Challenges in the diagnosis and treatment of chronic urticaria

Abstract

Introduction

Chronic urticaria (CU) is a multifactorial inflammatory skin disorder characterised by heterogeneous clinical manifestations, unclear aetiology, and significant diagnostic and therapeutic challenges.

Aim

The study aimed to identify the key problems that arise in the process of diagnosing and treating CU, as well as developing recommendations to improve the effectiveness of diagnostic and therapeutic approaches to this disease.

Methods

The study covered the analysis of the concepts of acute and CU/chronic urticaria, their features and causes. Methods of diagnosis of CU, including clinical history, physical examination, laboratory and other tests, were addressed, and the views of other authors and their shortcomings were analysed. Treatment methods such as antihistamines, corticosteroids, psychotherapy, physiotherapy and dietary recommendations were analysed, comparing the achievements of other researchers.

Results

The study established that the diagnosis of CU is complicated by the variability of clinical manifestations, the lack of specific biomarkers and difficulties in identifying triggers, and in most cases the cause of this disease remains unknown. The high prevalence of concomitant autoimmune disorders, together with the heterogeneous course of the disease, further complicates the diagnosis and selection of optimal therapy. The analysis of the main diagnostic methods demonstrated that a comprehensive approach, including clinical history, physical examination, laboratory tests, and provocative tests, is necessary to accurately establish the diagnosis.

Conclusions

In the treatment of CU, the insufficient effectiveness of standard anti-allergic drugs has been found in many cases, which requires the use of alternative methods, such as biologic therapy, immunomodulators, and others. Recommendations were made to improve diagnostic and treatment methods, including improving diagnostic methods, developing new biomarkers, and using modern laboratory technologies and digital platforms to improve communication between patients and doctors. Therapy involves the use of antihistamines with possible dose increases and the use of biological agents, with an emphasis on avoiding provocative factors and psychological support for patients to improve their quality of life.

Introduction

Chronic urticaria (CU) is a relevant issue due to its significant impact on the quality of life of patients. Persistent itching and rashes, which may appear without an apparent cause, lead to discomfort and anxiety, disturb sleep, and may contribute to depression. The problem with diagnosis is that most cases are idiopathic, meaning that their cause remains unknown. Treatment of CU remains challenging, as standard antihistamines – the mainstay of therapy – are not always effective. In many patients, symptoms persist or recur, requiring the use of more complex and expensive treatments, such as biologics.

According to the data presented by Gonçalo et al. [1], the prevalence of CU is approximately 1% of the global population, which represents a substantial disease burden worldwide. The study emphasises that young and middle-aged women suffer most from CU. In a study conducted among children and adolescents in Krakow, Poland, the lifetime prevalence of urticaria was 3.3%, affecting 2.1% of children and 1.1% of adolescents [2].

Recent research on urticaria focuses on its prevalence, mechanisms of development, pharmacological treatment and impact on quality of life. Important areas of research, as noted by Fu et al. [3], include chronic idiopathic urticaria, the presence of autoantibodies and histamine release processes. Autoimmune mechanisms underlying CU have been investigated by Greiner et al. [4], who focused on the role of autoantibodies targeting immunoglobulin E (IgE) and the high-affinity IgE receptor (FcεRI), leading to mast cell degranulation and urticarial eruptions.

Other studies have observed the dynamics of growth in the number of cases of this disease. Pu et al. [5] analysed the global, regional, and national burden of urticaria between 1990 and 2019. In 2019, an estimated 114 million prevalent cases of urticaria were reported worldwide, indicating a substantial and increasing global disease burden. The study also demonstrated temporal changes in incidence rates across regions, with notable demographic and geographic differences, including a higher burden among women.

The association between interleukin-33 (IL-33) gene polymorphism and CU was examined by Dobrican-Băruta et al. [6], who found that IL-33 genetic variability may influence susceptibility to CU through elevated serum IL-33 levels. Moos et al. [7] reported that cigarette smoking affects the immune profile of patients with urticaria by altering the neutrophil-to-lymphocyte ratio. Furthermore, Kolkhir et al. [8] demonstrated that chronic spontaneous urticaria (CSU) may persist for years and substantially impair patients’ quality of life due to its unpredictable course. Despite extensive research on urticaria and its subtypes, clinically focused studies addressing diagnostic and therapeutic challenges in CU remain limited, which provides the rationale for the present study.

Aim

The study aimed to identify the main difficulties encountered in the diagnosis and treatment of CU and to develop recommendations for improving the methods of diagnosis and therapy of this disease. To achieve this goal, the following objectives of the study were implemented, namely, to analyse the concept of acute urticaria and its difference from CU, to identify existing methods of diagnosis and treatment of this disease, and to provide recommendations for their improvement.

Theoretical overview

Urticaria is a common skin condition characterised by the appearance of transient wheals, often accompanied by angioedema. A characteristic feature of the disease is that these wheals usually disappear within 24 h without any residual marks. This disease can be acute or chronic and is the result of mast cell activation, which leads to the release of histamine and other inflammatory mediators that cause skin manifestations [9, 10]. Acute urticaria appears suddenly and lasts up to 6 weeks, after which the symptoms usually disappear without a trace. It often occurs in response to infectious factors, stress, medications or certain foods. CU lasts for more than 6 weeks and can persist for months or years, significantly impairing the quality of life of the patient. Distinguishing between these forms is essential for accurate diagnosis and appropriate treatment selection.

