Hive, a terrible itch – urticaria care in Ireland

Urticaria is from the Latin ‘urtica’ meaning nettle. Most of us have experienced the itchy red, lumps arising from an unintentional brush with this common garden weed, followed by a frantic search for a dock leaf to alleviate symptoms. Nettle stings cause a type of contact urticaria that is both mechanical (tiny sharp spicules penetrate the skin) and biochemical (formic acid and histamines).

This symptom is implicated in many disease processes and, frustratingly, its most common form is spontaneous, arising without provocation. This article will address the different types of urticaria and treatment options, including their accessibility.

Chronic spontaneous urticaria and angioedema (CSUA) is characterised by the sudden appearance of hives/wheals, angioedema, or both. Wheals are defined as transient, erythematous, blanching, and oedematous swellings of the skin that are usually intensely pruritic but non-tender, while angioedema refers to a deeper form of swelling of the dermis and subcutaneous tissue.

Angioedema is associated with approximately 40 per cent of cases of CSUA. The lifetime prevalence of urticaria in the general population is estimated to be around 20 per cent, with chronic forms affecting 1 per cent at any given time.

Many people are referred to immunology services to identify a cause for chronic urticaria, but in most adults there is no triggering allergen. CSUA is not an allergy. A study carried out in the Immunology Department of St James’s Hospital, Dublin, in 2014 revealed 5 per cent of referrals received queried CSUA as the working diagnosis, whereas 56 per cent of patients referred in that timeframe were diagnosed with CSUA (n=93).

Chronic spontaneous urticaria refers to hives that occur sporadically without any obvious trigger, lasting for longer than six weeks. It is three times more common in women than men. It can have a protracted course with mean time to diagnosis in Europe of two-to-four years.

Patients with chronic urticaria have reduced quality-of-life as assessed by patient-reported questionnaires and have poor sleep quality. Despite its common occurrence, urticaria can significantly impair patients’ physical and emotional wellbeing. Comorbid mood disorders such as anxiety and depression are common.

Pathophysiology

The pathogenesis of urticaria involves a complex interplay of immunologic and non-immunologic mechanisms. The hallmark of the condition is the release of histamine and other inflammatory mediators from mast cells and basophils in the skin. In the case of acute urticaria, this may be triggered by food allergens or medications. In chronic spontaneous urticaria, where no exogenous stimuli are implicated, autoantibodies against the high-affinity IgE receptor (FcεRI) or IgE itself can lead to mast cell degranulation.

Classification

Urticaria can be classified based on its duration and triggers. Acute urticaria lasts less than six weeks and is often associated with a hypersensitivity reaction to infections, drugs, or food. Viral infections are a common cause of acute urticaria in children. Chronic urticaria persists for more than six weeks, with CSUA and chronic inducible urticaria (CIndU) being its main subtypes.

CSUA occurs without an identifiable trigger, whereas CIndU may be provoked by specific stimuli such as temperature or pressure. CIndU can also be factitious. CSUA is diagnosed when a patient experiences urticaria daily or almost daily for six weeks, in the absence of a history consistent with allergy or inflammatory disease.

Clinical manifestation

The clinical presentation of urticaria varies among patients. Wheals are typically round or annular, pruritic, and resolve without scarring within 24 hours. Hives that resolve with bruising could be a sign of vasculitis and need to be investigated further. Angioedema, which may accompany urticaria or occur independently, is characterised by deeper, more painful swellings that can last up to 72 hours.

Diagnosis

The diagnosis of CSUA is primarily clinical with the main focus of patient assessment being a detailed history and clinical examination. Unless the patient is presenting during a flare, they may not have any skin findings. Residual marks of urticaria can often be seen on examination in the form of excoriation marks.

Check for dermographism, scratch an area of skin on the patient’s arm or back, using a tongue depressor, and assess for response after five minutes. It is always worthwhile asking the patient if they have any photographs of their skin when symptomatic; review the photos and document findings in the clinical notes.

Urticaria can be exacerbated by NSAID use and patients with urticaria should be advised to avoid these medications. In a patient with hypertension who presents with new onset angioedema, it is important to bear ACE inhibitor-induced angioedema in mind. Symptoms of this form of angioedema resolve on ACE inhibitor discontinuation. Laboratory tests and skin provocation tests may be employed to identify underlying causes, particularly in chronic or inducible forms.

Management

The management of urticaria focuses on symptom relief, identification and avoidance of triggers (if any). For the majority of patients, they can be managed effectively in the primary care setting. First-line therapy includes second-generation H1 antihistamines, which are preferred to first-generation antihistamines, due to their efficacy and low sedative effects.

