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Chronic Spontaneous Urticaria

In silico Identification of Immune Cell-Types and Pathways Involved in Chronic Spontaneous Urticaria Connor Prosty

By Selected articles

Prosty C, Gabrielli S, Ben-Shoshan M, Le M, Giménez-Arnau AM, Litvinov IV, Lefrançois P, Netchiporouk E

Front Med (Lausanne). 2022 Jul 7;9:926753. doi: 10.3389/fmed.2022.926753. eCollection 2022.

Chronic spontaneous urticaria (CSU) is defined by the presence of wheals and/or angioedema that occur in the absence of specific external stimuli and persist for more than 6 weeks. Its immunopathogenesis is not yet fully understood, but there are new trends on dividing patients into auto allergic and autoimmune subtypes.

The aim of this study was to investigate immune cells and pathways of CSU through the reanalysis of available transcriptomic data.

Investigators obtained microarray data of CSU and healthy control skin and blood from the Gene Expression Omnibus. Differentially expressed genes were analyzed using ToppGene and KEGG and cell-type enrichment was determined by CIBERSORT and xCell and correlated with clinical characteristics.

Th2 (IL-4/13 signaling) and Th17-related (IL-17/23 signaling) patways were found to be upregulated in lesional samples. CIBERSORT analysis showed that non-lesional samples had increased regulatory T-cells and resting mast cells. The xCell analysis revealed no significant differences between samples, however, Th2 scores in both types of samples correlated positively with disease severity. There were few differentially expressed genes and pathways identified between CSU and healthy control blood samples.

These results revealed and supported the connection of Th2 and Th17-related genes and pathways in CSU. Th2 scores related to disease severity, where increased resting mast cell and Treg scores in non-lesional samples indicate local suppression of wheal formation. Furthermore, disease activity seemed to be restricted to the skin as there were limited findings from blood. More studies are needed to further support this information.

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Autoimmune chronic spontaneous urticaria

By Artículos seleccionados, Selected articles

Kolkhir P, Muñoz M, Asero R, Ferrer M, Kocatürk E, Metz M, Xiang YK, Maurer M

J Allergy Clin Immunol. 2022 Jun;149(6):1819-1831. doi: 10.1016/j.jaci.2022.04.010. PMID: 35667749.

Chronic spontaneous urticaria (CSU) symptoms include the recurrent spontaneous appearance of wheals and intense itch that may last from hours to days and occur for several years. Some patients develop localized and self-limiting angioedema. These manifestations result from a temporary increase in vascular permeability. Almost 13% of patients with CSU experience angioedema and do not develop wheals.

There are 2 main autoimmune mechanisms for CSU: type I autoimmune (autoallergic) CSU, which is associated with with IgE antibodies against autoantigens; and type IIb autoimmune CSU, which is mediated by autoantibodies that activate mast cells via IgE and FceRI. Type IIb autoimmune CSU is present in almost 10% of patients and is characterized by higher disease severity, concomitant autoimmune diseases, low levels of total IgE, elevated levels of IgG-anti–thyroid peroxidase, basopenia, eosinopenia, poor response to antihistamines and to omalizumab, and a good response to cyclosporine. Some new targeted therapies are under development, such as the anti-IgE, ligelizumab, and the Bruton’s tyrosine kinase inhibitors, fenebrutinib and remibrutinib, and an anti-IL-4Ra, dupilumab.

There are missing some studies on the overlap between autoallergic and type IIb autoimmune CSU and on the optimal management of both types of autoimmune CSU, with easy-to-perform, noninvasive and inexpensive markers to assess the treatment response.

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Autoimmune chronic spontaneous urticaria detection with IgG anti-TPO and total IgE

By Artículos seleccionados, Selected articles

Pavel Kolkhir, Elena Kovalkova, Anton Chernov, Inna Danilycheva, Karoline Krause, Merle Sauer, Andrey Shulzhenko, Daria Fomina, Marcus Maurer

J Allergy Clin Immunol Pract . 2021 Aug 4;S2213-2198(21)00884-9. doi: 10.1016/j.jaip.2021.07.043. Online ahead of print.