Acute urticaria is characterised by a sudden onset of pruritic wheals and/or angioedema lasting less than 6 weeks. It is most commonly triggered by infections and stress-related immune activation, while medications and dietary factors are less frequent causes. Diagnosis is based on clinical assessment of symptom onset, potential triggers, and lesion duration. In most cases, acute urticaria is self-limiting and resolves within days or weeks [11–13]. From a pathophysiological perspective, acute urticaria is mediated by mast cell activation and histamine release, resulting in transient wheals and pruritus [14–16]. Clinically, it is characterised by the rapid onset of wheals and/or erythema lasting less than 6 weeks. Acute urticaria is primarily managed with antihistamines, which remain the first-line treatment in most cases.

According to Ghaffari and Ghaffari [17], acute urticaria is defined as the rapid onset of wheals and erythema persisting for less than 6 weeks, affecting approximately 1–5% of the population, with antihistamines as the primary treatment. Minasi et al. [18] emphasise that acute urticaria in infants is uncommon due to immune system immaturity and may present with generalised wheals requiring careful differential diagnosis. Acute urticaria must be distinguished from anaphylaxis, as the latter is a life-threatening reaction requiring immediate epinephrine administration, despite shared clinical manifestations such as wheals and angioedema [19]. Infectious triggers, particularly in children, stress, medications such as antibiotics and non-steroidal anti-inflammatory drugs, and specific foods are recognised causes, whereas elevated body mass index and allergic rhinitis are identified as risk factors [20].

CU/CSU is a long-term condition in which itchy, raised red rashes or blisters appear on the skin for more than 6 weeks, often for no apparent reason. It can be associated with immune or autoimmune disorders and has a wave-like course. CSU occurs when a specific trigger cannot be identified. Up to 50% of CSU cases have an autoimmune mechanism, in which the body produces antibodies that attack its tissues, causing the release of histamine [21]. Mostmans et al. [22] determined that 4% of patients have an autoimmune subtype of CSU associated with low levels of IgE and high levels of antithyroperoxidase antibodies (anti-TPO). Pozderac et al. [23] noted chronic induced urticaria (CIU), which occurs due to physical or external stimuli (cold, heat, pressure, vibration, contact with water).

The pathogenesis of CU involves the activation of mast cells and basophils, which release histamine, leukotrienes, and cytokines, causing inflammation, oedema, and itching [24]. In some patients, the disease is autoimmune in nature, with the presence of autoantibodies to the IgE receptor or IgE itself, which affects the choice of therapy, in particular the use of omalizumab. Vitamin D deficiency can exacerbate the course of CU by affecting the immune response [25, 26]. CU affects up to 1% of the adult population, more often in women. It reduces the quality of life due to constant itching, rashes and sleep disturbances, and is accompanied by comorbid conditions, which complicates treatment [27]. Thyroid disorders, such as autoimmune thyroiditis or hypothyroidism, are observed in 30–45% of patients [28].

Clinical manifestations of CU include recurrent pruritic wheals and angioedema, the latter posing potential risks when mucosal involvement occurs [29]. In addition, CU is associated with a significant psychosocial burden, as patients frequently exhibit increased levels of anxiety and depression, which may influence disease severity and persistence [30].

To summarise, CU is a complex multifactorial disease, often of an autoimmune nature. Triggers include chronic infections, stress, and emotional distress. In many cases, the cause remains unknown, leading to a diagnosis of idiopathic CU. The disease requires an individualised approach to diagnosis and treatment to reduce symptoms and improve the patient’s quality of life.

Methods

The first stage of the study analysed and compared the concepts of acute and CU to determine their distinctive features and define the characteristics of each disease. The search for relevant literature was carried out to analyse the main approaches to the classification, aetiology and pathogenesis of these diseases. Scientific sources describing the pathophysiological mechanisms, causes and triggers of urticaria were reviewed. Since CU is a complex multifactorial pathology, the analysis of the root causes of the disease has become an important step in further development of approaches to diagnosis and treatment.

Several reputable databases were used to search for scientific sources, including PubMed, Scopus, Medline, Cochrane Library and Google Scholar. By employing specific keywords, such as “diagnosis of chronic urticaria”, “treatment approaches for chronic urticaria”, “immune mechanisms in chronic urticaria”, “biomarkers for urticaria diagnosis”, “second generation antihistamines”, “biologic therapy for urticaria”, “omalizumab for chronic urticaria treatment”, “psychotherapy and urticaria”, a maximum amount of relevant information was collected. In total, 150 scientific articles and publications potentially relevant to the research topic were identified and pre-selected.

The literature search focused on the most relevant studies and papers, published in the last 5 years to ensure the relevance of the data, but also included classic studies that have a significant impact on current practice. The criteria for inclusion in the analysis were as follows: original research studies related to CU; literature reviews and meta-analyses addressing diagnosis and treatment; studies published in English and Polish; papers containing information on diagnostic and treatment methods, with a focus on immunological/immune and autoimmune aspects.

In turn, the exclusion criteria were as follows: articles that do not provide data on clinical trials or are based only on theoretical models; papers that do not indicate the number of patients studied or lack details of methodology; studies published before 2010, if they do not contain key theoretical information or are not fundamental to understanding the topic; publications that have not been peer-reviewed or have a low concentration/level of scientific credibility. After applying the inclusion and exclusion criteria, the number of sources was reduced to 80. These sources were subject to a more detailed analysis, which included an assessment of methodological quality, statistical significance of the results and their relevance to the research objectives. During the detailed analysis, additional sources were rejected due to insufficient data quality or lack of relevance to the topic. In the end, 44 sources of literature that met the criteria of scientific significance and practical value were used.

