1.1.1.1 Urticaria

15 -20 % of the global population is estimated to have at least one episode of urticarial flare during their lifetime, or acute urticaria. Urticaria is associated in 33-67% with angioedema (see chapter 1.1.1.2). For non-acute urticaria, less information is available. The current estimated point prevalence of chronic spontaneous urticaria (CSU) in worldwide surveys ranges from 0.5% to 1%. The reason for the large variations between these figures is unclear. Possible explanations include differences in the methods employed as well as geographical and cultural characteristics.

Urticaria is a mast cell-driven disease. Histamine and other mediators, such as platelet-activating factor (PAF) and cytokines released from activated skin mast cells, result in sensory nerve activation, vasodilatation and plasma extravasation leading to the formation of urticarial hives. The mast cell-activating signals in urticaria are poorly defined and likely to be heterogeneous and diverse. The non-lesional (uninvolved) skin of chronic spontaneous urticaria (CSU) patients shows upregulation of adhesion molecules infiltrating eosinophils and altered cytokine expression. Some authors have also reported a mild to moderate increase of mast cell number in the chronic type. Skin affected by wheals virtually always exhibits upregulation of endothelial cell adhesion molecules, neuropeptides and growth factors. These findings underline the complexity of the pathogenesis of urticaria, which is composed of the wide spectrum of different features in addition to the release of histamine and other mediators from dermal mast cells. Some of these features, characteristic for urticaria are also detected in the whole variety of different inflammatory conditions and are thus considered to be not specific or of any diagnostic value.

A sudden appearance of raised erythematous lesions (wheals, hives), developing within the time period ranging from minutes to a few hours.  It is accompanied by pruritus and/or burning sensation. The lesion presents the tendency to enlarge to the margins and show a flattening in the middle often leading to a circular pattern until they flatten more and more and finally disappears. Angioedema often occurs simultaneously with the hives. If individual hives persist for more than 24 hours, the possibility of another pathology i.e., urticarial vasculitis must be considered (skin biopsy is very much useful at that stage).

Hives may appear on any part of the skin (no specific skin region). They are of different sizes, as well as shapes and may aggregate into plaques. Hands and feet are prone to present with angioedema (rather than hives), and may significantly impair the normal mobility of the fingers and wrists. Angioedema also tends to involve eyelids and lips. Some special types of urticaria are of a papular morphology and follicular distribution as in e.g., cholinergic urticaria.

The spectrum of clinical manifestations of different urticaria subtypes is very wide. Additionally, two or more different subtypes of urticaria may coexist in case of one particular patient.

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

• Chronic Spontaneous Urticaria is characterized by the appearance of wheals, angioedema or both for > 6 weeks due to known or unknown causes.

• Chronic Inducible Urticaria include: symptomatic dermographism, cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria and aquagenic urticaria.

Triggers or exacerbating factors affecting acute and chronic urticaria may vary. IgE-mediated allergic reaction (Type I Reaction) caused by hypersensitivity to specific foods, medications, venom allergens (bee or wasp and other stinging insects), foreign proteins and other exogenous materials such as latex or plant products (contact urticaria) are sometimes involved.

Chronic Urticaria is mostly an autoimmune-related process (e.g., autoantibodies against IgE or the FcE-receptor, IgE against autoantigens). Also, non-immunological factors (pseudoallergic) may be involved as direct mediator release from mast cells: caused by foods/food additives/medications i.e. NSAID (non-steroidal anti-inflammatory drugs). Commonly severe features with emotional impact in the patient prone to develop chronic urticaria can be involved as triggers. Other underlying diseases such as intestinal parasitic infestations, foci of infection, thyroid diseases, liver diseases (viral hepatitis), other viral infections, connective tissue autoimmune disorders may occasionally be present in acute and chronic urticaria.