Common spontaneous urticaria (CSU) is a common skin condition driven by mast cells and characterized by the development of wheals, angioedema, or both for more than six weeks. Recently, studies have demonstrated the existence of two endotypes on the pathogenesis of CSU: type I (“autoallergic”) and type IIb autoimmune CSU.

Type IIb autoimmune CSU (aiCSU) is related to IgG, IgM, and IgA autoantibodies against the high affinity IgE receptor, FcɛRIα, activating skin mast cells. At least 8% of the CSU cases are aiCSU and represent a high disease burden (high disease activity, high rates of autoimmune comorbidity, and inadequate response to treatment). aiCSU can be challenging to diagnose because the existing tests (autologous serum skin test (ASST), autoantibody immunoassays, and basophil testing) are not usually available and have limitations. Also, aiCSU responds poorly to treatment.

This study aimed to evaluate how high anti-thyroid peroxidase (aTPO) and low IgE relate to aiCSU and treatment response.

A total of 1120 patient records were analyzed for demographic, clinical, laboratory parameters and treatment responses. Total IgE and aTPO were measured, and four markers were analyzed (ASST, basophil activation test (BAT), eosinophil, and basophil counts).

One of ten patients (n=123) had both high aTPO and low IgE, which was linked to higher age at CSU onset, female, angioedema, and shorter CSU duration. It was also related to positivity to aiCSU markers. A positive BAT was present in 44% of the patients with high aTPO and low IgE. These patients had low response rates to antihistamine treatment compared to the remaining patients.

In conclusion, a high aTPO and low IgE may constitute a valuable biomarker for diagnosing aiCSU in daily clinical practice.

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The Role of Coagulation and Complement Factors for Mast Cell Activation in the Pathogenesis of Chronic Spontaneous Urticaria

By Artículos seleccionados, Selected articles

Yuhki Yanase, Shunsuke Takahagi, Koichiro Ozawa y Michihiro Hide

Cells. 2021 Jul 12;10(7):1759. doi: 10.3390/cells10071759.

Chronic spontaneous urticaria is a skin condition characterized by skin edema and itchy flares for more than six weeks. Inflammatory mediators, such as histamine, are released from skin mast cells and/or peripheral basophils at the cell level. It is known that the extrinsic coagulation cascade triggered by tissue (TF) and complement factors is based on the pathogenesis of chronic spontaneous urticaria (CSU).

This review aimed to give a detailed role of vascular endothelial cells, leukocytes, extrinsic coagulation factors, and complement components on TF-induced activation of skin mast cells and peripheral basophils to form edema.

The extrinsic coagulation system triggered by TF and activated coagulation factors has been suggested in urticaria’s pathogenesis. Some studies have reported its improvement with heparin or warfarin treatment.

The detailed role of vascular endothelial cells in plasma leakage, especially at local areas of the skin in CSU is unclear. In vitro studies revealed that vascular endothelial cells might have a role in the early stage of CSU pathogenesis, as human umbilical vein endothelial cells and human dermal microvascular endothelial cells express a large amount of TF on their surface in response to the combination of several molecules such as histamine. TF-expressing leucocytes can generate the extrinsic coagulation cascade and produce activated coagulation factors, followed by the induction of intercellular gap formation of human umbilical vein endothelial cells. TF expression on monocytes may be utilized as a marker for pathological conditions of CSU and a therapeutic target of severe and refractory CSU. Studies have also shown that complement factors, such as C5a are increased in people with CSU.

Medications that target the activated coagulation factors and/or complement components may constitute a new and effective treatment for severe and refractory urticaria, namely low-molecular-weight antagonists of C5a and targets of the TF-triggered extrinsic coagulation pathway – complement system – mast cell and/or basophil activation axis.

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Positive effect of Helicobacter pylori treatment on outcome of patients with chronic spontaneous urticaria

By Artículos seleccionados, Selected articles

Mohammed Elhendawy, Maha Hagras, Shaimaa Soliman, Engi Seif Shaker

Am J Clin Pathol. 2020 Sep 17;aqaa134. doi: 10.1093/ajcp/aqaa134. Online ahead of print.

