Managing CSU

Prevalence of CSU

Urticaria is more common than previously thought¹

Chronic spontaneous urticaria (CSU) affects approximately 0.5–1% of the global population.² It can affect individuals of all ages, but is most common in adults between 30 and 70 years old, with a peak incidence between 20 and 40 years of age, and the highest prevalence in women over 30 (Figure 1).^1,3

Figure 1. CSU as a percentage of chronic urticaria cases and the ratio of males to females with CSU.^1,4 CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria.

Studies show no significant sex difference in children under 15, and the male-to-female ratio appears more balanced in pediatric cases.⁵

There is no evidence for clear correlation between CSU prevalence and factors such as education, income, occupation, place of residence, or ethnic background.³ Common triggers of CSU include stress, nonsteroidal anti-inflammatory drugs, and respiratory tract viral infections.⁶

CSU endotypes include autoimmune (IgE, IgG, or both; >50%), nonautoimmune (<35%), and, rarely, associations with infections, malignancy, thyroid disorders, rheumatic diseases, or type 1 hypersensitivity.¹

CSU duration

In very rare cases, CSU can last up to 50 years.^3,7-10 Half of patients will have their symptoms resolved within 6 months after their initial diagnosis, as displayed in Figure 2.¹¹

Figure 2. The percentage of patients with CSU symptoms at 6 months, 3 years, 5 years, and 25 years after their initial diagnosis.¹¹ CSU, chronic spontaneous urticaria.

The evolution of CSU is unpredictable, with spontaneous remissions and relapses¹: remission rates are 17% at 1 year, 45% at 5 years, and 73% at 20 years.¹²

Prognostic factors for the duration of CSU

The duration of CSU is generally longer in patients with:

• More severe disease^3,7
• Concurrent angioedema^3,7
• Concurrent inducible urticaria³
• A positive autologous serum skin test (ASST) or autologous plasma skin test (APST)^3,13

Acute versus chronic urticaria

While the lifetime prevalence for CSU estimates are around 0.5–1%, the lifetime prevalence for acute urticaria is thought to be as high as 20%.^2,6 Furthermore, acute urticaria accounts for 7–35% of dermatological conditions seen in emergency care.¹⁴

Acute urticaria is defined as the occurrence of spontaneous hives, angioedema, or both for <6 weeks.⁶

Etiology of acute urticaria

The underlying causes of acute urticaria remain idiopathic in 50% of cases, with infections responsible for approximately 40% and adverse reactions to drugs (9%) and food (1%) responsible for the remaining 10% of cases.¹⁵

Managing acute urticaria

For patients with an identifiable trigger, such as a food allergy, it is essential to confirm sensitization to support trigger avoidance and prevent recurrence. As acute urticaria is typically self-limiting, management focuses on symptomatic relief, most often with second-generation H1-antihistamines.⁶

In a study of 100 patients presenting with acute urticaria to a French emergency department, 79% of those treated with levocetirizine reported resolution of pruritus within 2 days.¹⁴ Current guidelines also support the short-term use (up to 10 days) of oral corticosteroids for acute exacerbations.⁶ However, in the same study, the addition of prednisone did not enhance outcomes compared with levocetirizine alone, suggesting that corticosteroids may not offer additional benefit in all cases.¹⁴

Sensitization to insect bites, such as mosquitos, is common and can provoke immediate urticarial reactions and pruritic papules, though systemic anaphylaxis is rare.¹⁶ These reactions are mediated by antisaliva immunoglobulin E (IgE) antibodies and histamine release, making oral second-generation H1-antihistamines a logical therapeutic option.¹⁶