For patients unresponsive to standard doses, the European Academy of Allergy and Clinical Immunology recommends up to a four-fold increase in the dose. High-dose antihistamine prescriptions for the treatment of CSUA can often result in phone calls from the pharmacy to ensure correct dosing. Some common dosing regimens are outlined below:

• Telfast 180mg QDS;
• Bilastine 40mg BD;
• Cetirizine 10mg QDS;
• Loratadine 10mg QDS;
• Desloratadine 5mg QDS.

If control is still not achieved, addition of H2 antihistamines, leukotriene receptor antagonist (montelukast), or an anti-IgE monoclonal antibody (omalizumab) may be considered. Montelukast is best used in patients with concomitant atopy, allergy, or nasal polyps. Avoid if the patient has a significant psychiatric history as side-effects include nightmares or sleep disturbance. Additional treatments for chronic or refractory cases include omalizumab, ciclosporin, methotrexate, azathioprine, high-dose intravenous immunoglobulins, or dapsone.

Omalizumab

Omalizumab is a monoclonal anti-IgE antibody which leads to downregulation of FcεRI on mast cells and basophils. The drug currently costs approximately €1,000 per month. Omalizumab, for patients with CSUA, is only accessible to those under the care of a specialist centre. On commencing injections, it requires in-hospital administration for the first four doses.

Home administration of omalizumab is an option for suitable candidates once they are established on treatment – this requires initial education and ongoing support. Home administration reduces the frequency of hospital visits for patients.

In 2021, a retrospective review of 47 patients commenced on omalizumab for CSUA was carried out in St James’s Hospital. Unplanned primary and secondary care attendances and urticaria symptomatology were evaluated before and after treatment with omalizumab.

As expected, patients with refractory disease that were commenced on omalizumab had objective improvements in urticaria symptoms, which was reflected in a dramatic reduction in unplanned healthcare interactions at primary care and emergency departments.

Emerging therapies

Recent advances in the understanding of the pathophysiology of CSUA have led to the exploration of novel therapeutic targets. Biologic agents, such as ligelizumab, an alternative anti-IgE monoclonal antibody and inhibitor of mast cell signalling pathways, are currently under investigation. Janus kinase (JAK) inhibitors for CSUA are another treatment currently under development. These emerging therapies offer hope for improved management of refractory cases.

Like most chronic conditions, it is important to know when to refer to a specialist centre. Referral should be sent when a patient’s symptoms are refractory to high-dose antihistamines for consideration of additional therapies such as omalizumab. CIndU can be particularly challenging to treat, if avoidance of triggers is impossible, this may also prompt referral to a specialist centre.

Specialist centre

In 2022, St James’s Hospital, was designated Ireland’s first UCARE Centre (Urticaria Centre of Reference and Excellence) following accreditation from the Global Allergy and Asthma European Network (GA2LEN).

The UCARE accreditation outlines a comprehensive protocol that aims to provide excellence in urticaria management, to increase the knowledge of urticaria through research and education, and to promote the awareness of urticaria by advocacy activities. This work was led by Prof Niall Conlon, Consultant Clinical Immunologist; Dr Cliodhna Murray, Immunology Specialist Registrar; and Dr Katie Ridge, Immunology Specialist Registrar and Wellcome Health Research Board ICAT Fellow.

Specialist urticaria clinics offer patients protocol driven treatment and can identify resistant cases that require third- or fourth-line interventions. However, a centralised specialised clinic can be burdened with long waiting times and once attending the clinic, patients are usually reluctant to return to their primary care physician for management of their condition. The need to equip both patients and healthcare professionals with a greater understanding of CSUA is imperative.

October 1 is designated Chronic Urticaria Awareness Day. To celebrate the day in 2023, St James’s Hospital teamed with the Irish Skin Foundation (ISF) to provide accurate online information about urticaria. This is available at https://irishskin.ie/urticaria/. It is an invaluable resource for healthcare professionals and the public, giving a jargon-free overview of urticaria and its management. The ISF website also gives access to the ‘Ask A Nurse’ service. This is an email helpline providing free and specialist guidance on living with a chronic skin condition.

In summary

In the vast majority of cases, no trigger is identified in CSUA making it an understandably frustrating condition for patients. As part of a search for a ‘cause’ of their symptoms, patients may seek out allergy testing or engage in restrictive diets. A study in 2020 by King et al revealed that Ireland has the highest frequency of Googling allergy testing per capita worldwide.

Furthermore, the proportion of evidence-based websites in the first five search results is lower than that of google searches in other urban areas. The provision of accurate information on CSUA as well as its management can reassure patients and give them better control over their symptoms.

Chronic urticaria is a debilitating condition which can be challenging for clinicians to treat. In most cases, CSUA can be managed in the community. Understanding the complex pathophysiology, clinical diversity, and evolving treatment landscape is essential for improving patient outcomes. As research continues to unveil new mechanisms and therapeutic targets, the prospects for patients with chronic urticaria looks increasingly promising.