People with chronic urticaria have chronic hives, itching, and wheels that come and go for long periods. Chronic spontaneous urticaria represents 80 – 90 % of chronic urticaria cases, and the release of histamine and other inflammatory mediators from mast cells and basophils may be immunoglobulin E (IgE)–mediated or non-IgE-mediated. Helicobacter pylori is a gram-negative bacterium with a high prevalence worldwide, and that persistently colonizes the stomach. Its presence is associated with an increased risk of peptic ulcer and gastric cancer. The association between Helicobacter pylori and chronic spontaneous urticaria is controversial. This study’s objective was to assess the relationship between Helicobacter pylori eradication therapy and chronic spontaneous urticaria remission.

This was a randomized, double-blind, placebo-controlled pilot study that included 72 patients with urticaria. From these, 27 were positive for Helicobacter pylori stool antigen and PCR in gastric biopsy and were randomly assigned to receive anti-Helicobacter pylori treatment or placebo.

Participants with Helicobacter pylori had significantly lower hemoglobin concentrations with microcytic hypochromic anemia and a significantly higher occurrence of dyspepsia symptoms. All Helicobacter pylori patients (except 2) had significant improvement of the urticaria itching and red wheals after two weeks of therapy compared to placebo.

This study showed an association between chronic spontaneous urticaria and the presence of Helicobacter pylori in the gastric tissue. Patients with urticaria who do not respond to usual chronic urticaria treatment should be tested for Helicobacter pylori as therapy of Helicobacter pylori showed to improve the symptoms of chronic spontaneous urticaria.

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Urticaria Crónica Espontánea

Targeted Therapy for Chronic Spontaneous Urticaria: Rationale and Recent Progress

By Artículos seleccionados, Selected articles

Ana M. Giménez‑Arnau, Andaç Salman

Drugs . 2020 Aug 28. doi: 10.1007/s40265-020-01387-9. Online ahead of print.

Chronic spontaneous urticaria is characterized by wheals, angioedema, or both for at least 6 weeks and can last for a long time, up to 5 years. The effects of chronic spontaneous urticaria on quality of life are comparable to psoriasis, atopic dermatitis, or even ischemic heart disease.

Antihistamines continue to be the first choice for treatment of urticaria, however rates of response are low (ranging from 38.6% in standard doses to 63.2% in higher doses), some patients don’t experience a complete of symptoms. The use of omalizumab has shown a major advance in treating patients with chronic spontaneous urticaria, however, there is a subgroup of patients who have a partial or even lack of response to omalizumab.

Some of the upcoming targeted therapies for chronic spontaneous urticaria include:

  1. anti-IgE antibodies, such as ligelizumab, a monoclonal antibody directed against the Cε3 domain of IgE and which has shown a six- to ninefold greater potency in vivo compared to omalizumab; UB-221, another monoclonal antibody against IgE with up to eightfold greater affinity for free IgE, compared to omalizumab; quilizumab, a humanized monoclonal antibody directed against membrane-bound IgE.
  2. Anti-Siglec-8. Siglecs are a transmembrane family with regulatory effects on intercellular and intracellular signaling, with Siglec-8 having expression on eosinophils and mast cells.
  3. Bruton’s Tyrosine Kinase (BTK) inhibitors. BTK is a tyrosine kinase expressed in hematopoietic cells, including macrophages, mast cells and basophils. BTK inhibitors are used to treat different malignancies of B-cell origin. Ibrutinib, dasatinib, AVL-292 and CNX-774 effectively suppressed IgE-induced activation and histamine release from basophils and mast cells.
  4. Chemoattractant receptor-homologous molecule expresses on Th2 (CRTH2) inhibitors; Spleen Tyrosine Kinase (SYK) inhibitors; Anti-CD20; Anti-IL-1; Anti-IL-4/13; and Anti-IL-5.

The future treatment of chronic urticaria will probably change once potential new treatments are completely developed.

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Clinical Control of CSU with Antihistamines Allows for Tolerance of NSAID-Exacerbated Cutaneous Disease

By Selected articles

Jorge Sánchez

J Allergy Clin Immunol Pract . 2020 Jul 14;S2213-2198(20)30700-5. doi: 10.1016/j.jaip.2020.06.057. Online ahead of print.

A great number of patients with chronic spontaneous urticaria experience exacerbations after treatment with non-steroidal anti-inflammatory drug (NSAID). Although international guidelines suggest that people with urticaria avoid NSAIDs, this is sometimes difficult. Some case reports recommend that H1-antihistamines can help prevent these exacerbations.

