Clustering the Clinical Course of Chronic Urticaria Using a Longitudinal Database: Effects on Urticaria Remission

Chronic urticaria (CU) is defined as transient itchy wheals and/or angioedema present for at least 6 weeks.1 A common allergic skin disease, CU, affects between 0.5% and 5% of the general population,2 and its prevalence in adults and children has been increasing worldwide.3 Reportedly, CU poses significant impairments in quality of life, including loss of productivity, psychological distress, and sleep disturbance.4

Although higher disease severity and the presence of angioedema are associated with a longer duration of urticaria,4 research has yet to propose any significant demographic factors predicting the prognosis of CU. In a previous study published in 2004, urticaria was cleared after 1 year in 80% of 5,003 Spanish patients with CU, whereas 11% still had CU after 5 years.5 For Korea, a 10-year (2004-2013) follow-up, nationwide, population-based study reported a remission rate for CU at 1 year of 52.6%.6 Another study using the Korean Health Insurance Database (2010-2014) noted that 38.2% of CU patients achieved remission within 1 year.7 In addition, more than 10% of CU patients were found to be affected for longer than 5 years.5, 6, 8

Guidelines for urticaria recommend step-wise treatment.1, 2, 9 In the first step, the use of approved doses of non-sedative antihistamines is recommended. For individuals whose urticaria remains uncontrolled after 2–4 weeks of treatment, increasing doses up to 4-fold is considered. For patients with antihistamine-resistant urticaria, the use of omalizumab or cyclosporine is recommended. Based on these stepwise treatment guidelines, a recent study developed medication scores as a means with which to assess treatment intensity or requirements.10 Although variability in treatment steps over time has been shown to be important for forecasting the clinical prognosis of CU patients, to date no recommendations have been given on how to incorporate medication scores into characterization of the clinical course of the disease.

Research has shown that stratifying a population into more homogenous subgroups facilitates better prediction of individualized models. Therefore, by applying medication scores during the initial 3 months of treatment, we attempted to classify CU patients in a longitudinal database into 4 individual treatment requirement clusters. In doing so, we aimed to estimate remission rates of CU for the identified clusters and to identify prognostic factors of CU remission.

In this retrospective cohort study, we were able to apply medication scores to partition a large number of CU patients treated at a single university hospital over the most recent 20 years. Using K-medoids clustering analysis, we noted 4 distinct clusters of CU patients with discernible differences in disease activity. Moreover, we found that CU clusters, based on daily medication scores for the initial 3 months of treatment, were useful in predicting long-term treatment outcomes.

Studies describing the natural course of CU are rare, and those which are available report varying results. Differences in study population, design, and period as well as definitions of outcomes may account for the variability in the results. Observational studies have reported 5-year CU remission rates of 29%–86%.14, 15 The lowest remission rate was noted in a retrospective study conducted between 1968 and 1990,14 and therein 5- and 10-year remission rates were 29% and 44%, respectively.16 Toubi et al.,9 however, reported relatively higher 2- and 5-year remission rates of 48% and 86%, respectively, in their prospective study performed between 1998 and 2003.

Epidemiological studies have reported remission rates for CU within 3 months ranging from 12.0% to 50%5, 6, 7 and 5-year remission in about 90% of CU patients.5, 6 In the present study, we found that the proportion of patients who achieved CU remission differed significantly among the 4 CU clusters. One-year remission rates for clusters 1 and 2, which were reflective of lower disease activity, were similar with those reported in previous epidemiological studies for Korea,6, 7 while those for clusters 3 and 4 were remarkably lower. We believe that because the aforementioned studies were based on data from a health insurance database, in which omalizumab was excluded and some cyclosporine prescriptions were not included, many patients with severe CU may have been lost. This may account for the better CU remission rates in those studies, compared to ours.