Placebo-controlled trials have demonstrated the efficacy of cetirizine, ebastine, and rupatadine in managing mosquito-bite allergy in adults. Rupatadine 10 mg, administered prophylactically, led to a 48% reduction in mean hive size and a 21% decrease in itch intensity, with symptom relief observed as early as 15 minutes post-dose.¹⁶ In another study, cetirizine 10 mg and ebastine 10 mg significantly reduced hive size, whereas loratadine did not. Cetirizine showed superior efficacy for pruritus, though it was associated with increased sedation. Despite this, no patients discontinued treatment, indicating minimal clinical impact.¹⁶

Burden of disease

The impact of CSU extends beyond skin symptoms, with treated patients experiencing greater impairment in daily functioning, both at work and outside of work, as well as reduced quality of life (QoL) and increased healthcare use compared with individuals without the condition¹⁷

Quality of life

CSU adversely affects many aspects of patients’ lives, as shown in Figure 3.³

Figure 3. The impacts of CSU on quality of life.^18,19

Many aspects of QoL are reduced in patients with CSU, and the presence of angioedema further impairs QoL scores.^20,21

QoL in patients with CSU may be measured using specific skin disease questionnaires, such as the Dermatology Quality of Life Index (DQLI)²²

In addition to the classical symptoms associated with CSU, factors that contribute to a reduced QoL of major importance to patients include:⁹

• Unpredictability of attacks
• Persistent lack of sleep
• Fatigue

• Disfigurement

Patients with CSU also often experience comorbidities, such as depression and anxiety.²³ Over 60% of patients with CSU report anxiety at some point during their flares, and 17% are diagnosed with depressive or somatoform disorders.^9,24

In patients with chronic urticaria refractory to H1-antihistamines, the AWARE study demonstrated significant improvements in disease control, QoL, and healthcare utilization over 2 years with guideline-adherent treatment, particularly with the use of omalizumab.²⁵ However, many patients still experienced suboptimal control, highlighting the need for better management and stricter adherence to treatment guidelines in real-world settings.²⁵

The socioeconomic burden

CSU carries a heavy socioeconomic burden, not just from medical expenses, but also from time lost at work or school.^3,26 Around 60–70% of patients miss work or school as a direct result of CSU, with over a quarter reporting absences of three or more days per year.²⁶

Patients with severe CSU face higher direct and indirect costs than those with mild or moderate forms of the disease, driven by more frequent healthcare visits, the need for ongoing medication, and greater loss of productivity.^3,26

Continuous treatment and regular access to healthcare are often necessary, particularly for those who experience angioedema.^3,26 Nearly three-quarters of people with moderate to severe CSU see a healthcare professional at least once per year (mean of 3.3), primarily consultant allergists (39.0%) and dermatologists (38.5%).²⁷

While the management of CSU varies across regions and healthcare systems, the condition consistently presents a significant unmet need, with a substantial impact on QoL and daily functioning.²⁸