The second stage was the study of methods for diagnosing CU. Particular attention was devoted to a comprehensive approach to diagnosis, which included a clinical history, physical examination and several laboratory tests, including a complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), thyroid function tests, allergy tests, autologous serum skin test (ASST), complement and antinuclear antibody (ANA) levels. Data confirming the effectiveness of each of the diagnostic methods were used, and so were the disadvantages and limitations of each of them. Particular attention was devoted to the autoimmune mechanisms of the disease and the importance of excluding other autoimmune diseases.

The third stage was the study of CU treatment methods. The effectiveness of various treatment approaches was analysed, including second-generation antihistamines, increasing their doses, adding leukotriene antagonists, short-term use of systemic corticosteroids (typically for several days up to 1–2 weeks), the use of biologics such as omalizumab, and immunosuppressive drugs such as cyclosporine. In addition to pharmacotherapy, attention was devoted to non-pharmacological approaches, such as trigger avoidance, psychotherapy and stress management, physiotherapy and dietary recommendations, as well as an analysis of the effectiveness and limitations of these treatments. The results of treatment and diagnostics were compared with the data of other researchers, which was used to identify the shortcomings of certain approaches and suggest ways to improve them.

Results and discussion

Challenges and difficulties in diagnosing CU Early diagnosis of CU is clinically important, as it ensures faster identification of the causes and triggers of the disease, which makes it possible to prescribe effective treatment and alleviate symptoms. A timely diagnosis helps reduce the frequency and intensity of exacerbations, which improves the patient’s overall quality of life.

CU is a dermatological disease characterised by prolonged itchy rashes (urticaria) and/or angioedema that persist for 6 weeks or more. The diagnosis of this condition is challenging due to several factors that hinder accurate aetiological identification. One of the key challenges in diagnosing CU is the variety of clinical manifestations, which may differ in shape, size, duration, and severity, making it difficult to distinguish them from other dermatological conditions such as atopic dermatitis, contact dermatitis, or autoimmune dermatoses [31, 32].

Another difficulty is determining the cause of CU. In many cases, even after a thorough examination, it is not possible to establish a clear trigger for the symptoms. This diagnostic uncertainty creates significant challenges for clinicians, as it requires numerous tests to rule out other possible causes, such as allergic reactions, autoimmune diseases or infections.

A further challenge is the high prevalence of concomitant autoimmune disorders among patients with CU. Patients with CU often have autoantibodies that affect the process of mast cell activation, which indicates a potential autoimmune component in the pathogenesis of the disease, requiring specific laboratory tests to confirm or exclude the autoimmune mechanism [33].

The lack of specific biomarkers to detect CU complicates the diagnosis. Most diagnostic procedures are based on the exclusion of other possible causes of symptoms. Doctors often rely on anamnesis, physical examination and laboratory tests to identify allergens or other triggers, but these methods do not always allow for an accurate determination of the cause of the disease, which leads to delays in diagnosis and selection of appropriate therapy [34–36].

This variability in disease course complicates both diagnosis and the selection of optimal therapy. As effective management of CU requires an individualised approach, diagnostic uncertainty may directly limit the effectiveness of standard therapeutic strategies. The choice of a therapeutic strategy depends on the correct diagnosis, as it is necessary to address possible comorbidities and the patient’s response to various drugs [37, 38]. Thus, the diagnosis of CU is a complex process that includes identifying clinical manifestations, excluding other possible causes, searching for autoimmune triggers, and assessing treatment response. The absence of clear biomarkers, the diversity of the disease course and a significant number of idiopathic cases make it difficult to establish an accurate diagnosis, which requires a comprehensive and multidisciplinary approach. The main existing diagnostic methods are presented in Table 1 [39–41].

Table 1.

Methods of diagnosing CU and their characteristics

Diagnostic method	Characteristics and purpose
Clinical history and physical examination	Assessment of the symptoms, duration and frequency of the rash, as well as the patient’s medical history, including triggers.
CBC	A laboratory test to assess general health and detect infections or anaemia, and assess inflammatory or allergic responses.
ESR	A test to detect inflammatory processes in the body.
CRP	An inflammatory marker whose elevated levels indicate an active inflammatory process.
Thyroid function testing	Determination of thyroid hormone levels to identify autoimmune diseases that may cause urticaria.
ASST	A test to detect autoantibodies that may be the cause of chronic autoimmune urticaria.
Allergy tests (skin prick tests, specific IgE)	Testing to identify sensitisation to specific allergens.
Determination of complement levels (C3, C4)	Assessment of the complement system to identify possible immune disorders.
ANA	A test to detect autoimmune diseases such as systemic lupus erythematosus.
Tests for infections (including Helicobacter pylori)	Tests to identify chronic infections that can cause urticaria.
Tests for physical urticaria	Conducting specific tests (cold, heat, pressure) to detect physical urticaria.
Skin biopsy	A skin sample analysis for histological examination to exclude urticarial vasculitis and other inflammatory dermatoses.

CBC – complete blood count, ESR – erythrocyte sedimentation rate, CRP – C-reactive protein, ASST – autologous serum skin test, ANA – antinuclear antibody. Source: compiled by the authors based on [39–41].