A recent review article indicated that female sex, higher age at disease onset, long urticaria duration, and non-steroidal anti-inflammatory drug hypersensitivity may be linked with both severe CU and a longer time to remission.15 In the current study, female sex was identified as an indicator predictive of difficulty in achieving CU remission. Similar results of a longer time to remission and more heavily impaired CU-specific quality of life have been reported for women with chronic spontaneous urticaria (CSU).16, 17 Considering that estradiol enhances histamine release from mast cell lines,18 changes in the hormonal milieu in women may be associated with fluctuations in urticaria activity and poor control. Regarding age, we found that mean ages of urticaria onset were higher for clusters 3 and 4 than for clusters 1 and 2. Furthermore, the proportions of patients aged 60 years and older were also higher for clusters 3 and 4. Nevertheless, age, in itself, had no influence on time to CU remission.

Among laboratory markers, increases in total IgE, erythrocyte sedimentation rate, complement 3 and 4, and peripheral basopenia and neutrophilia were observed for cluster 4, compared to the other clusters. Kessel et al.19 suggested that elevated total IgE could be a marker for urticaria severity and duration. In addition, in a prior study, we found elevated total IgE levels to be significantly correlated with both urticaria activity score and CU-specific quality of life.20 Highly cytokinergic IgE antibodies against thyroid autoantigens21, 22 or interleukin (IL) 2423 and those against staphylococcal enterotoxins24 have been suggested as potential causes of CSU in a subpopulation of patients. Moreover, previous results have indicated that these IgE antibodies show an association with urticaria activity score and may support our findings of elevated total IgE levels in cluster 4 patients who showed sustained, high disease activity. However, there has been few studies to affirm correlations between urticaria duration and total IgE levels, and we found no significant association between serum total IgE levels and CU remission or relapse. The complement system is a central part of the acute phase response (APR). IL-6 and CRP, well-known biomarkers of APR, have been demonstrated to correlate with severity and activity of CU.25, 26 It has also been reported that serum C3 and C4 concentrations were increased in CU patients as compared to the healthy subjects and significant differences were found between patients with mild and severe CU.25, 27 Elevated C3 and C4 may be due to enhanced production in the liver in response to acute phase reactants, such as, IL-6 or tumor necrosis factor, which are increased in active CU and are known to control synthesis of the acute phase reactant protein.25 Peripheral basopenia and eosinopenia are well-known clinical features of high disease activity in CU patients.15 Although the clinical relevance of basopenia and eosinopenia in CU is not yet unclear, 2 potential reasons have been suggested. One reason is that since higher numbers of eosinophils and basophils are observed in lesional skin of CU patients than in non-lesional skin, the recruitment of eosinophils and basophils to the skin during active disease can reduce eosinophils and basophils in the blood.28 The other is immunological destruction of eosinophils in the blood of patients with CU. It is supported by the finding that a complement-dependent IgG-related activity was observed in the serum of a patient with urticaria and complete eosinopenia.29 Our findings that elevated C3 and C4 levels and decreased peripheral basophils and eosinophils were observed in cluster 4 patients, consistent with previous results showing the same finding in patients with severe CU or refractory to H₁-antihistamine therapy.

In addition to female sex, strong sensitization to HDM was found to be an independent predictor for CU remission, even though proportions thereof did not differ among the 4 clusters. HDMs are major allergens known to induce allergic rhinitis, asthma, and atopic dermatitis.30 Sensitization to HDM, particularly to Dermatophagoides, has increased greatly with rapid industrialization in many countries,31, 32, 33, 34 as in the prevalence of CU.3, 7 There are several reports on the relationships between HDMs and CU.35, 36, 37, 38, 39, 40 Previous studies have described positive skin reactivity and/or serum specific IgE to HDM in 18% to 63% of patients with CU.35, 36, 37, 39, 40 In a Turkish study, only sensitivity to HDM was more common in CU patients without allergic diseases than in healthy controls, whereas rates of skin reactivity to other aeroallergens, such as pollen, mold, and animal dander, were similar.33 Song et al.37 reported significantly higher urticaria activity scores in HDM-sensitive CU patients than in patients with a negative skin test to HDM. Furthermore, a clinical benefit from mite immunotherapy has been proven in CU patients with mite hypersensitivity.38, 41