References

1. Kolkhir, 2022. Urticaria. https://www.doi.org/10.1038/s41572-022-00389-z
2. Barzilai, 2023. Epidemiological and clinical characteristics of adult and pediatric patients with chronic spontaneous urticaria. https://www.mdpi.com/2077-0383/12/23/7482
3. Maurer, 2011. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. https://www.doi.org/10.1111/j.1398-9995.2010.02496.x
4. Weller, 2021. Epidemiology, comorbidities, and healthcare utilization of patients with chronic urticaria in Germany. https://www.doi.org/10.1111/jdv.17724
5. Sánchez-Borges, 2021. The challenges of chronic urticaria part 1: Epidemiology, immunopathogenesis, comorbidities, quality of life, and management. https://www.doi.org/10.1016/j.waojou.2021.100533
6. Zuberbier, 2022. The international EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. https://www.doi.org/10.1111/all.15090
7. Toubi, 2004. Clinical and laboratory parameters in predicting chronic urticaria duration: A prospective study of 139 patients. https://www.doi.org/10.1111/j.1398-9995.2004.00473.x
8. Młynek, 2009. The German version of the chronic urticaria quality-of-life questionnaire: Factor analysis, validation, and initial clinical findings. https://www.doi.org/10.1111/j.1398-9995.2008.01920.x
9. Gattey, 2016. Chronic spontaneous urticaria: A questionnaire survey. https://www.doi.org/10.1177/1203475415623777
10. Beck, 2017. A review of international recommendations for the diagnosis and management of chronic urticaria. https://www.doi.org/10.2340/00015555-2496
11. Curto-Barredo, 2018. Clinical features of chronic spontaneous urticaria that predict disease prognosis and refractoriness to standard treatment. https://www.doi.org/10.2340/00015555-2941
12. Balp, 2022. Clinical remission of chronic spontaneous urticaria (CSU): A targeted literature review. https://www.doi.org/10.1007/s13555-021-00641-6
13. Boonpiyathad, 2016. Autologous serum and plasma skin test to predict 2-year outcome in chronic spontaneous urticaria. https://www.doi.org/10.5415/apallergy.2016.6.4.226
14. Barniol, 2018. Levocetirizine and prednisone are not superior to levocetirizine alone for the treatment of acute urticaria: A randomized double-blind clinical trial. https://www.doi.org/10.1016/j.annemergmed.2017.03.006
15. Nagaraju, 2011. Urticaria and its management. https://www.doi.org/10.5005/jp/books/12013_5
16. Karppinen, 2012. Rupatadine 10 mg in the treatment of immediate mosquito-bite allergy. https://www.doi.org/10.1111/j.1468-3083.2012.04543.x
17. Balp, 2015. The impact of chronic urticaria from the patient’s perspective: A survey in five European countries. https://www.doi.org/10.1007/s40271-015-0145-9
18. Carne, 2018. Managing chronic spontaneous urticaria (hives) in primary care. https://www.doi.org/10.7748/ns.2018.e11198
19. Gonçalo, 2021. The global burden of chronic urticaria for the patient and society. https://www.doi.org/10.1111/bjd.19561
20. Kang, 2009. The impact of chronic idiopathic urticaria on quality of life in Korean patients. https://www.doi.org/10.5021/ad.2009.21.3.226
21. Silvares, 2011. Quality of life in chronic urticaria: A survey at a public university outpatient clinic, Botucatu (Brazil). https://www.doi.org/10.1016/S2255-4823(11)70114-X
22. Bernstein, 2024. Patient-reported outcome measures in chronic spontaneous urticaria, angioedema, and atopic dermatitis. https://www.doi.org/10.1016/j.jaip.2024.08.021
23. Engin, 2008. The levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria. https://www.doi.org/10.1111/j.1468-3083.2007.02324.x
24. Staubach, 2011. High prevalence of mental disorders and emotional distress in patients with chronic spontaneous urticaria. https://www.doi.org/10.2340/00015555-1109
25. Thomsen, 2022. Treatment patterns and clinical outcomes of chronic urticaria: Two-year follow-up results from the scandinavian AWARE study. https://www.doi.org/10.2340/actadv.v102.1620
26. DeLong, 2008. Annual direct and indirect health care costs of chronic idiopathic urticaria: A cost analysis of 50 nonimmunosuppressed patients. https://www.doi.org/10.1001/archdermatol.2007.5
27. Maurer, 2017. The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU. https://www.doi.org/10.1111/all.13209
28. Maurer, 2018. Differences in chronic spontaneous urticaria between Europe and Central/South America: Results of the multi-center real world AWARE study. https://www.doi.org/10.1186/s40413-018-0216-1

Diagnosis and assessment of CSU

Understanding chronic spontaneous urticaria (CSU) is essential for accurate diagnosis and effective management or referral.¹ Here, we round up the latest guidelines and recommendations for diagnosing CSU.