Clinical history and physical examination are fundamental to the diagnosis of CU. Gathering detailed information about the symptoms, their duration, and triggers, and examining the patient’s skin allows the doctor to assess the nature of the rash and identify possible causes. This excludes other dermatological conditions such as atopic dermatitis, contact dermatitis or vasculitis. A CBC is used to assess the patient’s general health and to identify signs of infection, anaemia, or eosinophilia that may indicate allergic or parasitic conditions and help exclude other causes of urticaria-like symptoms. The ESR and CRP are nonspecific markers of systemic inflammation, indicating underlying inflammatory or autoimmune processes that may require further evaluation.

Thyroid function testing is employed to identify thyroid disorders, including autoimmune diseases potentially linked to urticaria. Evaluation of thyroid hormone levels assists in excluding hypothyroidism or hyperthyroidism [42, 43]. The ASST is utilised to identify autoantibodies associated with chronic autoimmune urticaria and aids in distinguishing autoimmune CU from other disease variants. However, this approach may lack sensitivity in mild cases and relies on subjective interpretation, without identifying specific autoimmune triggers [44].

Allergy-related diagnostic methods, including SPT and specific IgE assessments, are employed to detect sensitisation to environmental or food allergens and to exclude an allergic origin of urticaria when results are negative [45]. Complement testing (C3, C4) and ANA assays are conducted to evaluate immune system involvement and to exclude immunocomplex disorders or systemic autoimmune diseases, including systemic lupus erythematosus. Furthermore, screening for chronic infections, such as Helicobacter pylori, may be warranted, as treatment of underlying infections can result in clinical improvement in selected patients [46].

Provocative testing is essential for identifying chronic inducible urticaria and involves controlled exposure to physical or environmental stimuli, such as cold, heat, or pressure, to reproduce symptoms and determine causal factors [47]. Although informative, these tests are labour-intensive and require careful monitoring due to the potential risk of inducing severe reactions. Skin biopsy is reserved for selected cases to exclude urticarial vasculitis or other inflammatory dermatoses and provides histological confirmation when the clinical presentation is atypical [48].

From a pathophysiological standpoint, chronic urticaria can be classified into autoimmune and non-autoimmune forms, a distinction that carries significant diagnostic and therapeutic consequences. Autoimmune chronic urticaria is characterised by the presence of functional autoantibodies targeting IgE or FcεRI, resulting in sustained mast cell activation and histamine release. This subtype is frequently associated with other autoimmune disorders and may respond inadequately to standard-dose antihistamines, often necessitating immunomodulatory or biologic therapies such as omalizumab or cyclosporine. Conversely, non-autoimmune CU lacks identifiable autoantibodies and is more commonly linked to non-specific triggers or remains idiopathic; in such cases, symptom control is typically achievable with antihistamines and trigger avoidance. Clear differentiation between autoimmune and non-autoimmune CU is therefore clinically relevant, as it informs diagnostic strategies, guides treatment escalation, and supports a more individualised therapeutic approach [8, 21].

Overall, the diagnostic evaluation of CU relies on a combination of targeted laboratory investigations and selected instrumental methods guided by clinical presentation. The absence of specific biomarkers, the high proportion of idiopathic cases, and the heterogeneity of disease manifestations – particularly across autoimmune and non-autoimmune forms – necessitate a comprehensive and individualised diagnostic approach to ensure accurate diagnosis and appropriate treatment selection.

Biomarkers, especially functional autoantibodies targeting IgE or FcεRI, have been suggested as potential instruments for distinguishing autoimmune chronic urticaria from non-autoimmune variants. The detection of such autoantibodies, for example, through the autologous serum skin test or more advanced immunological assays, supports the presence of an autoimmune mechanism and may be associated with reduced responsiveness to standard-dose antihistamines. However, variable sensitivity, a lack of standardisation, and restricted availability in routine practice continue to limit the clinical utility of these biomarkers. Therefore, while autoantibodies represent a promising adjunct in the diagnostic work-up of CU, they currently complement rather than replace clinical assessment and conventional diagnostic strategies. Overall, the absence of validated, standardised biomarkers remains a major unmet clinical need in chronic urticaria, particularly for reliable subtype differentiation and treatment stratification.

Main problems and difficulties in the treatment of CU

Treating CU is crucial to improving patients’ quality of life and preventing the development of serious complications. This disease is accompanied by a permanent or recurrent rash, itching and discomfort, which can significantly limit daily activities, cause sleep problems and affect emotional state. Effective treatment helps to control symptoms and reduce the frequency of exacerbations, which has a positive effect on the physical and mental state of patients.

With appropriate therapy selection, patients can maintain a good quality of life without constant fear of disease exacerbations, while reducing dependence on medications associated with adverse effects and minimising the risk of drug resistance. Timely and appropriate treatment of CU alleviates patients’ symptoms and reduces the burden on the healthcare system by decreasing the need for hospitalisation and emergency care.

The main difficulty in treating CU is determining its aetiology. In most cases, the cause remains unknown, and this condition is called CSU. Only a small percentage of patients can identify specific triggers, such as autoimmune processes, infections, or food allergens. This makes it difficult to choose an effective therapy, as the absence of a clear cause does not allow for targeted treatments. Instead, doctors are forced to use an empirical approach, which often takes a long time to find effective medicines [49].

Another major challenge is resistance to conventional treatment strategies. Antihistamines, which are commonly used to control symptoms, are the first line of therapy for CU. However, in a significant proportion of patients, they do not provide sufficient symptom control even with high doses, forcing doctors to look for alternative treatments such as immunomodulatory drugs and biologic therapies, but their efficacy and safety for long-term use have not yet been fully studied.

