AD was also associated with infections, including impetigo (OR 9.72), methicillin-resistant Staphylococcus aureus (OR 3.92), and cellulitis (OR 2.52). Patients with AD were more likely to have systemic conditions, including lymphoid/hematopoietic malignancy (OR 1.91), atherosclerosis (OR 1.69), and metabolic syndrome (OR 1.47). For all the above, P < .001. LIMITATIONS: Retrospective analysis of health care claims data. CONCLUSION: Adult AD is associated with various psychiatric and systemic comorbidities, emphasizing the systemic nature of AD and the need for the collaborative management of these patients.

Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels.

BACKGROUND: Pruritus is a common symptom that can significantly reduce quality of life through sleep disruption. OBJECTIVE: To examine features of disturbed sleep in patients with chronic pruritic dermatoses and test the hypothesis that systemic inflammation may serve as a biomarker for impaired sleep in these patients. METHODS: Cross-sectional analysis of the National Health and Nutrition Examination Survey investigating systemic inflammation using C-reactive protein (CRP) levels. Logistic regression was used to compare patients with and without sleep disturbances, adjusting for demographics (model 1) and medical comorbidities (model 2). RESULTS: Chronic pruritic dermatoses were associated with multiple sleep disturbances, including nighttime awakenings (model 1: odds ratio [OR], 1.646; 95% confidence interval [CI], 1.031-2.627; model 2: OR, 1.329; 95% CI, 0.888-1.989) and early morning awakening (model 1: OR, 1.669, 95% CI, 1.118-2.493; model 2: OR, 1.582; 95% CI, 1.008-2.481). Mean CRP levels were 52.8% higher among patients with pruritic dermatoses reporting trouble sleeping compared with those who did not (0.663 vs 0.434 mg/dL; P = .034). Trouble sleeping was also positively correlated with CRP levels (ß = 0.142, P = .025). LIMITATIONS: Potential recall bias among participants. CONCLUSIONS: In addition to confirming sleep disturbances with pruritic dermatoses, we found these disturbances are more likely to present with elevated CRP levels. Clinicians should consider the potential risk for sleep-related and cardiac comorbidities in patients diagnosed with itchy skin conditions.

Cerebellar transcranial magnetic stimulation in psychotic disorders: intermittent, continuous, and sham theta-burst stimulation on time perception and symptom severity.

Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms. Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive. Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons. Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029.

IL-31 Inhibition as a Therapeutic Approach for the Management of Chronic Pruritic Dermatoses.

Chronic pruritus is a debilitating symptom with limited treatment options. Identifying molecular targets underlying chronic pruritic dermatoses is essential for the development of novel, targeted therapies. IL-31 is an important mediator of itch by integrating dermatologic, neural, and immune systems. IL-31 helps induce and maintain chronic pruritus via both indirect stimulation of inflammatory cells and through direct neural sensitization. IL-31 is overexpressed in various chronic pruritic skin conditions, and exogenous IL-31 induces itch and scratching behavior. Studies have demonstrated that IL-31R and IL-31 antagonism significantly reduces itch in patients with atopic dermatitis and prurigo nodularis, two extremely pruritic skin conditions. Emerging evidence, including recent phase II clinical trials of IL-31R antagonists, demonstrates that IL-31 plays an important role in itch signaling. Additional studies are ongoing to evaluate IL-31R and IL-31 antagonism as treatments of chronic pruritus.

Auditory hallucinations across the psychosis spectrum: Evidence of dysconnectivity involving cerebellar and temporal lobe regions.

BACKGROUND: Auditory hallucinations (AH) are typically associated with schizophrenia (SZ), but they are also prevalent in bipolar disorder (BD). Despite the large body of research on the neural correlates of AH in SZ, the pathophysiology underlying AH remains unclear. Few studies have examined the neural substrates associated with propensity for AH in BD. Investigating AH across the psychosis spectrum has the potential to inform about the neural signature associated with the trait of AH, irrespective of psychiatric diagnosis. METHODS: We compared resting state functional magnetic resonance imaging data in psychosis patients with (n = 90 AH; 68 SZ, 22 BD) and without (n = 55 NAH; 16 SZ, 39 BD) lifetime AH. We performed region of interest (ROI)-to-ROI functional connectivity (FC) analysis using 91 cortical, 15 subcortical, and 26 cerebellar atlas-defined regions. The primary aim was to identify FC differences between patients with and without lifetime AH. We secondarily examined differences between AH and NAH within each diagnosis. RESULTS: Compared to the NAH group, patients with AH showed higher FC between cerebellum and frontal (left precentral gyrus), temporal [right middle temporal gyrus (MTG), left inferior temporal gyrus (ITG), left temporal fusiform gyrus)], parietal (bilateral superior parietal lobules), and subcortical (left accumbens, left palldium) brain areas. AH also showed lower FC between temporal lobe regions (between right ITG and right MTG and bilateral superior temporal gyri) relative to NAH. CONCLUSIONS: Our findings suggest that dysconnectivity involving the cerebellum and temporal lobe regions may be common neurofunctional elements associated with AH propensity across the psychosis spectrum. We also found dysconnectivity patterns that were unique to lifetime AH within SZ or bipolar psychosis, suggesting both common and distinct mechanisms underlying AH pathophysiology in these disorders.