Diagnostic approach to CSU

CSU symptoms are often transient and may not be visible during consultation, so patient-provided photographs or symptom diaries can be invaluable for supporting diagnosis¹

There is no definitive laboratory test to confirm CSU, so healthcare professionals rely on a comprehensive history, physical examination, and targeted investigations to rule out differential diagnoses.^1,2

CSU is defined by the spontaneous recurrence of hives (wheals) and/or angioedema without a known external trigger.¹ The symptoms are often fleeting, making clinical confirmation challenging if signs are not present during the consultation. In such cases, photographs or symptom diaries provided by the patient can support diagnosis.¹

A thorough history should explore symptom patterns, duration, frequency, associated factors (e.g., medications, infections), and treatment responses.³ Since many patients are misattributed with allergic causes, it is important to recognize that CSU is rarely immunoglobulin (Ig)E-mediated and typically not linked to foods or allergens.³

The 2021 international guidelines recommend a three-step process for the effective diagnosis of urticaria, as shown in Figure 1.¹

Figure 1. The three steps recommended in the 2021 international guidelines for the effective diagnosis of urticaria.¹

CSU is challenging to diagnose due to its varied presentation and the need to rule out other conditions.^1,2 Key differentials include urticarial vasculitis (longer-lasting lesions, often painful), bradykinin-mediated angioedema (e.g., hereditary angioedema), and autoinflammatory syndromes, such as Schnitzler syndrome or cryopyrin-associated periodic syndromes.^1,4

Accurate diagnosis is essential, as CSU can mimic other conditions like urticarial vasculitis or hereditary angioedema^1,4

A focused clinical history is essential to determine whether an allergic cause is likely. Useful questions include whether reactions occur reproducibly within 60 minutes of eating specific foods, particularly shellfish or meat, or following food intake combined with exercise, suggestive of food-related or exercise-induced anaphylaxis. Sensitization to allergens such as animals, grass, latex, or certain foods should also be considered. Medication history is also essential, especially the use of ACE (angiotensin-converting enzyme) inhibitors, NSAIDs (non-steroidal anti-inflammatory drugs), or aspirin, which can exacerbate symptoms of CSU.²

Assessment for urticarial vasculitis should establish whether episodes are persistent and whether individual lesions last longer than 24 hours. Painful rather than itchy lesions warrant further investigation. Additional features such as petechiae, purpura, or systemic symptoms, including fever, arthralgia, malaise, hypertension, or urinary abnormalities, should prompt consideration of an underlying systemic disease.²

The European Academy of Allergy and Clinical Immunology (EAACI) 2021 guidelines highlight the importance of identifying exacerbating factors in CSU, as this can help physicians better understand each patient case.¹ Clinicians should consider potential culprits such as medications, specific foods, or known allergens, but if this does not provide clarity, it may be worth conducting extended diagnostic testing.¹ These can include investigations for infectious or allergic causes, thyroid dysfunction, and functional autoantibodies.

Additional approaches may involve physical urticaria testing, a pseudoallergen-free diet, tryptase measurement (if systemic disease is suspected), autologous serum skin testing (ASST), and lesional biopsy in selected cases. However, unless strongly indicated by patient history (e.g., allergy), extended diagnostic tests should not be carried out in acute spontaneous urticaria.¹

Recommended diagnostic algorithm for urticaria

Figure 2 outlines the stepwise diagnostic approach for patients with hives and/or angioedema, as recommended by international guidelines.¹ This tool assists in differentiating between common urticaria subtypes based on key historical and clinical parameters. For example, hive duration exceeding 24 hours or the presence of vasculitic features on biopsy may suggest urticarial vasculitis, while inducible symptoms confirmed via provocation testing may indicate chronic inducible urticaria.¹

Figure 2. Diagnostic algorithm for CSU.¹ AAE, acquired angioedema; ACE, angiotensin-converting enzyme; AE, angioedema; AID, acquired autoinflammatory disorders; HAE, hereditary angioedema. Image licensed under Creative Commons license 4.0 by Zuberbier et al.¹