An important detail in the treatment of CU is its autoimmune nature in a certain percentage of patients. Some patients have autoantibodies to IgE or to IgE receptors on the surface of mast cells, which can cause uncontrolled histamine release; such autoimmune forms of CU are more difficult to treat with standard antihistamines, and therefore require the use of immunosuppressive or immunomodulatory drugs such as cyclosporine or omalizumab. The latter is a monoclonal antibody to IgE and is highly effective in treating patients with resistant disease, but its high cost and the need for long-term use limit its availability to a wide range of patients [50, 51].

An equally important aspect of treatment complications is the chronic nature of the disease and its impact on the psycho-emotional state of patients. CU is often accompanied by stress, depression, and anxiety disorders, which, in turn, can worsen the course of the disease and reduce the effectiveness of therapy. Given this, clinicians should account for psychosomatic aspects when treating such patients, and may involve psychologists or psychotherapists in the treatment process. Another important challenge is the need for long-term monitoring and adjustment of therapy. CU can spontaneously exacerbate or go into remission, requiring regular check-ups and review of prescribed medications, which puts an additional burden on the healthcare system and increases treatment costs. Many patients are forced to change therapy treatment due to side effects or insufficient treatment effectiveness, making disease control even more difficult. Table 2 shows the main treatments for CU [52–54].

Table 2.

Treatment methods for CU and their characteristics. Source: compiled by the authors based on [52–54]

Treatment method	Characteristics and purpose
Second-generation antihistamines	Medicines that block H1 histamine receptors, reduce the symptoms of urticaria without causing significant drowsiness.
Increasing the dose of antihistamines	Increase in the standard dose of antihistamines up to 4 times under medical supervision to achieve better symptom control.
Adding leukotriene antagonists	Drugs that block leukotrienes, reducing the inflammatory reaction in urticaria (e.g., montelukast).
Short-term use of systemic corticosteroids	Hormonal medications that quickly reduce inflammation and symptoms are prescribed for a short period due to side effects.
Omalizumab	Monoclonal antibody against IgE, used in CU resistant to antihistamines.
Cyclosporine	An immunosuppressant that suppresses the immune system is used in severe cases of urticaria under close medical supervision.
Avoiding known triggers	Identification and avoidance of urticaria triggers (e.g., certain foods, medications, physical factors).
Psychotherapy and stress management	Psychological support methods to reduce the impact of stress, which can worsen urticaria symptoms.
Physiotherapy (e.g., graduated exposure)	Methods of gradual exposure of the skin to physical factors to reduce sensitivity in physical urticaria.
Immunomodulators (e.g., dapsone, methotrexate)	Drugs that change the body’s immune response are used for resistant forms of urticaria.
Topical products (creams, ointments)	Topical medications to reduce itching and inflammation, often containing antihistamines or corticosteroids.
Dietary recommendations	Changes in diet, including the exclusion of foods that can provoke symptoms (pseudoallergens, histamine liberators).

Second-generation antihistamines are the first line of treatment for CU. They block histamine H1 receptors, which helps to reduce symptoms such as itching, swelling, and rashes. These drugs have fewer side effects, including drowsiness, than first-generation antihistamines, making them safer for long-term use. However, in some cases, standard doses may not be effective enough, especially in severe forms of the disease. Increasing the dose of antihistamines to up to four times the standard dose may be necessary if symptoms are not controlled with regular doses, using second-generation agents such as cetirizine, loratadine, or desloratadine, under medical supervision. Not all patients improve with dose increases, and some may remain resistant to therapy, requiring other approaches.

The addition of leukotriene antagonists, such as montelukast, may be useful in patients in whom antihistamines do not provide sufficient control; these drugs block leukotrienes involved in the inflammatory processes associated with urticaria. However, the efficacy of leukotriene antagonists may be limited, and they do not always provide significant symptom relief, especially in the autoimmune form of the disease.

Short-term use of systemic corticosteroids may be necessary for severe flare-ups of hives. Corticosteroids quickly reduce inflammation and symptoms, but because of the risk of serious side effects, they are only used for a short period. In the long term, corticosteroids are not safe, and symptoms may return after treatment is stopped. Omalizumab is a monoclonal antibody against IgE and is used in patients with CSU that is resistant to antihistamines [55]. It reduces the amount of free IgE, which leads to a decrease in the activation of mastocytes and basophils. Omalizumab has shown high efficacy but may not be effective in some patients.

Cyclosporine is an immunosuppressant that suppresses the activity of T-lymphocytes and reduces the release of inflammatory mediators. It is used in severe cases of urticaria that do not respond to other types of therapy. It is worth noting that cyclosporine has a significant risk of side effects, such as nephrotoxicity and hypertension, so its use is limited and requires careful monitoring [56, 57]. In some patients, the effect may be insufficient or unacceptable due to side effects. Avoidance of known triggers is an important component of treatment. Identification and avoidance of triggers (e.g., certain foods, medications, physical factors) can significantly improve the patient’s condition. It is not always possible to identify specific triggers, especially in CSU, which limits the effectiveness of this approach.

Psychotherapy and stress management can be helpful as stress can worsen urticaria symptoms. Relaxation techniques, cognitive behavioural therapy and other stress reduction methods can complement mainstream treatment, but they are usually not sufficient to control symptoms and have limited effectiveness in severe cases. Physiotherapy, such as graduated exposure to physical factors (cold, heat, pressure), can help reduce skin sensitivity in physical urticaria, which can reduce the frequency and severity of symptoms. This method is not suitable for all forms of urticaria and may not be effective in CSU. Immunomodulators, such as dapsone or methotrexate, are used in resistant forms of urticaria. They change the body’s immune response, which can lead to a reduction in symptoms. These medications have a risk of serious side effects and require careful monitoring, and their effectiveness can be variable, and not all patients respond to such treatment.

