Speaker: Sophia TSABOURI
Refractory urticaria in children under 15 years old does not show a gender preference and is equally common among boys and girls. It is most prevalent in Latin America and Asia. In Europe, it is most common in France and least common in Germany, particularly affecting children aged 7-11 years. Refractory urticaria refers to cases where children do not respond to any dose of antihistamines or Omalizumab or in combination. The condition can become severe, similar to adult urticaria, but the disease course differs between children and adults. Children who do not respond to fourfold increased doses of standard second-generation antihistamines prescribed for at least three continuous months and often require repeated short-term courses of oral steroids, at least one course per month. Therapy aims to achieve symptom control, improve quality of life, and minimize therapy-related side effects. Patient preferences vary; those who can be controlled wish to minimize medication use due to fears about antihistamines. They need to be convinced to accept a low level of ongoing symptoms. Importantly, urticaria does not lead to permanent organ damage and usually resolves in most patients with or without treatment, though serious side effects from treatment are not guaranteed. The Urticaria Control Test (UCT) is used to assess disease control. A UCT score of 16 indicates controlled disease, while a score below 12 indicates uncontrolled disease, requiring increased antihistamine doses and Omalizumab. A score between 12 and 15 indicates the disease is well controlled, allowing for continued therapy and optimization. Once a UCT score 16 is reached, therapy can be stepped down.
All guidelines recommend administering second-generation antihistamines for treatment. If necessary, the dosage can be doubled every two to four weeks. Should symptoms persist, the interval between doses can be shortened, and another step in the treatment can be taken by adding Omalizumab to the second-generation antihistamines. If symptoms continue, cyclosporine may be added, but guidelines advise against using cyclosporine before Omalizumab. Steroids should be used only as a third-line treatment and only for short periods. A task force team of esteemed colleagues aims to refine diagnosis and management practices for urticaria and the use of relevant drugs. In Europe, treatment generally adheres to these guidelines, though Northern Europe may follow their national guidelines more strictly. The adherence to these protocols has resulted in a high response rate of up to 74% using standard and double doses of antihistamines, suggesting that there may be no need to triple or quadruple the dosage.
The findings from two double-blind, randomized control trials involving 605 patients indicate that rupatadine's efficacy is comparable to the standard dose, even at double the standard dose. Among patients who received three to four full doses, 80% required subsequent treatment with Omalizumab. Approximately 75% of patients responded to double doses, while those who did not respond to higher doses (three to four times the standard) needed Omalizumab. Safety data suggest that the type and higher doses of antihistamines are generally safe, although there is no clear guidance on the optimal duration for up-dosing. For patients with chronic urticaria unresponsive to approved doses, 50% of physicians wait two weeks before increasing the dose, influenced by patient or parental pressure, while 20% wait four weeks. In the treatment analysis, steroids are used in about 60% of third-line treatments, with geographical differences noted: southern regions use 12% steroids, 21% Omalizumab, 11% Montelukast, and 0.8% Cyclosporine, while 5% of treatments involve first-generation antihistamines for quick results. The research team is working on optimizing treatment protocols and will publish the results soon.
The guidelines strongly advise against the use of oral steroids for treating hives in children, as they are not evidence-based and can potentially worsen the condition. Despite this, some physicians may resort to oral steroids for quick relief, but this is not recommended. A task force is working on establishing a treatment algorithm for assessing and managing children with hives. The study compared children treated with a standard dose of antihistamines to those treated with four times the standard dose across three age groups: 0-4, 5-11, and 12-18 years. Results showed that higher doses of antihistamines were more effective in controlling hives, though some children still required further treatment. A 2020 study found that about 10-11% of children on high-dose antihistamines needed Omalizumab, which is supported by guidelines. Omalizumab inhibits the interaction between IgE and its receptor, preventing the activation of mast cells and basophils, making it effective for urticaria. In practice, 25% of physicians use Omalizumab as a third-line treatment, particularly for chronic spontaneous urticaria. The drug is typically prescribed to children over 12 years old, as physicians feel more comfortable with this age group and because it is approved for this use in many countries. Physicians usually administer Omalizumab every four weeks at a dose of 300 mg, though some use lower doses (150 mg) for younger children, indicating a lack of familiarity or comfort with the higher doses in these age groups.
Omalizumab can effectively bind to IgGs and form complexes with IgE antibodies. Children with a slow response to Omalizumab often exhibit type two autoimmunity, characterized by a slow loss of high-affinity membrane receptors. This results in a delayed adaptation to the treatment. A major issue with Omalizumab is the relapse that occurs after discontinuing treatment. Studies show that longer durations of Omalizumab treatment result in fewer relapses. For patients refractory to initial doses of Omalizumab, reconsideration of dosage is necessary before escalating to stronger therapies like cyclosporine. Although data for children is limited, guidelines suggest considering cyclosporine when antihistamines plus Omalizumab are insufficient or unavailable. Cyclosporine can provide complete resolution within two days to three months, with no adverse effects when used safely. Interestingly, 50% of physicians use cyclosporine for patients refractory to Omalizumab, while 20% use steroids. The Urticaria Control Test (UCT) is the primary tool for evaluating response to Omalizumab in chronic spontaneous urticaria patients. However, the long-term impact of Omalizumab is questionable as relapses can occur post-discontinuation. Urticaria often resolves naturally within a few years, making it challenging to assess the long-term efficacy of treatment. Studies indicate no correlation between treatment response and factors like age, medication, UAS, angioedema, gender, and abnormal laboratory results.
A study investigated the remission rate and prognostic factors of urticaria, showing that it is better controlled with a standard dose of antihistamines, which predicts a good prognosis. A significant biomarker, IgE, was identified to predict better treatment outcomes. The study involved 142 patients aged 1 to 16, with an average UST7 score of 23 initially. After antihistamine treatment, there was a decrease in VCAM and ICAM molecules, which play a role in the pathogenesis of urticaria. This reduction correlated with a lower UST7 score. The study found that remission rates are significant, with about 50% remission at 1 year and approximately 60% after 4 years. For patients who relapse after discontinuation of treatment, re-treatment with Omalizumab is recommended. If Omalizumab is unavailable, patients are treated with antihistamines, possibly increased dosages, and short-term steroids. The study emphasized the need to reassess patients after three to six months of being symptom-free and to consider the quality of life for patients and their families. In conclusion, although chronic urticaria can be challenging, it often remits over time. Second-generation antihistamines, with up to fourfold dosages, are the main treatment, and around 10% of refractory cases in children may require Omalizumab.
European Academy of Allergy and Clinical Immunology (EAACI), 2024 31st May-3rd June, Valencia