The objective of this study was to evaluate if H1-antihistamines can help prevent NSAID-exacerbated reactions in people with chronic spontaneous urticaria.

This was a cross-over, multi-center, and ambispective study in 3 centers in Medellín, Colombia that included 121 participants with chronic spontaneous urticaria and a history of NSAIDs exacerbations. A diagnostic challenge test without the use of antihistamines and a challenge test using antihistamines were performed using the NSAID reported in the medical record. The order in which test were performed in each participant was determined by the investigator: participants with a positive first diagnostic challenge, were subject to a second challenge using H1-antihistamines, those with a negative first challenge using H1-antihistamines, were subject to a second one without the use of H1-antihistamines, and those with a negative first diagnostic challenge or a positive first challenge using H1-antihistamines, did not undergo a second challenge. Some patients were subject to an alternative NSAID before the diagnostic challenge test or the challenge test using H1-antihistamines.

The diagnostic challenge test retrieved 96 participants testing positive, with 75 % (72 participants) tolerating the NSAID involved in the reaction when they added H1-antihistamines.

In conclusion, although NSAID may represent some restrictions for people with chronic spontaneous urticaria, the use of H1-antihistamines can help control further urticaria exacerbations due to NSAID treatment.

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Characteristics and determinants of patient burden and needs in the treatment of chronic spontaneous urticaria

By Selected articles

Rachel Sommer, Neuza da Silva, Anna Langenbruch, Marcus Maurer, Petra Staubach-Renz, Matthias Augustin

Eur J Dermatol. 2020 Jun 1;30(3):259-266. doi: 10.1684/ejd.2020.3763

About 1 % of the population suffers from chronic spontaneous urticaria. The highest incidence is between 30 and 40 years of age, with women being most affected. The objective of this study was to characterise the specific needs and treatment objectives in chronic spontaneous urticaria from the view of the patient.

This was a cross-sectional study that included 103 participants from 4 German outpatient dermatology clinics. The validated Patient Needs Questionnaire (PNQ) for chronic spontaneous urticaria was used to determine patient needs and potential treatment objectives. To determine the relationship between patient needs and disease burden, different scales were used: disease-specific (CU-Q2oL), skin-generic (DLQI) and health generic (EQ VAS).

Most participants were female (71,4 %), with a mean age of 43,92 ± 14,96 years. The most important treatment objective was the absence of visible skin lesions (92,3 % considered important/ very important), then to be free of itching (91,5 %) and lately the desire to be healed of all skin defects (89,5 %). All other 26 items analysed, were considered to be quite important/ very important by, at least, 30 % of the participants. In relation to patient specific needs, this were related to gender and duration of disease.

In conclusion, these data show that people with chronic spontaneous urticaria have an individual broad range of needs, enabling specialists to adapt treatment to their needs. Innovative treatments may also help increase overall benefits. Independently of the treatment, the decision should be shared to help a better management of the condition.

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Effectiveness, safety and tolerability of Bilastine 20 mg versus Levocetirizine 5 mg for the treatment of chronic spontaneous urticaria: a double-blind, parallel group, randomized controlled trial

By Articles about Bilastine

Indrashis Podder, Anupam Das, Shouvik Ghosh, Debalina Biswas, Sujata Sengupta, Satyendra Nath Chowdhury

Dermatol Ther. 2020 Jul 2;e13946. doi: 10.1111/dth.13946. Online ahead of print.

Chronic urticaria is characterized by wheals with or without angioedema for, at least, 6 weeks. It is a debilitating condition that affects people’s quality of life. Bilastine is a novel non-sedative H1 antihistamine approved for symptomatic treatment of allergic rhinoconjunctivitis and urticaria in patients older than 12 years old.

The objective of this study was to compare the effectiveness, safety and tolerability of bilastine 20 mg with levocetirizine 5 mg in moderate-to-severe chronic spontaneous urticaria.

This was a double-blind, randomized, controlled study with two arms: bilastine 20 mg once daily (31 participants) and levocetirizine 5 mg once daily (27 participants) for 42 days. The severity of urticaria, global urticaria-induced discomfort and quality of life were evaluated with UAS7 (urticaria activity score), VAS (visual analogue scale) and DLQI (dermatology life quality index) at baseline and follow-up visits.

