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Urticaria care in Ireland

By Prof Niall Conlon, Dr Aoife Gaffney and Dr Katie Ridge - 03rd Mar 2024

Urticaria

Chronic urticaria is a debilitating condition which can be challenging for clinicians to treat, but there are treatments and support as well as a specialist centre now in Ireland

Case report

A 37-year-old woman was referred to the immunology clinic with a three-month history of intermittent, red, itchy rash. She thinks that the rash might be associated with dairy intake and has eliminated this from her diet, but unfortunately, her symptoms have not resolved. She also complains of subtle lip and eye swelling that is not necessarily related to her rash. Her symptoms occur about three times a week and she describes frequently waking up with rash or swellings. She is otherwise systemically well. She has a background history of hypothyroidism that is well controlled. She is not taking any new medications. She is keen to find out what she is allergic to and would like to be referred for allergy testing. She has no rash visible on review, but skin testing is positive for dermographism.

Following history and examination, as well as review of photographs of the rash, the patient is diagnosed with chronic spontaneous urticaria and angioedema (CSUA) and is commenced on 40mg BD of antihistamine bilastine. She is reassured that this condition is not caused by an allergy to food or medicines. Further review in four months demonstrates an improvement in symptoms, but no resolution with ongoing impact on quality-of-life. Urticaria Control Testing (UCT) score is 5, suggesting poor symptom control. She is evaluated for omalizumab, an anti-IgE monoclonal antibody.

She attends the day ward to start on subcutaneous injections of omalizumab 300mg every four weeks. Six weeks after commencing treatment she has noticed a significant improvement in her symptoms. With nursing support, she is transitioned to home therapy where she administers the injections herself on a monthly basis. At follow-up six months later her updated UCT score is 13.

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 in adults is spontaneous, meaning it arises without a specific modifiable provocation. 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. This article will address the different types of urticaria and treatment options, including their accessibility.

Chronic spontaneous urticaria (CSU) ocurring with or without angioedema 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. 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 CSU. 

Many people are referred to immunology services to identify a cause for chronic urticaria, but in most adults there is no single modifiable allergic trigger. CSU is not an allergy. A  2014 examination of primary care allergy referrals to a major Irish immunology centre indicated that only 5 per cent were referred with a diagnosis of CSU, with 56 per cent having this as the final diagnosis. The overwhelming majority of these referrals were sent to investigate food allergy (n=93). 

CSU refers to hives that occur sporadically without any obvious trigger, lasting for longer than six weeks. Despite its common occurrence it is frequently misdiagnosed. 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. Urticaria can significantly impair patients’ sleep quality, physical and emotional well-being and reduce quality of life. 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 infection, food allergens, or medications. In CSU, 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 CSU and chronic inducible urticaria (CIndU) being its main subtypes. CSU occurs without an identifiable trigger, whereas CIndU may be provoked by specific stimuli such as temperature or pressure. CIndU can also be factitious. CSU 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 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 CSU 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 sometimes be seen on examination in the form of excoriation marks. It is important to 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 isolated angioedema, it is important to bear ACE inhibitor-induced angioedema in mind. Symptoms of this form of angioedema resolve on ACE inhibitor discontinuation. Skin provocation tests may be employed to identify underlying causes, particularly in chronic or inducible forms. As it is a clinical diagnosis, laboratory tests are often not required for the assessment of urticaria disorders. In particular, allergen sensitisation testing by skin prick testing or specific IgE testing is not relevant and may cause confusion for both patient and doctor. Screening for IgE mediated food allergies should be avoided when it is not supported by a clear history with a temporal association between symptoms and allergen exposure.