Topical treatments such as creams or ointments with antihistamines or corticosteroids can provide temporary relief from itching and inflammation. They are an adjunctive method and usually do not affect the underlying disease process. In severe cases, their effectiveness is limited, and they cannot guarantee sufficient symptom control. Dietary recommendations, including the exclusion of foods that may trigger symptoms (e.g., histamine liberators or pseudoallergens), may be helpful for some patients. In most cases of CU, diet has a limited impact, as food triggers cannot always be identified and not all patients respond to dietary changes.

The opinions of other researchers differ. Omalizumab, which is a monoclonal antibody against IgE, plays an important role in the treatment of patients who do not respond to antihistamines. This drug has proven to be highly effective for patients with CSU when other methods fail. Studies demonstrated that omalizumab reduces symptoms even with long-term use, which leads to a significant improvement in the quality of life of these patients [58]. Omalizumab is effective for patients with severe urticaria, however, its cost can be high, which limits accessibility for many patients. The use of omalizumab requires regular injections, which can be inconvenient, and there are side effects, including infections and injection reactions.

New biologic agents, including ligelizumab and dupilumab, have been the focus of growing research interest. Targeting specific inflammatory pathways and the body’s immune response, these drugs are seen as alternatives for patients who do not receive sufficient effect from omalizumab. The drugs target other inflammatory mechanisms, which makes them promising for further use in the treatment of CU [59]. The use of such drugs can be effective for patients who do not respond to other types of therapy, but their use is often accompanied by high costs and the need for specialised medical supervision, and they can cause side effects, including skin reactions and systemic infections.

When all other methods fail, immunomodulators such as cyclosporine can be used. They regulate the activity of the immune system and help control severe forms of urticaria. However, such drugs require special supervision due to the risk of side effects, which makes their use appropriate only in particularly severe cases [25]. Cyclosporine can be effective in patients with severe autoimmune urticaria, but its use is associated with a risk of nephrotoxicity, hypertension, and an increased risk of infections. Therefore, it is prescribed only in cases where other methods are not effective.

In addition to traditional medical approaches, there is a growing interest in the use of alternative methods such as acupuncture, dietary changes and gut microbiome normalisation. These methods can complement mainstream treatment and improve the overall health of patients, especially those who want to avoid long-term medication [60]. Alternative methods can be effective in reducing stress and improving patients’ quality of life, but scientific evidence for their effectiveness remains limited. Such approaches cannot always replace mainstream treatments, and their effectiveness depends on the individual patient.

Autologous serum therapy is another method that is effective in patients with chronic autoimmune urticaria. It involves administering the patient’s serum to regulate the immune response, an approach that is useful in cases where patients do not respond to other available treatments [44]. Autologous serum therapy can be effective for some patients with autoimmune disease, but the results can vary and are not always stable. The procedure requires regular injections, which can be inconvenient and may not meet patients’ expectations regarding the speed and duration of improvement. Thus, modern treatment of CU covers a wide range of methods, from traditional antihistamines to new biologic therapies and alternative approaches. This allows for more effective control of symptoms, even in complex and persistent cases, improving the quality of life of patients and making it possible to tailor therapy to each patient.

Recommendations for improving the diagnosis and treatment of CU

Improving the diagnosis of CU is a challenging task that requires a multidimensional approach, given the complexity of the pathophysiological mechanisms of this disease and the variety of its clinical manifestations. It is necessary to consider all aspects of the diagnostic process, from basic methods to the introduction of innovative technologies, to ensure accurate diagnosis.

According to the 2022 international guidelines developed by the European Academy of Allergy and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI), management of chronic urticaria should follow a stepwise approach, beginning with second-generation antihistamines and escalating to biologics or other advanced therapies based on disease control and patient response [9].

Existing diagnostic methods, such as the ASST, need to be improved. Standardisation of the procedure and interpretation of the results is critical. Developing protocols for determining serum concentration, injection site and depth, and criteria for evaluating the reaction will help reduce subjectivity and increase the diagnostic value of the test. Training staff in the correct technique of performing ASST and interpreting its results will help to more accurately detect autoimmune urticaria, even in mild cases. The introduction of more advanced laboratory methods is warranted. Determination of functional autoantibodies to FcεRI or IgE using techniques such as enzyme-linked immunosorbent assay (ELISA) or Western blot may allow more accurate identification of autoimmune mechanisms underlying CU. In addition to confirming the autoimmune nature of urticaria, these assays may help assess the activity of the autoimmune process, which is relevant for prognosis and therapeutic decision-making.

The development of new biomarkers for different forms of urticaria is a promising area. The use of highly sensitive methods, such as proteomics and genomics, can identify specific proteins or genetic variations associated with the disease. These approaches may be applied in the differential diagnosis of various urticaria subtypes and in monitoring treatment effectiveness. In particular, component-resolved diagnostics allows precise identification of allergen molecules a patient is sensitised to, which is especially important in cases of polysensitisation and cross-reactions. This approach will facilitate a more individualised approach to treatment, including the possibility of specific immunotherapy.