Primary objective was to assess the variation of the UAS7, and secondary objectives assessed changes in DLQI and VAS. Safety, tolerability and compliance were evaluated by analysis of drug-related adverse events, biochemical investigations and electrocardiogram.

Both bilastine and levocetirizine improved UAS7, DLQI and VAS at the end of treatment. Also, all parameters showed greater improvement with bilastine, but only the UAS7 revealed a significant reduction (p = 0,03). Sedation was also significantly less with bilastine (p = 0,04). Both treatments improved UAS7 and VAS significantly from day 14. No serious adverse effects were registered.

In conclusion, bilastine demonstrated a better efficacy and less sedation for chronic spontaneous urticaria when compared to levocetirizine, however similar effect on quality of life.

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Eosinopenia, in chronic spontaneous urticaria, is associated with high disease activity, autoimmunity and poor response to treatment

By Selected articles

Pavel Kolkhir, Martin K. Church, Sabine Altrichter, Per Stahl Skov, Tomasz Hawro, Stefan Frischbutter, Martin Metz, Marcus Maurer.

(2019) The Journal of Allergy and Clinical Immunology: In Practice

Chronic spontaneous urticaria is characterized by the degranulation of skin mast cells and the influx of basophils and eosinophils to affected skin sites. Blood basopenia has been linked to severe antihistamine-resistant urticaria and type IIb autoimmunity, whereas the role of eosinophils in chronic spontaneous urticaria is largely unknown.

This study analysed the prevalence, role and relevance of eosinopenia of 1613 patients with chronic spontaneous urticaria from two centres. Peripheral blood eosinophil and basophil counts were analysed, and patient files were screened for clinical characteristics, results of laboratory tests, the autologous serum skin test, the serum-induced basophil-histamine release assay, and response to second generation H1-antihistamines and omalizumab.

Ten percent of the patients analysed had eosinopenia. This was also associated with being female, high disease activity, autologous serum skin test and basophil-histamine release assay positivity, low total IgE and high levels of C-reative protein and IgG-anti-TPO. Non-responders to treatment had even lower eosinophils compared to responders. Blood eosinophil counts correlated with basophil counts and 81% of patients with undetectable eosinophils had basopenia.

Investigators concluded that the combination of eosinopenia and basopenia is a better predictor of non-response to sgAHs than eosinopenia alone and that eosinopenia in patients with chronic spontaneous urticaria is associated with type IIb autoimmunity, high disease activity and poor response to treatment. This makes eosinophils as excellent biomarkers for the management of people with chronic urticaria.

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Treatment of urticaria: a clinical and mechanistic approach

Treatment of urticaria: a clinical and mechanistic approach

By Selected articles

Kaplan AP.

Urticaria can be divided into three general subtypes. Acute urticaria is defined as urticaria of relatively short duration that can be as brief as a day or two or can last up to 6 weeks. “Physical urticarias or inducible urticarias” consist of cold urticaria, cholinergic urticaria, and dermatographism as the most common, plus solar urticaria, local heat urticaria, aquagenic urticaria, vibratory urticaria/angioedema, and delayed pressure urticaria. The third subtype is chronic spontaneous urticaria (CSU) where the urticaria is present for over a minimum of 6 weeks up to many years.

Antihistamines are effective in about 50% of patients with CSU by interacting with the H1 receptor rendering it unresponsive to histamines. Omalizumab is effective in 65–80% of antihistamine-resistant patients and acts by binding IgE, thereby eliminating IgE directed to an autoantigen, downregulating IgE receptors, so that antireceptor antibodies are blocked, and ultimately leading to unresponsiveness of cutaneous mast cells and basophils. The addition of omalizumab represents a major advance because of its efficacy, easy utility, and favourable side-effect profile. Cyclosporine inhibits not only T cells but also histamine release from basophils and mast cells, has a success rate of about 70%, and is recommended third-line with care directed to potential side effects affecting blood pressure and renal function.