Management

The management of chronic urticaria focuses on symptom relief. 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 (EAACI) recommends up to a four-fold increase in the dose. High-dose antihistamine prescriptions for the treatment of CSU can often result in phone calls from the pharmacy to ensure correct dosing. Though unlicensed, these higher doses are widely used, safe and effective. Some common dosing regimens are outlined below:

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

If the patient fails to respond to high-dose antihistamines, then progression to more advanced therapies that require specialist assessment is needed. The majority of cases of urticaria resistant to high-dose antihistamines will respond to anti-IgE therapy in the form of omalizumab. A minority of individuals respond poorly or not at all, requiring higher doses of omalizumab. Patients that fail treatment with omalizumab may benefit from treatment with the calcineurin inhibitor ciclosporin. This immunosuppressant therapy is often well tolerated, but needs careful patient monitoring for its well-known toxic effects. Efforts continue to try to endotype patients and select the best therapy in the most timely manner. A small number of cases remain poorly controlled despite these approaches. The management of these highly-refractory cases is uncertain and based on limited evidence with a variety of agents including methotrexate, azathioprine, dapsone, and high-dose IVIG being trialled.

Omalizumab

Omalizumab is a monoclonal anti-IgE antibody which leads to downregulation of FcεRI on mast cells and basophils. It has revolutionised the management of patients with CSU.  Omalizumab, for patients with CSU, is only accessible to those under the care of a specialist centre. It is an expensive agent and is not currently available in Ireland for community reimbursement. On commencing injections, it requires in-hospital administration for the first three doses. Omalizumab is licensed for home administration but this is not widely available in Ireland. St James’s Hospital, Dublin, runs a home treatment service for suitable candidates once they are established on treatment, and this requires initial education and ongoing support. Home administration reduces the frequency of hospital visits for patients and increases patient satisfaction with the treatment programme.

In 2021, a retrospective review of 47 patients commenced on omalizumab for CSU 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 CSU 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, have proven disappointing. Candidate small molecules such as the bruton tyrosine kinase (BTK) inhibitor remibrutinib have delivered promising results. Other approaches including mast cell depletion with anti-c-kit monoclonal antibodies and janus kinase (JAK) inhibitors are also being explored. 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 occur 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- orfourth-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 CSU is imperative.

October 1 is designated Chronic Urticaria Awareness Day. To celebrate the day in 2023, St James’s teamed up 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 ISF 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 CSU, 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 comparable population centres. The provision of accurate information on CSU 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, CSU 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.

References

Conlon NP, Abramovitch A, Murray G, et al. Allergy in Irish adults: A survey of referrals and outcomes at a major centre. Ir J Med Sci. 2015;184:349-352

Conlon NP, Edgar JDM. Adherence to best practice guidelines in chronic spontaneous urticaria (CSU) improves patient outcome. Eur J Dermatol. 2014;24:385-386

Donnelly J, Ridge K, O’Donovan R, et al. Psychosocial factors and chronic spontaneous urticaria: A systematic review. BMC Psychol. 2023;11:239

Ferrer M, Sastre J, Jáuregui I, et al. Effect of antihistamine up-dosing in chronic urticaria. J Investig Allergol Clin Immunol. 2011;21(Suppl 3):34-39

King C, Cox F, Sloan A, et al. Rapid transition to home omalizumab treatment for chronic spontaneous urticaria during the Covid-19 pandemic: A patient perspective. World Allergy Organ J. 2021;14:100587

King C, Judge C, Byrne A, Conlon N. Googling allergy in Ireland: Content analysis. J Med Internet Res. 2020;22:e16763

Ridge K, Redenbaugh V, Conlon N. Omalizumab reduces unplanned healthcare interactions in Irish patients with chronic spontaneous urticaria. Front Allergy. 2021;2:810418

Weller K, Groffik A, Church MK, et al. Development and validation of the urticaria control test: A patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol. 2014;133:1365-1372.e6

Zuberbier T. Pharmacological rationale for the treatment of chronic urticaria with second‐generation non‐sedating antihistamines at higher than standard doses. Acad Dermatol Venereol. 2012;26:9-18

Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77:734-766

Authors: Prof Niall Conlon, Consultant Immunologist and Head of Immunology Department, St James’s Hospital, Dublin; Dr Aoife Gaffney, Senior House Officer in Immunology, St James’s Hospital, Dublin; and
Dr Katie Ridge, Immunology Specialist Registrar, St James’s Hospital, Dublin, and Wellcome Health Research Board ICAT Fellow

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