The release of histamine and inflammatory mediators from activated mast cells are regarded as the primary mechanism for CU.42, 43 Currently, primed mast cells ready to release mediators upon exposure to various stimuli are thought to be at play.43 Sensitization of mast cells with monomeric IgE in the absence of antigen has been found to promote mast cell proliferation, differentiation, survival, and mediator production.43, 44 A prior study described significant increases in tryptase-positive and chymase-negative mast cells (MC_T) in wheals from CSU patients, whereas tryptase- and chymase-positive mast cells, which are the major subtype of skin mast cells, showed no difference from healthy skin.45 Consequently, as MC_T has been shown to be associated with allergic disease,46 this would indicate that CU may stand in the line of atopic march, along with asthma, allergic rhinitis, and atopic dermatitis. As HDMs are considered as key players in the progression of atopic march,47 the presence of specific IgE against HDM may also play a role in priming mast cells in CU patients. However, the clinical relevance of HDM sensitivity to the etiology and management of CU still needs to be established. Although the presence of specific IgE to HDM in CU patients may simply reflect an epiphenomenon of exposure to environmental dust, not a direct cause of the disease, the literature does support a significant association between sensitization to HDM and difficulty in achieving CU remission. Indeed, research has proven that HDMs activate nociceptors to release substance P from sensory neuron,48 and there is direct evidence that mast cells are activated by substance P via mas-related gene X2 (MRGX2) signaling, thereby initiating type 2 immune-mediated allergic inflammation in the skin.48 Furthermore, MRGX2 has been found to be highly expressed in CSU skin, particularly in severe CSU,49 and in CU patients who express MRGX2, exposure to HDM, can induce mast cell degranulation. Since CU has been widely recognized as a chronic allergic skin disease, we now need to dig a little deeper into the relationship between HDM sensitization and CU.

To date, only a few studies have investigated CU relapse, and how CU relapse ought to be defined is still unclear. Kim et al.50 has defined recurrent CU as urticaria recurring at least 6 months after stopping controller medications and resolution of prior urticarial symptoms. They reported that 13% of 341 patients had recurrent CU under this definition. In our study, relapse of CU was defined as the reappearance of H1-antihiatamine and/or immunomodulators prescriptions for urticaria under the primary diagnosis of L50 after previously achieving CU remission (no medication for more than a year). Similar to Kim et al.'s50 report, we found the relapse rate in CU patients overall to be 19.7%. Furthermore, we also found the use of immunomodulators to pose a higher risk of CU relapse, similar to a previous study.50 Considering that relapse rates or mean times to relapse of CU did not differ among the 4 clusters, we believe that maintaining proper treatment steps for controlling urticarial symptoms is important and that patients who need immunomodulators, such as omalizumab and cyclosporin, should be more cautious about stopping medications.

There are potential limitations in the present study. First, the operational definitions of CU, remission, and relapse from a retrospective investigation were incontrovertibly different from the actual epidemiology of the disease. Thus, we used strict definitions to minimize misclassification of CU and to avoid overestimation of CU remission. As a result, about half of all cases with L50 as a principal diagnosis were excluded. Since this study institution was a tertiary referral center for CU, some patients with mild CU and some referred patients who had already maintained H₁-antihistamines at the initial visit, but had not stayed for more than 3 months, might have been excluded. Due to a nature of retrospective study, differences in compliance with treatment among patients could not be considered. Nonetheless, we were able to identify 4 distinct clusters of CU based on exact medication scores during the first 3 months, and then, a longitudinal cohort covering up to 21 years was established. Secondly, this study did not include information specific to CU, such as urticaria activity score, the presence of autoantibodies, and urticaria subtypes. Thirdly, the subjects of the present study were from a single ethnicity. In the future, expanding this study to include multiple clinical sites from various regions would be helpful to improving the generalizability of the CU clusters.

In conclusion, we established 4 CU clusters reflective of medication scores during the first 3 months of treatment. These 4 clusters were able to depict differences in clinical features of CU, including demographics, laboratory results, and the remission rate of CU. A strong sensitization against HDM and female sex were also found to affect the prognosis of CU. The use of immunomodulators was implicated in the risk for CU relapse.

Supplementary Table S1

Medication score applied for clustering analysis