Optimisation of provocation tests is essential for the diagnosis of chronic-induced urticaria. The development of standardised protocols for cold, heat, pressure and other physical factors, considering patient safety, will help improve diagnostic accuracy. Modern technologies, such as digital temperature or pressure sensors, can be used to accurately control test conditions and objectively assess patient responses. A detailed history and physical examination can be improved by the introduction of standardised questionnaires and symptom scales, such as the Urticaria Activity Score (UAS) or the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL). This method will help not only to objectify the patient’s subjective feelings but also to assess the impact of the disease on quality of life, which is important for a comprehensive assessment of the patient’s condition and treatment effectiveness.

The use of digital technologies, such as mobile apps and online platforms, can significantly improve communication between patients and doctors. Patients can keep electronic diaries of symptoms, and note triggers and the effectiveness of medications, which will help to more accurately track the dynamics of the disease and timely correct therapy.

A joint approach to the diagnosis and treatment of CU is key. Collaboration between dermatologists, allergists, immunologists, endocrinologists, gastroenterologists and other specialists will help identify comorbidities that may cause or exacerbate urticaria, which is especially important in cases where standard treatment does not produce the expected result. The use of advanced imaging and diagnostic methods, such as dermatoscopy, skin ultrasound, and confocal laser scanning microscopy, can help identify morphological changes characteristic of urticarial vasculitis or other dermatoses. A skin biopsy with subsequent histological and immunohistochemical examination will confirm or exclude the presence of vasculitis, amyloidosis and other pathologies with similar clinical manifestations.

Educational activities for healthcare professionals are an integral part of improving diagnosis. Regular seminars, webinars, participation in conferences and the publication of clinical guidelines will help to disseminate up-to-date knowledge and approaches to the diagnosis and treatment of CU. Establishing specialised centres or counselling services can provide patients with access to highly qualified medical care. Supporting research in the field of CU is important to increase understanding of the pathogenesis of the disease. Studying the role of genetic factors, the immune system, neuropeptides, the microbiome and other aspects can open up new perspectives for diagnosis and therapy. Clinical trials of new medicines, such as biologics (e.g., omalizumab), can improve treatment outcomes for patients who are resistant to standard therapy. Providing patients with access to information about the disease, diagnostic and treatment options is an important component of successful disease management. Educational materials, support groups, and online resources can help patients better understand their disease, follow doctor recommendations, and actively participate in the treatment process.

Given the variety of treatments for CU and their specificities, a detailed and comprehensive action plan can be developed to improve the treatment of this disease. Treatment should begin with the administration of second-generation antihistamines in standard doses. They effectively block H1 histamine receptors, reducing symptoms of itching, swelling and rashes, and have minimal side effects, including no significant drowsiness. If the standard dose does not provide sufficient symptom control, it is advisable to gradually increase the dose up to four times under close medical supervision. This approach may increase treatment effectiveness without significantly increasing the risk of adverse reactions.

If increased doses of antihistamines do not give the desired result, the addition of leukotriene antagonists, such as montelukast, should be considered. These drugs reduce the inflammatory response by blocking leukotrienes and may be particularly useful in patients where leukotrienes are central in the pathogenesis of urticaria. However, the effectiveness of this method can be individual and not all patients will experience significant relief.

In severe exacerbations of CU that cannot be controlled with antihistamines and leukotriene antagonists, short-term therapy with systemic corticosteroids can be used. They quickly reduce inflammation and relieve symptoms, but due to the risk of serious side effects (such as hypertension, hyperglycaemia, and osteoporosis), they should be used only for a short period and under medical supervision.

If conventional treatments fail, especially in CSU, biologic medications should be considered. Omalizumab, an anti-IgE monoclonal antibody, reduces the amount of free IgE in the blood, which leads to a decrease in the activation of mastocytes and basophils. This can significantly reduce symptoms in patients who are resistant to antihistamines. However, the high cost of the drug and side effects, such as injection site reactions or an increased risk of infections, should be considered. For patients who do not get sufficient effect from omalizumab, new biologic drugs such as ligelizumab and dupilumab are promising. They target other components of the immune system and may be effective alternatives. The prescription of these drugs should be based on a thorough assessment of the patient’s condition, risks and benefits, and should consider the availability and cost of therapy.

In cases of severe and resistant CU, the use of immunomodulators such as cyclosporine may be considered. This drug suppresses the immune response by reducing the activity of T-lymphocytes and the release of inflammatory mediators. However, due to the high risk of side effects, including nephrotoxicity and hypertension, its use should be carried out under the careful supervision of a physician with experience in prescribing immunosuppressants, with regular monitoring of renal function and blood pressure. In parallel with pharmacotherapy, it is important to identify and avoid known risk factors for urticaria, which may necessitate a detailed history and allergy testing to identify potential triggers, such as certain foods, medications, or physical factors (e.g., cold, heat, pressure). Avoiding these factors can significantly reduce the frequency and intensity of symptoms. However, CSU triggers may be uncertain or multiple.

Stress management and psychological support are an integral part of comprehensive treatment. Stress is a known factor that can worsen urticaria. The use of relaxation techniques, participation in cognitive behavioural therapy and other psychological support methods can improve the patient’s overall condition, reduce the frequency of exacerbations and improve quality of life. Physiotherapeutic methods, such as graded exposure to physical factors, can be useful for patients with physical urticaria. Gradually increasing the exposure to the driving forces of physical stimuli can reduce skin sensitivity and decrease reactivity to these factors. This method should be carried out under the supervision of a specialist and be individually adapted to the patient’s needs.