Diagnosis in pediatric patients

In children, CSU typically has a shorter disease duration, while in adolescents and adults it tends to be more severe and last longer.⁵ The diagnostic workup remains largely consistent across age groups, but special consideration may be required for atypical presentations, including urticarial vasculitis or autoinflammatory syndromes, which may present with overlapping features.⁴

Although assessment tools such as the Urticaria Activity Score over 7 days (UAS7) and the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) have been validated in adult populations, they are still useful for tracking disease activity and impact in children.⁴ In younger age groups where self-reporting is not feasible, caregiver-reported outcomes are critical for monitoring disease progression and therapeutic response.⁶

Assessment tools for CSU

With a CSU diagnosis confirmed, healthcare professionals then need to assess disease activity and control, and the impact on the patient’s quality of life (QoL). The 2021 guideline outlines a structured diagnostic and assessment model known as the “7 C’s” (Figure 3).¹

Figure 3. Diagnostic and assessment model (known as “7 C’s”) recommended in the 2021 international guidelines for the effective diagnosis of urticaria.¹ AAS, Angioedema Activity Score; CU-Q2oL, Chronic Urticaria Quality of Life Questionnaire; IgE, immunoglobulin E; NSAID, non-steroidal anti-inflammatory drug; QoL, quality of life; TPO, thyroid peroxidase; UAS7, Urticaria Activity Score over 7 days.

Watch the content presented in an EAACI 2023 symposium for further insights into the practical application of the 7 C’s model in CSU management.

Other commonly used tools include UAS7, AAS, and CU-Q2oL. These patient-reported methods are easy to implement and suitable for routine clinical care.⁷

Urticaria Activity Score over 7 days (UAS7)

The Urticaria Activity Score (UAS) is a daily measure combining itch severity (0–3) and hive count (0–3), giving a score of 0–6 per day.¹ While daily UAS can be useful, the UAS7 (sum over 7 days, 0–42) is the gold standard for monitoring CSU severity and treatment response, as it accounts for symptom variability and provides a clearer picture of disease control (Figure 4). The UAS7 gives a measure of hive and pruritus severity over the course of a week, and therefore helps track disease severity and treatment response in the longer term.¹

Figure 4. Calculating the UAS7.^1,8 UAS7, Urticaria Activity Score over 7 days.

The Angioedema Activity Score (AAS)

The AAS is used to assess presence, frequency, and impact of angioedema in patients with CSU with or without hives.¹ Patients score each of five key factors relating to their symptoms from 0 to 3 (giving a daily score of 0–15). Daily AAS can be summed to give 7-day scores (AAS7), 4-week scores (AAS28), and 12-week scores (AAS84).⁹

The Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL)

The CU-Q2oL patient questionnaire assesses QoL specifically in chronic urticaria, including the physical, psychosocial, and practical aspects of the condition.¹⁰ It consists of 23 questions covering six key domains relevant to:¹⁰

• Pruritus
• Swelling
• Impact on life activities
• Sleep problems

• Looks

The effects of disease on each domain are scored from 1 (not at all) to 5 (extremely) and totaled to give an overall score ranging from 0–92, with higher scores indicating a greater impairment in QoL. The CU-Q2oL is simple to implement and takes approximately 5 minutes to complete.⁹

The Angioedema Quality-of-Life Questionnaire (AE-QoL)

The AE-QoL is the first angioedema-specific patient-reported QoL questionnaire. It consists of 17 questions across four domains, as illustrated in Figure 5.¹¹

Figure 5. The four domains of the Angioedema Quality-of-Life Questionnaire (AE-QoL).¹¹

Autoimmune CSU: A distinct subgroup

A subset of patients with CSU show evidence of autoimmune involvement, often referred to as type IIb autoimmune CSU.¹ These patients may demonstrate:^12,13

• Positive basophil activation test (BAT) or ASST
• Coexisting autoimmune diseases, particularly autoimmune thyroiditis