Acute urticaria usually does not require a diagnostic workup, as it is usually self-limiting. The only exception is the suspicion of acute urticaria due to a type I food allergy in sensitized patients or the existence of other eliciting factors such as non-steroidal anti-inflammatory drugs (NSAIDs). In this case, allergy diagnostic tests as well as educational programs for patients are very useful and allow patients to avoid re- exposure to relevant causative factors. In Chronic Spontaneous Urticaria, limited set of investigations  is recommended. Basic tests include differential blood count and CRP and/or ESR. In CSU, further diagnostic measures based on the patient history and examinations are recommended. Such will help to identify clinically the most common endotypes including baseline total IgE and IgG- anti TPO. An extensive study can be considered especially in patients with long-standing and/or uncontrolled disease including cutaneous biopsy. Standardized provocation testing to diagnose chronic inducible urticaria are required for an accurate diagnosis.

Histologically, wheals are characterized by edema of the upper and mid dermis, with dilatation and augmented permeability of the post-capillary venules, as well as lymphatic vessels of the upper dermis leading to leakage of serum into the tissue. In angioedema, similar changes occur primarily in the lower dermis and the subcutis. Usually, a minimal cellular infiltrate is observed. If a mixed inflammatory perivascular infiltrate of variable intensity, consisting of neutrophils with or without eosinophils, basophils, macrophages, and mainly T-cells. Specific triggers such as drugs and autoimmune processes are often responsible for the development of inflammatory infiltration. Vessel-wall necrosis, which is a hallmark of urticarial vasculitis or other types of vasculitis is not observed.

Chronic spontaneous urticaria is a disease of long duration. One or more than one episode of Chronic Spontaneous Urticaria can be suffered by the patient long lasting among 1 to 5 years each.  There are four factors that seem to be associated with a long duration of urticaria:

1. Disease activity

2. Angioedema

3. Combination of chronic spontaneous urticaria with inducible urticaria

4. Autoreactivity (positivity in the autologous serum skin test).

Patients suffer significantly from the relapsing and chronic course of the disease.

Anaphylactic shock may occur in patients with the pre-existing urticaria, in such cases other diagnoses should be also considered such as acute urticaria of allergic origin, acquired cold urticaria or cholinergic urticaria. Anaphylaxis is not common in Chronic Spontaneous Urticaria. Of all diagnostic procedures, a thorough history is regarded as most important.

Urticaria should be differentiated from other medical conditions clinically presenting with wheals, angioedema, or both, e.g., anaphylaxis, autoinflammatory syndromes, urticarial vasculitis, or bradykinin-mediated angioedema including hereditary angioedema (HAE) and maculo-papular cutaneous mastocytosis (formerly called urticaria pigmentosa). If individual hives persist for more than 24 hours, the possibility of urticarial vasculitis must be considered (in such cases skin biopsy is recommended). Other diseases such as syndromes that can manifest with wheals and/or angioedema are not considered to be subtypes of urticaria, due to their distinctly different pathophysiologic mechanisms. An important differential diagnosis in this context is Sweet’s Syndrome.

The first step in the management is the attempt to identify and eliminate underlying cause(s) and/ or eliciting trigger(s). A thorough case history is essential.

The second step consist in several therapeutic approaches aimed at providing symptoms relief. While eliminating the cause is the most desirable option, this seems to be not applicable in many cases. Currently, an intensive diagnostic program is recommended, particularly for patients that suffer from long-standing and severe urticaria (S3 guidelines). The objective is to obtain complete control of the signs and symptoms as quickly as possible and treat the disease until it is completely controlled by the effective and safe management. For Chronic Urticaria, the use of second generation anti H1 at licensed dose and at higher doses is recommended. In case the high dosage anti H1 fails the recommendation is to add anti-IgE therapy, nowadays omalizumab and its biosimilar. There now new even more effective drugs to come for prescriptions such as the Bruton Tyrosinase Inhibitors (BTK’s fenebrutinib, remibrutinib, rilzabrutinib) which are essential for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Targeting the hive inflammatory infiltrate and pruritus dupilumab is also proposed as active treatment for CSU. Actually omalizumab, remibrutinib and dupilumab obtained the indication to treat Chronic spontaneous urticaria refractory to anti-H1.

Ciclosporin is also an effective drug for CSU, dedicated to patients with no response to omalizumab. A good number of alternative treatments may be considered e.g., methotrexate. Some special diets, which limit or eliminate certain allergens or pseudoallergens, can be considered. However, validated in vitro and in vivo test results must be verified before commencement of such treatment.