Background
Chronic spontaneous urticaria (CSU) is defined as the spontaneous appearance of itchy weals, angioedema, or both, for at least 6 weeks [
1]. It is a self limiting disorder, persisting for 2–5 years in the majority of cases, although 20% of patients suffer for more than 5 years [
2]. Beyond the visual impact of weals and angioedema, quality of life is substantially reduced in patients due to interference with sleep, daily activities, social interaction, work productivity [
3] and emotional well-being [
4]. There is also a high socioeconomic impact from both the direct (medication and healthcare visits) and indirect costs (absence from or reduced efficiency while at work) [
5,
6].
The introduction of omalizumab as an add-on therapy to H1 antihistamines as a management option has markedly improved the therapeutic possibilities for both CSU patients and physicians dealing with this chronic disease. Nevertheless, there are still many patients who do not tolerate or benefit from existing therapies including omalizumab.
This review describes possible future treatment options and novel therapeutic targets in CSU based on the pathophysiology of the disease and summarizes ongoing clinical studies in CSU.
Pathophysiological events in chronic spontaneous urticaria
Understanding the pathophysiology of urticaria is important for the identification of potential targets for novel treatments. Weals and angioedema in CSU result from the degranulation of skin mast cells, which release histamine, proteases and cytokines with generation of platelet-activating factor and other arachidonic acid metabolites (prostaglandin D2, leukotrienes C4, D4 and E4). These mediators induce vasodilatation, increase vascular permeability, and stimulate sensory nerve endings that lead to swelling, redness and itch [
7].
The weal is characterized by dermal oedema, vasodilatation and a perivascular mixed infiltrate composed of predominantly CD4+ lymphocytes with variable numbers of monocytes, neutrophils, eosinophils and basophils similar to allergen-mediated late-phase skin reactions, but the cytokine profile is characterized by an increase in IL-4, IL-5 and interferon-gamma, which is suggestive of a mixed Th1/Th2 response [
8‐
10]. Cytokines that promote a Th2 profile of inflammation [IL-33, IL-25 and thymic stromal lymphopoietin (TSLP)], are increased in lesional but not uninvolved skin [
11]. Vascular markers, with eosinophil and neutrophil infiltration, are dominant in lesional skin, whereas eosinophils and microvascular changes persist at uninvolved sites by comparison with healthy controls. They may prime the skin for further wealing in conjunction with increased mast cell numbers [
12]. Biopsies from both lesional and nonlesional skin of CSU patients show upregulation of soluble mediators and adhesion molecules, which is indicative of a “widespread immunologic activation” possibly lowering the threshold of mast cell degranulation to triggering stimuli [
13‐
15]. Some authors suggest that CSU is an “immune-mediated inflammatory disorder” that involves an immunological activation event following exposure to an exogeneous or modified endogeneous trigger (such as functional autoantibodies) in the presence of susceptibility factors (e.g. stress, pathogen exposures) [
16]. The inflammatory cascade in CSU may be modulated by an altered chemokine–cytokine network and is attributed to immune dysregulation as a consequence of disturbed innate and adaptive immunity [
15].
The mechanisms by which cutaneous mast cells are activated to induce hives in CSU are still not completely understood. It is widely accepted that CSU is due to autoimmune/autoreactive mechanisms in some patients. There is considerable evidence for a role and clinical relevance of functional IgG autoantibodies to IgE or to the extracellular α subunit of the high affinity IgE receptor (FcεRIα) in approximately 30–50% of patients [
17,
18]. These autoantibodies belong mainly to the complement fixing and activating subtypes IgG1 and IgG3. The activation of complement generates C5a, which interacts with the C5a receptor on the surface of skin mast cells and induces activation [
19].
The stimulus for mast cell activation in the remaining 50–70% of urticaria patients is less clear. They potentially include IgE antibodies against autoallergens, neuropeptides such as substance P, alarmins and complement activation due to chronic infections [
20,
21]. The relevance of observed coagulation abnormalities on mast cell degranulation is uncertain although a role for thrombin generated by extrinsic factor activation has been proposed [
22].
Basophils also appear to be involved in the pathogenesis of CSU. Peripheral blood basopenia is seen in patients with high disease activity and may be explained by the recruitment of basophils from the blood into skinlesions [
23]. CSU basophils also show functional abnormalities during active disease that revert during disease remision. Greaves was first to show the hyporesponsiveness of basophils of patients with CSU to anti-IgE [
24]. Reduced basophil responsiveness to anti-IgE and altered signal transduction are reportedly seen in at least half of the patients [
24‐
28]. Vonakis and coworkers reported basophil hypo-responsiveness in about half of the patients with chronic urticaria that is linked to excessive activity of the negative regulator Src homology inositol phosphatase (SHIP). SHIP dephosphorylates kinases such as spleen tyrosine kinase (Syk) and consequently decreases cell responsiveness. Reversal of anti-IgE hypo-responsiveness was observed upon disease remission, which suggests a relationship with the disease pathogenesis [
28].
The current guidelines for CSU recommend the use of non-sedating H1 antihistamines followed by leukotriene antagonists (LTRA), ciclosporin and omalizumab as add-on treatment to antihistamines. Although histamine is a major contributor, approximately 40–55% of patients are refractory and achieve little or no benefit even from updosing antihistamines [
29]. Leukotriene inhibitors are not superior to placebo or H1 antihistamines and should be used in combination with an antihistamine [
30]. Ciclosporin is often effective, especially in patients with a positive basophil histamine release assay [
31], but some patients do not tolerate treatment or have to be discontinued due to adverse events. Ciclosporin is generally used in short courses but long term treatment with low doses has been reported to be safe and effective [
32]. Omalizumab has provided a substantial advance in the treatment of CSU, but not everyone responds, the drug is expensive and is not readily available for many patients in many countries.
Conclusion
CSU is a chronic disabling inflammatory skin disease, which is in many cases well-controlled by the existing licensed treatment options. In approximately 1 of 5 CSU patients, these treatment options are not sufficient. Novel drugs are needed and are under development. Ligelizumab, PGD2 receptor antagonists, a topical Syk inhibitor, and canakinumab are promising candidates for future CSU treatment options and are currently being tested in clinical trials for their efficacy and safety in CSU. Substance P antagonists, DARPins, blockers of C5a/C5aR, therapies targeting IL-4, IL-5 and IL-13, and drugs that target inhibitory mast cell receptors should be tested in controlled CSU trials. Many other mediators and receptors are held to be of pathogenic relevance, and this should be explored in skin profiling studies and functional proof of concept studies.
One important point must not be forgotten when we search for new and better medication for the prevention and symptomatic treatment of CSU; the ultimate goal is to develop strategies and drugs that can cure CSU, rather than stop the signs and symptoms. The exploration of novel therapeutic targets for their role and relevance in CSU can help to achieve this, by providing a better understanding of its etiopathogenesis.
Authors’ contributions
Conceived and designed the study: EK and CG. Wrote the manuscript: EK. Critically reviewed and revised the manuscript: CG, MM, MM. Final language editing: CG. Agreement with manuscript and conclusions: all designed the figures and tables: MM, EK. All authors read and approved the final manuscript.