Medication Requirements for Disease Control Predict the Prognosis of Chronic Urticaria

Chronic urticaria (CU) is a common skin disease characterized by repetitive wheals and pruritus with or without angioedema lasting for more than 6 weeks.¹ Although CU is considered to be a non-serious and self-limiting disease, its unpredictable and long-term nature has a large impact on the quality of life in terms of impaired productivity in work or daily activity.²,³,⁴

A stepwise treatment of CU is well established by the International Consensus Guideline: 1) second-generation H1-antihistamines for the first step, 2) four-fold dose-up of H1-antihistamines for the next step, 3) omalizumab - humanized monoclonal anti-immunoglobulin E (IgE) antibodies, and/or 4) cyclosporine for CU patients unresponsive to H1-antihistamines.¹ A recent meta-analysis showed that approximately 60% of chronic spontaneous urticaria (CSU) patients who were not responsive to standard doses of H1-antihistamines improved following up-dosing of antihistamines.⁵ In addition, approximately 60%–70% of H1-antihistamine-refractory CU patients were responsive to omalizumab or cyclosporine.⁶ Although most CU patients are well controlled by way of this stepwise approach towards CU treatment, we still do not have accurate information about the prognosis of CU, especially the time to spontaneous remission.

Studies on the natural course of CU are rare, and various results have been reported. Five-year CU remission rate of 86% was reported in a prospective observational study conducted between 1998 and 2003.⁷ According to a Spanish study in 2004, CU was resolved after 1 year in 80%, whereas 11% still had CU after 5 years.⁸ In Korea, a 10-year (2004–2013) follow-up, nationwide, population-based study reported a remission rate for CU of 52.6% at 1 year.⁹ Another study using the Korean Health Insurance Database (2010–2014) reported a one-year CU remission rate of 38.2%.¹⁰ In addition, more than 10% of CU patients were found to be affected for longer than 5 years.⁷,⁸,¹⁰ Little is known about who has a longer duration and/or who needs a higher treatment step among CU patients.

The urticaria activity score (UAS), which assesses the itch severity and hive count, is commonly used to assess and monitor disease activity in CSU patients.¹¹ However, disease activity does not reflect the long-term status of CU; therefore, it has limitations in reflecting the severity of CU. Instead, medication requirements to reach a well-controlled status of CU can better reflect the disease severity of CU. The development of biomarkers associated with disease severity stratified by medication requirements could predict the long-term prognosis of CU patients in real clinical practice.

In the current issue of the Allergy, Asthma and Immunology Research, Ye et al.¹² reported that CU clusters based on daily medication scores (0–70) for the initial 3 months of treatment were useful in predicting long-term treatment outcomes (n = 4,552, retrospective cohort study from 1997–2007), where cluster 1, 2, 3 and 4 represented low, low-to medium, medium and high disease activities, respectively. They found that the CU remission rate differed significantly among the 4 CU clusters. The 1-year remission rates were 37.5%, 32.6%, 11.8%, and 4.2% in clusters 1, 2, 3, and 4, respectively, and the 5-year remission rates were 63.1%, 56.2%, 41.0%, and 30.1% for clusters 1, 2, 3, and 4, respectively. The 10-year remission rates were >70% for clusters 1 and 2, 66.2% for cluster 3, and 53.1% for cluster 4. In addition, as reflected in median years and 95% confidence intervals (CI), time to CU remission was 2.1 (1.8–2.6) for cluster 1, 3.3 (2.9–4.4) for cluster 2, 6.4 (5.6–7.3) for cluster 3, and 9.4 (7.7–10.5) for cluster 4 (P < 0.001). Taken together, the authors suggest that more severe CU with higher medication requirements for urticaria control predicts a lower possibility of remission and a longer time to remission. Ye et al.¹² also found that a strong sensitization to house dust mites (hazard ratio [HR], 0.731; 95% CI, 0.632–0.847; P < 0.001) and female sex (HR, 0.886; 95% CI, 0.795–0.988; P = 0.029) were independent predictors of poor CU remission, while serum total IgE levels showed no influence on CU remission.¹²

Recently, there have been many studies to develop promising biomarkers to predict disease activity, response to specific treatments, and disease prognosis. Higher D-dimer levels were reported to be associated with higher disease activity and poor response to H1-antihistamines and cyclosporine.¹³ Higher total IgE levels were associated with poor response to omalizumab.¹⁴ For a disease course, the presence of antithyroid antibodies is associated with longer disease duration, and higher levels of CD63 expression are associated with earlier spontaneous resolution in pediatric CSU patients.¹³ Furthermore, Bae et al. recently reported that serum transglutaminase 2 (TG2) activity was correlated with CU disease severity, which was stratified by medication requirements for disease control, and response to omalizumab.¹⁵ Thus, several potential biomarkers have been associated with the disease prognosis of CU, but their clinical use in real clinical settings is still remote, as further studies will be needed to validate these biomarkers.

In conclusion, the disease severity of CU stratified by medication requirements is useful for predicting the long-term clinical course of CU such as remission rate and the time to remission. Further studies are needed to develop potential biomarkers of disease severity of CU stratified by medication requirements.