IgG food hypersensitivity: A potential hidden precipitant for chronic spontaneous urticaria

Background: While the link between foods and chronic spontaneous urticaria (CSU) is controversial, many immunological mechanisms have been proposed to establish a causal relationship. Objective: To explore the potential benefit of avoiding immunoglobulin G (IgG)-mediated food hypersensitivity as a triggering factor in a case with CSU. History: The patient is a 50-year-old woman who complained of CSU for 1 and half year, which responded partially and temporarily to antihistamine medications. Of interest, it started 6 months after she followed an oat-rich diet. Her Urticaria Activity Score 7 was 23 out of 40. Results: Specific immunoglobulin E responses to common food and inhalant allergens were negative. A food-specific IgG antibody test was conducted, and it was mainly elevated for chicken eggs, rye, sweet pepper, gluten, garlic, wheat, and pineapple. Avoiding these foods had a curative effect on the CSU over a 2-month period. Conclusion: To the best of our knowledge, this is the first case report of symptoms of CSU that resolved after identifying and avoiding food items with IgG antibodies. Furthermore, well-controlled studies are advocated to verify the potential role of IgG food hypersensitivity in the pathogenesis of CSU (AU)

Biopsy-proven kidney involvement in hypocomplementemic urticarial vasculitis.

BACKGROUND: Hypocomplementemic urticarial vasculitis (HUV) is a rare systemic vasculitis. We aimed to describe the kidney involvement of HUV in a multicenter national cohort with an extended follow-up. METHODS: All patients with HUV (international Schwartz criteria) with a biopsy-proven kidney involvement, identified through a survey of the French Vasculitis Study Group (FVSG), were included. A systematic literature review on kidney involvement of HUV was performed. RESULTS: Twelve patients were included, among whom 8 had positive anti-C1q antibodies. All presented with proteinuria, from mild to nephrotic, and 8 displayed acute kidney injury (AKI), requiring temporary haemodialysis in 2. Kidney biopsy showed membrano-proliferative glomerulonephritis (MPGN) in 8 patients, pauci-immune crescentic GN or necrotizing vasculitis in 3 patients (with a mild to severe interstitial inflammation), and an isolated interstitial nephritis in 1 patient. C1q deposits were observed in the glomeruli (n = 6), tubules (n = 4) or renal arterioles (n = 3) of 8 patients. All patients received corticosteroids, and 9 were also treated with immunosuppressants or apheresis. After a mean follow-up of 8.9 years, 6 patients had a preserved renal function, but 2 patients had developed stage 3-4 chronic kidney disease (CKD) and 4 patients had reached end-stage kidney disease (ESKD), among whom 1 had received a kidney transplant. CONCLUSION: Renal involvement of HUV can be responsible for severe AKI, CKD and ESRD. It is not always associated with circulating anti-C1q antibodies. Kidney biopsy shows mostly MPGN or crescentic GN, with frequent C1q deposits in the glomeruli, tubules or arterioles.

Acquired Idiopathic Generalized Anhidrosis (AIGA) and Its Complications: Implications for AIGA as an Autoimmune Disease.

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.

Acetylcholine-induced whealing in cholinergic urticaria - What does it tell us?

BACKGROUND: Cholinergic urticaria (CholU) is characterized by the occurrence of itchy wheals induced by sweating. Intradermal injections of acetylcholine (ACh) have been proposed to help with diagnosing CholU and subgrouping of patients, but controlled studies are largely missing. OBJECTIVE: To compare the rates of positive ACh test results in well characterized CholU patients and controls and to identify clinical features of CholU linked to ACh reactivity. METHODS: Acetylcholine was injected intradermally into 38 CholU patients and 73 matched healthy controls. Wheal and flare skin responses were assessed after 15 and 30 min and correlated with clinical features of CholU. RESULTS: At 15 min after intradermal injections of ACh, wheal and flare responses were significantly more frequent in CholU patients than healthy controls, wheals: 34 % vs.15% (P = 0.028); flares: 50 % vs.18 % (P <0.001). Also, wheals were 37 % and flares 172 % larger and of longer duration in CholU patients than in healthy controls (both P < 0.01). CholU patients with ACh-induced wheals (ACh+) had larger flare but not wheal responses in response to histamine than those without (ACh-; P = 0.011). Also, ACh-induced wheal responses were significantly correlated with sweating (r = 0.54, P = 0.046) in CholU patients. Finally, wheal responses lasted longer in ACh+ than in ACh- patients (P = 0.03). CONCLUSION: Intradermal ACh testing does not allow for the identification of CholU patients due to its low sensitivity. ACh-induced wheals, in patients with CholU, is linked to sweating and longer lasting symptoms. Intradermal ACh testing is an interesting tool for mechanistic studies in CholU.

Advanced Biomarkers: Therapeutic and Diagnostic Targets in Urticaria.

