**3.2 Underlying pathogenesis**

There is little doubt that the release of histamine by mast cells (MC) and basophils represent the final stage in the pathogenesis of CU cases [4]. There is however still uncertainty about the factors that activate these cells and lead to cell degranulation

[11]. Several lines of evidence suggest that different biologic systems like immunity, inflammation and coagulation may contribute to wheal development [4, 11].

There are immunologic and non-immunologic mechanisms that lead to MC degranulation and release of mediators including histamine, leukotrienes and prostaglandins [4, 6]. These mediators recruit basophils, eosinophils, polymononuclear cells and lymphocytes [4, 6] and cause the typical skin manifestations of (a) pruritus via sensory nerve stimulation, (b) vascular dilatation and permeability that leads to extravasation and (c) oedema in upper dermis (wheals) and lower dermis/subcutaneous tissue (angioedema) [6].

The **non-immunologic** pathogenesis involves dysregulation of intracellular signalling pathways within MCs and basophils that lead to defects in trafficking and function of these cells [4]. The immunologic pathway involves the development of autoantibodies to IgE or the high affinity IgE receptor FcεRIα on MCs and basophils [4, 9].

Two types of **immunological CSU** have been identified namely Type I and Type IIb [9]:


In type I autoimmune CSU, autoantigens crosslink IgE autoantibodies and bind on MCs and basophils to cause release of vasoactive mediators. Thyroperoxidase (TPO) is the commonest autoallergen binding to IgE (IgE-anti-TPO), other autoantigens include thyroglobulin, tissue factor and IL-24 [4, 9]. Furthermore, some studies have demonstrated that the raised IgE autoantibodies contribute to the increased total serum IgE level found in CSU patients [4, 9].

In type IIb autoimmune CSU, autoantibodies of IgG or IgM type bind to antigen on the target cell (MC) and cause release of mediators. Furthermore, IgG and to a lesser degree IgM and IgA autoantibodies to IgE high affinity receptor FcεRI on MCs and basophils have been identified in roughly 50% of CSU [5, 9]. CSU patients show positive reaction to autologous serum skin test (ASST), that is flare and wheal development to intradermal injection of patient's own serum [4, 9, 12].

Some evidence suggests that type I and IIb autoimmune CSU differ in their clinical features, laboratory markers and response to therapy [9, 13]. Type IIb autoimmune CSU is thought to exhibit higher disease activity, longer duration, higher rates of associated autoimmunity and eosinopenia and basopenia, both markers of recalcitrant disease [9, 13].

CSU is characterised by a **systemic pro-inflammatory state** [11]. Many patients have slightly raised levels of C-reactive protein [8, 13]. Studies [4, 11] also suggest higher association with metabolic syndrome, hyperlipidemia, Multiple sclerosis and other autoimmune conditions (Rheumatoid arthritis, Systemic Lupus Erythematosus) [4, 9].

#### **3.3 Trigger factors**

**Higher emotional stress** is known to contribute to low grade inflammation [8]. Patients with CSU are reported to experience higher rates of anxiety, depression and somatiform disorders [5], although it is unclear if they are cause or effect of CSU [8]. Psychiatric comorbidity has been linked as an additional factor that affects quality of life in CSU patients [5, 12].

**Coagulation pathway:** Specific studies have demonstrated that the coagulation pathway is activated in CU and involves first the extrinsic pathway followed by

### *Chronic Spontaneous Urticaria – Diagnosis and Management DOI: http://dx.doi.org/10.5772/intechopen.97646*

the intrinsic pathway. This activation of coagulation pathway is thought to be an intermediate step in CSU pathophysiology [4, 11].

**Drugs** have been implicated in CU development. The commonest include angiotensin- converting enzyme (ACE) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) [3, 5]. NSAIDs are an aggravating factor in 12–30% of CSU patients [3, 5]. They can also induce urticaria/angioedema in the absence of urticaria history [5]. ACE inhibitor – induced urticaria/angioedema is caused by non-immunologic accumulation of bradykinin and other neurokinins [5] and can occur from weeks to years after ACE inhibitor therapy is commenced.

**Food:** Type I food allergy is a rare cause of CSU. It should be considered in patients with intermittent symptoms and within 1 hour of exposure to food [5]. The role of food additives as a cause of CSU is unclear. Some studies demonstrated resolution of CSU symptoms after 14 days of pseudoallergen avoidance in up to 30% of patients [5, 8, 14]. Low serum Vitamin D levels and vitamin D supplementation has been reported to improve small numbers of recalcitrant CSU [8, 15].

**Infections** have been implicated as cause of CSU and include bacterial, viral, parasitic and fungal organisms. Frequency and relevance depend on local population and geographic location [5]. *Anisakis simplex*, a sea fish nematode is relevant in the Mediterranean in the context of CSU [5, 16]. *Helicobacter Pylori* (HP) gastritis has been reported in association with CSU and some studies have reported CSU improvement with HP eradication [3, 5, 8, 17] (**Table 2**).

#### *3.3.1 Contact urticaria*

Not all urticaria are mast cell or histamine dependent. Contact urticaria to sorbic acid, methyl nicotinate, cinnamic acid, cinnamic aldehyde and dimethyl sulfoxide are thought to be due to prostaglandins released directly from the epidermis. They do not respond to treatment with antihistamines but improve with salicylic acid and NSAIDs [5].
