Managing CSU

Prevalence of CSU

Urticaria is more common than previously thought¹

Though there is little epidemiological data for chronic urticaria (CU), a recent meta-analysis reported a point and lifetime prevalence rates of 0.7% and 1.4% respectively¹. Interestingly, the results of this study also suggest that CU prevalence is on the rise, though there is substantial variation between geographical regions¹.

Overall, chronic spontaneous urticaria (CSU) accounts for over two-thirds of the cases of CU, and most studies show that it is more common among women than men^1,2.

Terminology
Lifetime prevalence is the proportion of a population that at some point in their life (up to the time of the assessment) have experienced the condition³

Figure 1. CSU as a percentage of chronic urticaria cases and the ratio of male to female CSU sufferers (Adapted^2,4). CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria.

Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age⁵. There is no apparent correlation of prevalence with education, income, occupation, place of residence or ethnic background; although prevalence of chronic urticaria has been noted as higher in Asian studies compared with Europe or the USA¹. Interestingly, a Korean study published in 2017 also found that CSU had a greater impact on children and the elderly than was expected⁶.

The majority of patients have no evidence of any exacerbating factor, however a recognised trigger for CSU is nonsteroidal anti-inflammatory drugs⁷.

A population-based study on the epidemiology of CSU in Italy over a 12-year period (2002–2013) demonstrated that the risk of CSU was statistically significantly higher in the presence of the following variables⁸:

• obesity
• anxiety
• dissociative and somatoform disorders
• malignancies
• use of immunosuppressive drug
• schronic use of systemic corticosteroids

CSU duration

CSU has a duration of at least 1 year in most patients and more than 5 years in a considerable proportion. In very rare cases it can last up to 50 years^5,9–12.

Figure 2. The percentage of patients with CSU symptoms at 6 months, 3 years, 5 years, and 25 years after their initial diagnosis (Adapted¹³).

The evolution of CSU is unpredictable, with spontaneous remissions and relapses⁷. At least 50% of CSU patients will experience at least one recurrence of CSU symptoms after an apparent resolution¹⁴

Prognostic factors for the duration of CSU

The duration of CSU is generally longer in patients with:

• more severe disease^5,9
• concurrent angioedema^5,9
• concurrent inducible urticaria^5,15
• a positive autologous serum skin test (ASST) or autologous plasma skin test (APST)^5,16,17

The autologous serum skin test (ASST) is a screening test for autoantibodies in CSU.

Diagnosis is based on a thorough medical history and physical examination as well as diagnostic tests¹⁸.

CSU pathophysiology

Chronic spontaneous urticaria (CSU) is driven by the activation of mast cells, which release histamines and other immune modulators, although the precise mechanism is not fully known⁴².

Mast cell activation in CSU

Urticaria is a mast-cell-driven disease¹⁸.

Figure 4. Interactions of mast cells on urticaria symptoms (Adapted^43,44).

Though the pathophysiology of urticaria is complex and yet to be fully characterised, it is thought that activated mast cells release histamine and other inflammatory mediators, such as platelet-activating factor (PAF) and cytokines⁴⁵. The mediators cause sensory nerve activation, vasodilatation, and plasma extravasation as well as cell recruitment to urticarial lesions, and form the basis for antihistamines being first-line management^12,46,47.

CSU skin lesions show recruitment of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes^18,48–52.

Figure 5. The recruitment of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes in CSU skin lesions (Adapted^18,48–52).

The mast cell activating signals in urticaria are ill-defined and likely to be heterogeneous and diverse¹⁸.

Basophils
Basophils, along with mast cells, play an important role in the pathophysiology of CSU. Peripheral blood basophils from CSU patients have unique features that reverse upon remission and in response to therapy^7,53:

- basopaenia is typically found in CSU patients

- basophils from CSU patients also tend be less responsive to stimuli that act through the IgE receptor

- basophils from CSU patients are hyperresponsive when stimulated with other sera regardless of source

CSU symptoms

The symptoms of chronic spontaneous urticaria (CSU) include itchy hives (wheals) and angioedema¹⁸

The symptoms of CSU may appear without warning with a variable intensity^5,18 and may profoundly impact patients' day-to-day lives^{5,27,32,69,70}. In CSU, itchy hives, angioedema or both, may occur spontaneously every day, or almost daily for six weeks or more¹⁸.