Urticaria is a type of skin disease characterized by rapid onset of hives (superficial dermis edema, erythema, pruritus, or burning sensation). According to whether the natural course exceeds 6 weeks, urticaria can be divided into acute and chronic urticaria (CU). At present, the evaluation of CU activity mainly depends on the Urticaria Activity Score (UAS), but the evaluation indicators are relatively single, and we need more reliable experimental data for evaluation. We typically summarize advanced biomarkers and several related pathogenic pathways discovered in recent years on urticaria, including the cell adhesion/chemotaxis pathway, interleukin (IL)-6/Janus tyrosine kinase/STAT pathway, IL-17/IL-23 pathway, basophil- and mast cell-related pathway, coagulation/fibrinolysis-related pathways, single-nucleotide polymorphism, and some other pathways. This review aims to find appropriate biomarkers so that we can evaluate disease activity, discover novel therapeutic targets, and predict the patients' response more accurately to therapeutic agents.

CME suggestions for pediatricians, allergists, and dermatologists, directed by an online survey on urticaria knowledge

BACKGROUND: The Mexican Guidelines for the diagnosis and treatment of urticaria have been published. Just before their launch, physicians' knowledge was explored relating to key issues of the guidelines. OBJECTIVE: The aim of this study was to investigate the opinion of medical specialists concern­ing urticaria management. METHODS: A SurveyMonkey(R) survey was sent out to board-certified physicians of three medical specialties treating urticaria. Replies were analyzed per specialty against the evidence-based recommendations. RESULTS: Sixty-five allergists (ALLERG), 24 dermatologists (DERM), and 120 pediatricians (PED) sent their replies. As for diagnosis: ALERG 42% and PED 76% believe cutaneous mastocyto­sis, urticarial vasculitis, and hereditary angioedema are forms of urticaria, versus DERM 29% (P < 0.005). Most of the specialties find that the clinical history and physical examination are enough to diagnose acute urticaria, except DERM 45% (P < 0.01). DERM 45% believe laborato­ry-tests are necessary, as opposed to <15% ALLERG-PED (P < 0.005). However, PED 69% did not know that the most frequent cause of acute urticaria in children is infections, versus ALLERG- DERM 30% (P < 0.005). Many erroneously do laboratory testing in physical urticaria and ALLERG 51%, DERM 59%, and PED 37% do extensive laboratory testing in chronic spontaneous urticaria (CSU); many more PED 59% take Immunoglobulin G (IgG) against foods (P < 0.005). More than half of non-allergists do not know about autologous serum testing nor autoimmunity (P < 0.05). As for treatment, there were a few major gaps: when CSU was controlled, >75% prescribed antihistamines pro re nata, and > 85% gave first-generation antiH1 for insomnia. Finally, > 40% of DERM did not know that cyclosporine A, omalizumab, or other immunosuppressants could be used in recalcitrant cases. CONCLUSION: Specialty-specific continuous medical education might enhance urticaria management

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D-dimer concentrations in acute urticaria in children

INTRODUCTION: Urticaria is a clinical entity presenting as wheals, angioedema, or both simultaneously. Elevated D-dimer levels were reported in the course of chronic spontaneous urti-caria. Data regarding D-dimer levels in acute urticaria in children are limited. OBJECTIVES: To assess potential associations between duration of glucocorticosteroid (GCS) therapy and D-dimer concentrations in children with acute urticaria. Patients, materials, and methods: Hospital records of 106 children (59 females), aged 5.57 ± 4.91 years, hospitalized in 2014-2018 were analyzed retrospectively. The study group consisted of pediatric patients admitted to the hospital due to severe acute urticaria resistant to anti-histaminic treatment that was ordered in the ambulatory care (out-patient clinic). Patients were divided into subgroups: no GCS treatment, short-duration treatment (up to 5 days) and long-duration treatment (6 and more days) GCS treatment. Simultaneously, patients received antihistaminic drugs. D-dimer level and other inflammatory factors such as white blood cell (WBC) count, platelet (PLT) count, and C-reactive protein (CRP) in each group were analyzed. RESULTS: The D-dimer level was elevated in 51% of cases. In the subgroup with longer GCS treatment, D-dimer concentration was significantly higher in comparison to patients with a shorter GCS course. There were no differences in the distribution of CRP, PLT, and WBC concentrations between these subgroups. CONCLUSIONS: In the studied group of children, there was a tendency for higher D-dimer levels in patients, who required a longer GCS treatment. This finding is hypothesis-generating and requires further investigation to confirm if D-dimers can be used as a prognostic factor in acute urticaria in children

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Hereditary alpha-tryptasemia in 101 patients with mast cell activation-related symptomatology including anaphylaxis.