Resistance to standard-dose antihistamines has been observed more frequently in patients with chronic urticaria who test positive for anti-thyroid peroxidase (anti-TPO) antibodies, supporting a possible autoimmune mechanism.¹³

While the ratio of anti-TPO to total IgE has been proposed in some studies as a potential marker, it is not yet an established diagnostic tool.¹³ However, findings suggest patients with low total IgE and elevated anti-TPO antibodies may benefit from immunomodulatory treatments, such as cyclosporine or omalizumab.^1,13,14

References

1. Zuberbier, 2022. The international EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. https://www.doi.org/10.1111/all.15090
2. Powell, 2015. BSACI guideline for the management of chronic urticaria and angioedema. https://www.doi.org/10.1111/cea.12494
3. Ryan, 2022. Clinical review: The suggested management pathway for urticaria in primary care. https://www.doi.org/10.1002/clt2.12195
4. Ensina, 2022. Urticaria and angioedema in children and adolescents: Diagnostic challenge. https://www.doi.org/10.15586/aei.v50iSP1.538
5. Özçeker, 2023. Differences between adult and pediatric chronic spontaneous urticaria from a cohort of 751 patients: Clinical features, associated conditions and indicators of treatment response. https://www.doi.org/10.1111/pai.13925
6. Bernstein, 2023. European Academy of Dermatology and Venereology (EADV). Urticaria Voices: The use of patient-reported outcome measures for monitoring chronic spontaneous urticaria in clinical practice.
7. Bernstein, 2024. Patient-reported outcome measures in chronic spontaneous urticaria, angioedema, and atopic dermatitis. https://www.doi.org/10.1016/j.jaip.2024.08.021
8. Hollis, 2018. Comparison of urticaria activity score over 7 days (UAS7) values obtained from once-daily and twice-daily versions: Results from the ASSURE-CSU study. https://www.doi.org/10.1007/s40257-017-0331-8
9. Hawro, 2014. Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. https://www.doi.org/10.1111/all.12316
10. Baiardini, 2011. Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: A GA(2)LEN taskforce position paper. https://www.doi.org/10.1111/j.1398-9995.2011.02580.x
11. Weller, 2012. Development and construct validation of the angioedema quality of life questionnaire. https://www.doi.org/10.1111/all.12007
12. Sella, 2023. Type I and type IIb autoimmune chronic spontaneous urticaria: Using common clinical tools for endotyping patients with CSU. https://www.doi.org/10.1016/j.jacig.2023.100159
13. Kolkhir, 2021. Autoimmune chronic spontaneous urticaria detection with IgG anti-TPO and total IgE. https://www.doi.org/10.1016/j.jaip.2021.07.043
14. Maurer, 2023. The crucial role of IgE as a predictor of treatment response to omalizumab in chronic spontaneous urticaria. https://www.doi.org/10.1016/j.jaip.2023.06.026

Comorbidities in CSU

For many patients living with chronic spontaneous urticaria (CSU), the burden extends beyond the distressing symptoms of itchy hives and angioedema.¹ A significant proportion also face a range of comorbidities that often accompany the condition, adding further complexity to their care and overall quality of life.²

Autoimmune diseases in CSU

In a subset of patients, CSU appears to be driven by an autoimmune mechanism involving immunoglobulin (Ig)E or IgG autoantibodies.^2,3 Notably, CSU has been strongly linked with several major autoimmune diseases, with studies suggesting that up to 50% of patients may have an underlying autoimmune component.^4,5 Patients with CSU are believed to face a higher risk of developing additional autoimmune conditions. While autoimmune diseases affect up to 1% of the general population, the rate appears to be even greater among individuals with CSU.^2,3

Evidence suggests a potential autoimmune etiology in up to 50% of patients with CSU⁵