Topical treatments, such as creams and ointments with antihistamines or corticosteroids, can be used to temporarily relieve itching and discomfort. They can be effective as an adjunctive treatment, especially in milder forms of urticaria, or as maintenance therapy. However, they do not affect systemic manifestations of the disease and do not replace systemic pharmacotherapy in severe forms. Dietary recommendations may include the exclusion of foods that act as histamine liberators or contain high levels of histamine, such as certain types of fish, cheeses, alcohol, and chocolate. Some patients may experience symptom relief after making dietary changes. A consultation with a nutritionist can help develop an individualised diet that accounts for the patient’s characteristics and ensures that they are receiving adequate nutrition.

Alternative therapies such as acupuncture, and normalisation of the gut microbiome with probiotics can be considered as complementary approaches. Although there is limited scientific evidence of their effectiveness, some patients report improvement with their use. It is necessary to discuss the possibility of using these methods with your doctor to avoid potential risks and to ensure that they are safely integrated into your overall treatment plan. Autologous serum therapy can be used in patients with autoimmune urticaria. The method involves injecting the patient with their serum, which can modulate the immune response and reduce symptoms. Although some studies show positive results, further research is needed to confirm the efficacy and safety of this approach.

A multidisciplinary approach is essential to achieve optimal results. Collaboration between dermatologists, allergists, immunologists, psychologists and other specialists can be used to address all aspects of the disease and develop an individual treatment plan. Regular monitoring of the effectiveness of therapy, assessment of side effects, and adjustment of treatment if necessary are key to successful control of CU. It is equally necessary to inform and educate patients regarding their disease. Explaining the nature of CU, triggers, treatments and self-management helps to increase compliance and patient involvement in their treatment. Patients should be made aware of the need to adhere to the prescribed therapy, the possible side effects of the medications and the importance of regular visits to the doctor.

Improving the diagnosis and treatment of CU is extremely important, as this disease significantly affects the quality of life of patients, causing constant discomfort, itching and psychological stress. Accurate diagnostic methods can identify the specific causes and triggers of the disease, which is key to developing effective and individualised therapy. Improved treatment approaches contribute to more effective symptom control, reduce the frequency and severity of exacerbations, and reduce the risk of side effects from therapy. Thus, innovations in the diagnosis and treatment of CU directly improve the health and well-being of patients, reducing the burden of the disease at the personal and societal levels.

In summary, the following key take-home recommendations highlight the most clinically relevant diagnostic and therapeutic priorities derived from the present analysis:

1. The diagnosis of chronic urticaria should be personalised and primarily guided by clinical presentations, with targeted investigations preferred over extensive routine testing.

2. The absence of validated and widely accessible biomarkers represents a major unmet clinical need, particularly for differentiating between autoimmune and non-autoimmune forms of CU.

3. Autoimmune chronic urticaria, characterised by functional autoantibodies to IgE or FcεRI, often requires treatment escalation beyond standard-dose antihistamines.

4. Management of chronic urticaria should follow a stepwise approach, starting with second-generation antihistamines and progressing to biologic or immunomodulatory therapies in refractory cases, in accordance with international guidelines.

5. Standardisation and optimisation of diagnostic tools, including the ASST and provocation tests, are essential to improve diagnostic accuracy and reduce subjectivity.

6. Psychological factors and comorbid conditions significantly influence disease course and treatment response and should be systematically integrated into patient management.

7. Multidisciplinary collaboration and patient education are key components of effective long-term disease control and improved quality of life.

These recommendations aim to enhance evidence-based decision-making, support personalised management strategies, and guide future advances in the diagnosis and treatment of chronic urticaria.

Conclusions

The study aimed to identify the main difficulties in the diagnosis and treatment of CU and to develop recommendations for improving existing therapeutic approaches. A review of the literature and scientific sources revealed that CU remains a complex dermatological disease with a diverse clinical picture and etiological heterogeneity, which significantly complicates diagnosis and selection of effective treatment. Diagnosis is often based on the exclusion of other possible causes of symptoms, which makes it difficult to establish an accurate diagnosis due to the lack of specific biomarkers.

The study determined that CU is a complex and multifactorial disease that significantly affects the quality of life of patients due to the duration of symptoms and difficulties in establishing a clear aetiology. The main difficulties in diagnosis are the variability of clinical manifestations, the lack of specific biomarkers and the difficulty of differentiating from other dermatological conditions. The existing diagnostic methods, including ASST, thyroid function test and other laboratory tests, their advantages and disadvantages were analysed.

The study confirmed that modern treatments, such as second-generation antihistamines, omalizumab and immunosuppressive therapy, have significant potential to improve the condition of patients with CU. However, in many cases, standard treatment regimens are not effective enough, which necessitates an individual approach to the choice of therapy and constant monitoring of patients. The study findings highlight the importance of psychological support for patients, given the well-established relationship between stress and symptom exacerbations.

Recommendations arising from the study include the need to standardise tests and introduce new methods that will allow for a more accurate determination of the autoimmune mechanisms of the disease. It is essential to formulate novel therapeutic strategies, incorporating biological agents and immunosuppressants, while considering the unique characteristics of the disease in each patient.

The main limitation of the study is the absence of large-scale clinical trials assessing the proposed recommendations, which do not fully cover all variants of CU and their treatment. Further research should be aimed at developing new biomarkers for diagnosis, studying the effectiveness of modern biological products and improving approaches to therapy based on individual patient characteristics.

Funding Statement

Funding No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.