BACKGROUND: Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait characterized by multiple copies of the alpha-tryptase gene at the TPSAB1 locus. Previously described symptomatology involves multiple organ systems and anaphylaxis. The spectrum of mast cell activation symptoms is unknown, as is its association with specific genotypes. OBJECTIVE: To describe clinical, laboratory, and genetic characteristics of patients referred for the evaluation of mast cell activation-related symptoms and genotype-confirmed HαT. METHODS: We retrospectively describe clinical characteristics, baseline tryptase, and tryptase genotype in 101 patients. Patients were referred for mast cell activation-related symptoms and underwent genotyping to confirm diagnosis of HαT. RESULTS: Of 101 patients, 80% were female with average tryptase of 17.2 ng/mL. Tryptase was less than 11.4 ng/mL in 8.9% and greater than 20 ng/mL in 22.3% (range 6.2-51.3 ng/mL). KIT D816V mutation was negative in all subjects tested. 2α:3ß was the most common genotype but did not correlate with tryptase levels. Unprovoked anaphylaxis was noted in 57% of the subjects with heterogeneous genotypes. Most common symptoms include gastrointestinal, cutaneous, psychiatric, pulmonary, cardiovascular, and neurologic. A total of 85% of patients were taking H1- or H2-antihistamines with partial symptom relief. Omalizumab was effective at suppressing anaphylaxis or urticaria in 94% of the patients. CONCLUSION: HαT encompasses a broad range of baseline tryptase and should be considered in patients with symptoms of mast cell activation and tryptase levels greater than 6.2 ng/mL. Patients may present with complex symptomatology including cutaneous, gastrointestinal, neurologic, and psychiatric symptoms and anaphylaxis, some of which respond to omalizumab.

Correlations between disease activity, autoimmunity and biological parameters in patients with chronic spontaneous urticaria.

Summary: Background. Biomarkers of disease activity/severity and criteria of autoimmune chronic spontaneous urticaria (CSU) are still a matter of debate. Objective. To investigate possible correlations between clinical and biological markers and their associations with: 1) disease activity, 2) resistance to H1-antihistamines, 3) autoimmunity and 4) autologous serum skin test (ASST) in patients with CSU. To also analyze biological parameter modifications in patients with CSU treated with omalizumab. Materials and methods. Disease activity, H1-antihistamines response and presence of concomitant autoimmune disease were prospectively recorded in 95 patients with CSU. For 60 of them, ASST was performed. Broad biological analysis were performed. Results. C-reactive protein (CRP) serum levels were higher in H1-antihistamines unresponders (p less-than 0.0001) and in more active diseases (p = 0.033). D-dimer plasma levels were higher in H1-antihistamines unresponders (p = 0.008) and in patients with autoimmune status (concomitant autoimmune disease and/or with autoantibodies) (p = 0.016). Total immunoglobuline E (IgE) serum level was lower in patients with positive ASST. Blood basophil counts were lower in patients with CSU and especially in H1-antihistamines unresponders (p = 0.023), in patients with more active disease (p = 0.023), with positive ASST (p = 0.001), and with autoimmune status (p = 0.057). Conversely, under omalizumab, a decrease of CRP (p = 0.0038) and D-dimer serum/plasma levels (p = 0.0002) and an increase of blood basophil counts (p = 0.0023) and total IgE serum levels (p = 0.0007) were observed. Conclusions. This study brings additional evidences of interest to investigate IgE, D-dimer serum/plasma levels and basophil blood counts in patients with CSU as they could be correlated to disease activity, response to treatment and/or autoimmunity.

The Multiple Roles of Urocanic Acid in Health and Disease.

Trans-urocanic acid (trans-UCA) is synthesized in the skin, liver, and brain. It is a major natural moisturizing factor in skin and maintains its acid pH. In skin, it isomerizes to cis-UCA following exposure to UVR. Both isomers fulfill multiple roles in health and disease. Cis-UCA has immunomodulatory properties linked with several cutaneous diseases such as skin cancer, atopic dermatitis, and urticaria and associates with systemic diseases including multiple sclerosis. The levels of UCA in the skin, brain, urine, and feces reflect some physiological processes and may be disease biomarkers. Both isomers of UCA have therapeutic potential for a range of disorders.

Review of adverse cutaneous reactions of pharmacologic interventions for COVID-19: A guide for the dermatologist.

The new coronavirus, severe acute respiratory syndrome coronavirus 2, is associated with a wide variety of cutaneous manifestations. Although new skin manifestations caused by COVID-19 are continuously being described, other cutaneous entities should also be considered in the differential diagnosis, including adverse cutaneous reactions to drugs used in the treatment of COVID-19 infections. The aim of this review is to provide dermatologists with an overview of the cutaneous adverse effects associated with the most frequently prescribed drugs in patients with COVID-19. The skin reactions of antimalarials (chloroquine and hydroxychloroquine), antivirals (lopinavir/ritonavir, ribavirin with or without interferon, oseltamivir, remdesivir, favipiravir, and darunavir), and treatments for complications (imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine and low molecular weight heparins) are analyzed. Information regarding possible skin reactions, their frequency, management, and key points for differential diagnosis are presented.