A large population-based study from Israel shed light on the link between chronic urticaria (CU) and autoimmune conditions, revealing a notably increased risk of thyroid dysfunction.⁴ Patients with CU were significantly more likely to develop hypothyroidism (9.8% vs 0.6%) and hyperthyroidism (2.6% vs 0.09%) compared with the general population. Interestingly, the burden of autoimmune comorbidities appeared to be higher in female patients. For instance, the risk of type 1 diabetes was markedly elevated, particularly among women with CU (female patients OR, 12.92; 95% CI, 6.53–25.53; p<0.0005 vs male patients OR, 2.34; 95% CI, 1.15–4.73; p=0.01), with most cases (84.8%) occurring after the initial CU diagnosis. Several autoimmune conditions, including rheumatoid arthritis (OR, 19.88; 95% CI, 10.15–38.92; p<0.0005), Sjögren’s syndrome (OR, 23.30; 95% CI, 7.31–74.20; p<0.0005), celiac disease (OR, 57.83; 95% CI, 7.99–418.29; p<0.0005), and systemic lupus erythematosus (OR, 26.71; 95% CI, 6.49–109.90; p<0.0005) were found to be significantly more prevalent in female patients with CU, further highlighting the need for heightened vigilance in this population.⁴

More recently, a Korean study used their national database to explore the presence of various conditions in patients with CU, patients with CSU, and patients without CU/CSU. Similar to Confino-Cohen et al., Korean patients with CU (12.34%) or CSU (11.34%) had a significantly increased rate of autoimmune thyroid diseases compared with controls (5.49%).⁶

Alopecia areata (AA) is another autoimmune disease with a global prevalence of 0.1–0.2%.⁷ However, this differs between populations and studies, with an observed prevalence of ~0.7–3% in the USA and ~2% in the UK. An Israeli study matched 1,751 patients with AA to 3,502 control patients and assessed their respective comorbidities. Patients with AA had a significantly higher risk of having comorbid CSU (OR, 6.15; 95% CI, 4.06–9.32; p<0.001) than the control group. Furthermore, patients with both AA and CSU were more likely to also have comorbid allergic rhinitis and atopic dermatitis than patients with CSU but not AA.⁷

A systematic review of 169 studies revealed a strong association between CSU and elevated levels of IgG antithyroid autoantibodies – particularly IgG–anti-thyroid peroxidase (anti-TPO) antibodies.^2,4 Some studies also pointed to higher levels of IgE–anti-TPO autoantibodies in patients with CSU compared with controls. These autoantibody elevations were closely tied to an increased prevalence of autoimmune thyroid diseases, with hypothyroidism and Hashimoto’s thyroiditis more commonly reported than hyperthyroidism or Graves’ disease. Echoing data from population studies, thyroid dysfunction appeared to be more prevalent in female patients with CSU, further underlining the importance of sex-specific screening and monitoring.^2,4

A separate systematic literature review looked at the published rates of a broader spectrum of autoimmune diseases in patients with CSU. The rates of comorbidity in the majority of studies were ≥1% for insulin-dependent diabetes mellitus, rheumatoid arthritis, psoriasis, and coeliac disease, ≥2% for Grave’s disease, ≥3% for vitiligo, and ≥5% for pernicious anemia and Hashimoto’s thyroiditis.³

Allergic disease

There are also data supporting a proposed link between CU and atopic diseases.⁸ Among a Korean population of patients with CU or CSU, the likelihood of having comorbid allergic rhinitis, drug or other allergies, or asthma was approximately 4.68 times higher than in the control group (Table 1).⁶

Table 1. Mean percentage of patients with CU, CSU, and non-CU/CSU diagnosed with a comorbidity between 2010 and 2013 in Korea.⁶ CSU, chronic spontaneous urticaria; CU, chronic urticaria.