Mouse models for actinic keratoses.

Actinic keratoses (AKs) represent a premalignant skin condition due to chronic sun damage that dramatically increases in prevalence in the aging population. Currently, animal models of AKs utilize photocarcinogenesis, chemical carcinogens, or targeted gene modulation, and each method possesses unique strengths and weaknesses. Models using photodamage most comprehensively describe methods for preferentially selecting AK lesions, while replicating the pathogenesis of AKs with greater fidelity than models utilizing other carcinogenic methods. The following review of current murine models of AKs will aid in the selection of mouse models appropriate for future in vivo studies to test the efficacy of novel therapeutic agents for the treatment of AKs.

Pathophysiology, diagnosis, and pharmacological treatment of prurigo nodularis.

Introduction: Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intensely pruritic, hyperkeratotic nodules distributed on the trunk and extensor surfaces of the extremities. PN has a profoundly negative impact on sleep and quality of life in patients with PN. There are currently no U.S. Food and Drug Administration-approved agents and patients are often recalcitrant to current therapies, highlighting the importance of further research into this severely debilitating condition. Areas covered: A PubMed search was conducted to find available literature on the pathophysiology and clinical management of PN. In this review article, we discuss the current understanding of the pathophysiology, recommended diagnostic approach, and treatment options available for PN. Expert opinion/commentary: PN is an extremely difficult condition to treat, because there is a lack of effective therapies available due to our limited understanding of its pathophysiology. Currently, available treatment options are often multimodal due to the intersection of neuroimmune etiologic factors in the pathogenesis of PN. Fortunately, as our knowledge of PN expands, novel treatments targeting specific molecular biomarkers of PN are emerging, providing hope to this long-suffering patient population.

Comorbidities Associated with Granuloma Annulare: A Cross-Sectional, Case-Control Study.

Background: Granuloma annulare (GA) is a cutaneous granulomatous disorder of unknown etiology. There are conflicting data on the association between GA and multiple systemic conditions. As a result, we aimed to clarify the reported associations between GA and systemic conditions. Methods: A retrospective, cross-sectional, case-control study was performed in which the medical records of biopsy-confirmed GA patients ≥18 years of age, who presented to the Johns Hopkins Hospital System between 1 January 2009 and 1 June 2019, were reviewed. GA patients were compared to controls matched for age, race, and sex. Results: After adjusting for confounders, GA patients (n = 82) had higher odds of concurrent type II diabetes (odds ratio (OR) = 5.27; 95% confidence interval (CI), 1.73-16.07; p < 0.01), non-migraine headache (OR = 8.70; 95% CI, 1.61-46.88; p = 0.01), and a positive smoking history (OR = 1.93; 95% CI, 1.10-3.38; p = 0.02) compared to controls (n = 164). Among GA patients, women were more likely to have ophthalmic conditions (p = 0.04), and men were more likely to have cardiovascular disease (p < 0.01) and type II diabetes (p = 0.05). No differences in systemic condition associations were observed among GA subtypes. Conclusions: Our results support the reported association between GA and type II diabetes. Furthermore, our findings indicate that GA may be associated with cigarette smoking and non-migraine headache disorders.

Aberrant cerebellar connectivity in bipolar disorder with psychosis.

BACKGROUND: The cerebellum, which modulates affect and cognition in addition to motor functions, may contribute substantially to the pathophysiology of mood and psychotic disorders, such as bipolar disorder. A growing literature points to cerebellar abnormalities in bipolar disorder. However, no studies have investigated the topographic representations of resting state cerebellar networks in bipolar disorder, specifically their functional connectivity to cerebral cortical networks. METHODS: Using a well-defined cerebral cortical parcellation scheme as functional connectivity seeds, we compared ten cerebellar resting state networks in 49 patients with bipolar disorder and a lifetime history of psychotic features and 55 healthy control participants matched for age, sex, and image signal-to-noise ratio. RESULTS: Patients with psychotic bipolar disorder showed reduced cerebro-cerebellar functional connectivity in somatomotor A, ventral attention, salience, and frontoparietal control A and B networks relative to healthy control participants. These findings were not significantly correlated with current symptoms. CONCLUSIONS: Patients with psychotic bipolar disorder showed evidence of cerebro-cerebellar dysconnectivity in selective networks. These disease-related changes were substantial and not explained by medication exposure or substance use. Therefore, they may be mechanistically relevant to the underlying susceptibility to mood dysregulation and psychosis. Cerebellar mechanisms deserve further exploration in psychiatric conditions, and this study's findings may have value in guiding future studies on pathophysiology and treatment of mood and psychotic disorders, in particular.