CSU diagnosis and assessment

Since there is no definitive test for chronic spontaneous urticaria, diagnosis is based on a thorough medical history and physical examination as well as diagnostic tests¹⁸.

The importance of earlier diagnosis of CSU

Despite the clear diagnostic algorithm included in international guidelines, evidence suggests that many patients with CSU experience delays in receiving a diagnosis^18,40,75,76

The Assessment of the Economic and Humanistic Burden of Chronic Spontaneous/Idiopathic Urticaria Patients (ASSURE-CSU) aimed to provide real-world evidence on the unmet needs of patients with uncontrolled CSU by assessing various aspects of the patient experience. Among the 673 patients included in the study, the mean disease duration was 4.8 years, and the mean (SD) duration of disease from symptom onset to diagnosis was 24.0 (63.36) months, with a median delay of 4.7 months. The authors attributed this delay in diagnosis and specialist referral to a lack of specialist knowledge in the primary and secondary care settings with regard to CSU⁴⁰.

For patients, these delays in obtaining a diagnosis represent a source of great frustration. Many of them will visit multiple healthcare providers before their diagnosis is confirmed and appropriate treatment is initiated⁷⁵. For example, in an Italian study published in 2017, three-quarters of the 190 patients included visited ≥3 different physicians before finally receiving a diagnosis of CSU⁷⁶. Other studies have shown that during this process, patients frequently resort to online resources in search of answers⁷⁵. This may result in inaccurate self-diagnoses and, alarmingly, attempts to self-medicate are not uncommon. There have even been reports of patients using unprescribed prednisone in a bid to alleviate their symptoms⁷⁵.

Of the patients included in the Italian study described above, 57% expressed hope for a more rapid and straightforward treatment process, particularly in terms of diagnosis⁷⁶. Better education for both patients and physicians to help raise awareness of CSU could help spare patients the frustration and anxiety associated with delayed diagnosis and facilitate earlier interventions with appropriate therapeutic agents⁷⁵.

Find out more about the journey to diagnosis from the patient perspective with our podcast, “All Things Urticaria: The Patient Voice”.

Comorbidities in CSU

Unfortunately for many patients with chronic spontaneous urticaria (CSU), the itchy hives and/or angioedema associated with the condition is not all they have to contend with. A substantial number of patients also experience comorbidities associated with the development of CSU⁹⁴.

Autoimmune diseases in CSU

The pathogenesis of CSU in a subset of patients is believed to be a consequence of an autoimmune response driven by immunoglobulin E (IgE) or immunoglobulin G (IgG) autoantibodies^94,95, and a strong association is found between CSU and major autoimmune diseases⁹⁶, with evidence suggesting potential autoimmune aetiology in up to 50% of CSU patients⁴². Patients with CSU, therefore, are thought to be at an increased risk of developing other autoimmune disorders. In fact, while the global prevalence of autoimmune diseases is considered to be ≤1%, in patients with CSU it is thought to be ≥1%^94,95.

Evidence suggests a potential autoimmune aetiology in up to 50% of patients with CSU⁴²

A large Israeli population study exploring the links between CSU and other autoimmune conditions found that a diagnosis of CU was associated with an increased risk of developing hypothyroidism (9.8% vs. 0.6%; p<0.0005) and hyperthyroidism (2.6% vs. 0.09%; p<0.0005). Interestingly, the presence of autoimmune disease was significantly higher in female patients than male patients. A similar effect was seen with type 1 diabetes (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). Importantly, the onset of type 1 diabetes was observed in the majority (84.8%) of patients in the years after receiving a diagnosis of CU. Meanwhile, a number of autoimmune conditions were only significantly increased in female patients. These included rheumatoid arthritis (OR, 19.88; 95% CI, 10.15–38.92; p<0.0005), Sjögen syndrome (OR, 23.30; 95% CI, 7.31–74.20; p<0.0005), coeliac 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)⁹⁶.

More recently, a Korean study utilised 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 (AITD) compared to controls (5.49%)⁶.