In an Israeli population study, 11,271 patients with CU were compared with 67,216 age- and sex-matched controls.⁸ While fewer people experienced allergic comorbidities than observed in the Korean study, they were still significantly more common in patients with CU than in the control group. In this setting, 9.8%, 10.8%, and 19.9% of patients with CU had been diagnosed with atopic dermatitis, asthma, or allergic rhinitis, respectively, compared with 3.7%, 6.5%, and 10.1% of patients in the control group.⁸ Even after adjusting for key factors such as age, sex, BMI, smoking, and ethnicity, CU remained significantly associated with allergic rhinitis (OR, 2.03; p<0.001), atopic dermatitis (OR, 2.77; p<0.001), and asthma (OR, 1.62; p<0.001).⁸ Meanwhile, a comparison of older (>60 years of age) and younger patients with CU in Korea revealed that older patients with CU were significantly more likely to have comorbid atopic dermatitis than younger patients (37.8% vs 21.7%, p=0.022).⁹ However, no difference was seen in the prevalence of asthma or allergic rhinitis.⁹

There is also growing interest in the potential overlap between CU and irritable bowel syndrome (IBS), given shared mechanisms involving mast cells and immune dysregulation. Given this possible pathophysiological similarity between IBS and CU, Shalom et al. produced a follow-up study addressing the epidemiological links between the two conditions in Israel.⁸ A total of 1.7% of patients with CU had concomitant IBS versus 0.8% of controls (p<0.001), giving an OR of 1.86 (95% CI, 1.57–2.19; p<0.001). While a pathophysiological explanation remains hypothetical, this study does suggest an association between IBS and CU, warranting further investigation.⁸

Differences in pediatric population

Angioedema is less common in children than in adults, affecting approximately 5–15% of pediatric patients compared with 30–50% of adults.¹⁰ Similarly, autoimmune diseases are also less frequently observed in the pediatric population.¹¹

Psychiatric conditions in CSU

It has been reported that nearly one-third of patients with CU have at least one psychiatric comorbidity¹²

The psychological burden caused by CSU is substantial although often overlooked. In a recent study comparing the burden of CSU, atopic dermatitis, and psoriasis, CSU was reported to cause a significantly greater mental health burden.¹ Psychological comorbidities were more common in CSU than in atopic dermatitis or psoriasis, potentially driven by the unpredictable nature of symptoms, the presence of angioedema, and the emotional strain of trying to identify triggers. Angioedema, in particular, was both distressing and under-recognized, reported by roughly one in four patients with CSU, though likely underestimated.¹

A previous UK study reported that 17% of dermatology patients required psychological support, while an overwhelming 85% reported that the psychosocial aspects of their skin condition are a major component of their illness.¹³

A systematic review and meta-analysis including a total of 25 studies revealed that nearly one-third of patients with CU have one or more psychiatric comorbidity.¹²These findings underscore the importance of a holistic approach to managing CU that includes consideration of emotional and psychological wellbeing.¹²

In a survey of 369 patients with CSU, the prevalence of psychological issues was roughly twice as high as reported by matched controls (Figure 1).¹⁴

Figure 1. Prevalence of mental health comorbidities and sleep difficulties among patients with CSU and matched controls.¹⁴ CSU, chronic spontaneous urticaria.

The psychological comorbidities associated with CSU have been shown to extend beyond anxiety and depression. Patients with CSU also have higher levels of alexithymia (the inability to identify and communicate emotions) than healthy controls, which may be related to a link between pruritus severity and state anger as assessed by the State-Trait Anger Inventory (STAXI).^15,16 Furthermore, post-traumatic stress disorder (PTSD) has been associated with CSU, with 34% of patients with CSU in one study meeting the diagnostic criteria for PTSD versus 18% of allergy control patients.^17-19

The impact of these associated comorbidities should not be underestimated. In a study of 746 patients with CU and 5,107 patients with psoriasis, patients with CU had a comparable impairment of mental/physical health to those patients with moderate-to-severe psoriasis (Figure 2).²⁰

Figure 2. Psychological burden of CU and psoriasis²⁰ CU, chronic urticaria. Image licensed under Creative Commons license 4.0 from Mendelson et al.²⁰

References

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