In conclusion, the use of antihistamines in high dosage (at least four times a day) is effective in close to half the patients with chronic spontaneous urticaria. For antihistamine resistance, the use of omalizumab has revolutionized therapy of antihistamine-resistant cases because of its efficacy and excellent side-effect profile. If the response is insufficient, cyclosporine is the next choice. Patients should be monitored regarding any adverse effects on blood pressure or renal function. All these are far safer than extended use of corticosteroid.

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Spontaneous Urticaria

Immunological effects and potential mechanisms of action of autologous serum therapy in chronic spontaneous urticaria

By Selected articles

Yu L, Buttgereit T, Stahl Skov P, Schmetzer O, Scheffel J, Kocatürk E, Zawar V, Magerl M, Maurer M.

The findings of this study suggest that the immunological effects of autologous serum therapy include a reduction of IgE-anti-IL24 autoantibodies, which may contribute to the pathogenesis of spontaneous chronic urticaria (CSU).

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Bilastina y anticuerpos anti-

The real-life effectiveness and safety of omalizumab updosing in patients with chronic spontaneous urticaria

By Articles about Bilastine

Andac Salman and Elif Comert

(2019) Journal of Cutaneous Medicine and Surgery

A retrospective cohort study was conducted to investigate the effectiveness and safety of 450 mg of omalizumab in chronic spontaneous urticaria.

Omalizumab is a third-line treatment for chronic spontaneous urticaria, however there are not enough studies regarding its use in patients that are unresponsive to regular doses of omalizumab.

A total of 72 patients were included, according to their Urticaria Activity Score over 7 days and the Urticaria Control Test and divided in two groups. Group 1 (n=59) included those showing a complete response to omalizumab 300 mg and group 2 (n=13) included those who received at least 3 doses of omalizumab 450 mg between 2016 and 2018.

The mean Urticaria Activity Score over 7 days decreased from 18,6 to 5,1 and the mean Urticaria Control Test score increase from 8,6 to 12 in group 2 participants after a mean 4,3 courses of omalizumab 450 mg. Of all 13 participants from group 2, 6 of them had a complete response, and 3 a good disease control. Those whose response to treatment was lower had low baseline total IgE levels (<43 IU/mL).

In conclusion, this team demonstrated that higher doses of omalizumab are effective and safe in patients with chronic spontaneous urticaria that is unresponsive to omalizumab 300 mg. Also, they predict that lower baseline total IgE levels might be related to a nonresponse to omalizumab and the need for higher doses.

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Urticaria Espontánea Crónica

Tumor necrosis factor-alpha and Fas/Fas ligand signaling pathways in chronic spontaneous urticaria

By Selected articles
Grzanka R, Damasiewicz-Bodzek A, Kasperska-Zajac A.

Tumor necrosis factor-alpha (TNF-a) is a key inflammatory and apoptotic mediator in urticaria. However, its role is still unclear in the apoptosis-inducing pathways in chronic spontaneous urticaria.

A group of people with chronic spontaneous urticaria and healthy people had their circulating concentrations of TNF-a, soluble TNF-a receptor types 1 and 2 and soluble Fas and Fas Ligand measured using enzyme-linked immunosorbent assay.

TNF-a and soluble TNF-a receptor types 1 and 2 concentrations were significantly higher in people with moderate-to-severe chronic spontaneous urticaria than healthy people. No significant differences were found between people with mild urticaria and healthy people. There were no differences observed in Fas and Fas Ligand concentrations in all participants.

In conclusion, chronic spontaneous urticaria is associated with the activation of the TNF-a/receptors signalling pathway marked by increased circulating concentrations of TNF-a and soluble TNF-a receptor types 1 and 2. In contrast, the circulating soluble Fas/Fas Ligand system is not up-regulated in chronic urticaria and does not seem to be an useful marker for the disease.

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Estudio de bilastina en pacientes japoneses

Association of positive and negative autologous serum skin test responses with clinical features of chronic spontaneous urticaria in Asian patients: A systematic review and meta-analysis

By Selected articles

Niu XL, Zhu LL, Shi MH, Zhang YJ, Gao XH, Qi RQ.

Previous studies on the correlation between positive autologous serum skin test (ASST) responses and the clinical features of patients with chronic spontaneous urticaria (CSU) have provided conflicting results. To evaluate the significance of ASST responses in CSU, a variety of databases were searched from inception to March 2018 to identify relevant studies on CSU.

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