Alopecia areata (AA) is another autoimmune disease with a global prevalence of 0.1–0.2%. 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. Interestingly, patients with AA had a significantly increased 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 in the control group⁹⁷.

To gain greater clarity on the association of AITD and CSU, a systematic literature review compared data from 169 identified publications. A strong correlation was seen between CSU and elevated IgG antithyroid autoantibodies, in particular IgG-anti-TPO antibodies. Furthermore, some evidence suggests that patients with CSU typically have higher levels of IgE-anti-TPO autoantibodies than controls. As expected, these changes in autoantibody levels are also associated with elevated rates of AITD. It was identified that patients with CSU are more likely to experience hypothyroidism and Hashimoto’s thyroiditis than hyperthyroidism and Grave’s disease. In addition, and supporting the Israeli population study, thyroid dysfunction was more commonly observed in female than male patients with CSU^94,96.

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 anaemia and Hashimoto’s thyroiditis⁹⁵.

The Aim of Treatment
The aim of treatment for urticaria is quick and complete symptom control^5,18,107

The recommended treatment algorithm

The 2017 European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA²LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) guidelines recommend the following step-wise approach to the treatment of urticaria (Figure 21)¹⁸.

Figure 21. The 2017 EAACI/GA²LEN/EDF/WAO recommended treatment algorithm for chronic urticaria (Adapted¹⁸). EAACI, European Academy of Allergy and Clinical Immunology; EDF, European Dermatology Forum; GA²LEN, Global Allergy and Asthma European Network; WAO, World Allergy Organisation.

A number of additional treatment options are mentioned in the EAACI/GA²LEN/EDF/WAO guidelines but are not included in the recommended treatment algorithm due to limited supporting evidence¹⁸.

It is recommended to reassess the need for continued or alternative drug treatment every three to six months, as the severity and symptoms of urticaria may fluctuate and spontaneous remission may occur at any time¹⁸.

An urticaria treatment algorithm should serve both patients with easy-to-treat symptoms and those more refractory to treatment and should allow the stepping up or stepping down of treatment depending on requirements over time¹⁰⁸.

CSU Guidelines

Best practice guidelines for CSU have been developed and published by a number of national and international groups, and those with major significance are described in this section. Broadly speaking they recommend second generation antihistamines of standard and then increased dose, followed by alternative agents such as anti-inflammatories, immunosuppressants or biologics.

CSU presents as wheals and/or angioedema which usually last for less than 24 hours and resolve without leaving a mark. These symptoms occur for six weeks or more¹⁸.

The diagnosis of CSU is usually made clinically. Not all possible causative factors need to be investigated in all patients, however, a thorough history should be taken as the first step. The following should be reviewed¹⁸:

• onset of disease
• frequency of attacks
• provoking factors
• diurnal variation
• shape, size and distribution of wheals
• angioedema
• pain, itch, burning, fever
• family history
• allergies
• psychosomatic/psychiatric history
• surgical implantations
• gastrointestinal symptoms
• induction by physical stimulation
• drugs
• correlation to food
• correlation to menstrual cycle
• smoking 
• work
• hobbies
• quality of life
• previous therapy (response)
• previous diagnostic results

Following the patient history, a physical examination of the patient should be made. This should include a diagnostic provocation test including drug, food and physical tests where indicated by the patient’s history. All subsequent diagnostic steps will depend on patient history and the nature of the urticaria subtype¹⁸.

EAACI Guidelines recommend only very limited routine diagnostic measures in chronic spontaneous urticaria¹⁸.

Routine

• C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR)
• Differential blood cell count

Extended

• Infectious diseases
• Type I allergy
• Functional autoantibodies
• Thyroid hormones
• Physical tests
• Pseudo allergen free diet

• Autologous serum skin test (ASST)

Table 6. Recommended diagnostic tests in frequent spontaneous urticaria subtypes (Adapted¹⁸). CIndU, chronic inducible urticaria; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Table 7. Recommended diagnostic tests in frequent inducible urticaria subtypes (Adapted¹⁸). CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; UV, ultraviolet.

Paediatric urticaria

Explore the available data in paediatric urticaria and discover its impact on younger patients, and how diagnosis and management compare to the recommendations for adult patients with CSU.

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