Periostin and Interleukin-13 Are Independently Related to Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is defined as urticaria that persists for at least 6 weeks.1, 2 Apart from mast cells which are the major effector cell type in urticaria, other cells of the skin tissue are infiltrated in CSU patients, including CD4+ T lymphocytes (especially the Th2 subclass), eosinophils, and neutrophils.3, 4 A few studies demonstrated that Th2 cytokines, such as interleukin (IL)-4 and IL-13, are increased in the sera of CSU patients or their production is increased in peripheral mononuclear cells from CSU patients.5, 6

Periostin, an extracellular matrix protein, plays an important role in the pathogenesis of chronic allergic inflammatory diseases, such as bronchial asthma and atopic dermatitis.7, 8, 9, 10, 11, 12 IL-4 and IL-13, key cytokines of the Th2-type immune response, have considerable influences on the synthesis and amplification of periostin by stimulating fibroblasts, the major source of periostin.7 It has been demonstrated that serum periostin levels are the most significant single predictor of eosinophilic airway inflammation in asthmatics, rather than fraction of exhaled nitric oxide (F_ENO), blood eosinophil count, or serum IgE levels, suggesting that periostin is a useful biomarker of eosinophilic airway inflammation in asthmatics and Th2-targeted asthma therapy.8 Furthermore, Periostin levels has been shown to be well correlated with disease severity and chronicity in atopic dermatitis.12 In this regard, periostin might be involved in the pathogenesis of CSU, for which a Th2 immune response has been implicated, and periostin levels could be a biomarker of disease severity or treatment response in CSU.

Thus, we measured serum concentrations of periostin and IL-13 in patients with CSU to evaluate the significance of periostin and IL-13 in the pathogenesis of CSU and possible application as a biological marker of disease severity.

Periostin levels were significantly lower in CSU patients than those in NCs (ng/mL, mean±SD, 71.4±21.8 vs 85.1±22.4, P=0.04; Fig. 1A). There were no significant differences in periostin levels according to the presence of angioedema, dermographism, atopy, antinuclear antibody, thyroid autoantibody, or the positivity of ASST. Periostin levels were not significantly correlated with IL-13 levels, total IgE levels, or blood eosinophil count. Interestingly, Severe to very severe group of CSU patients had lower periostin levels compared to the mild to moderate group of CSU patients with borderline significance (59.7±18.0 vs 73.4±22.0 ng/mL, P=0.04, Fig. 2).

Fig. 1
(A) Serum periostin and (B) IL-13 levels in CSU patients and NCs. CSU, chronic spontaneous urticaria; NCs, normal controls.

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Fig. 2
Comparison of periostin levels according to disease severity in CSU patients.

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On the contrary, IL-13 levels were higher in CSU patients compared to the NCs (508.5±51.2 vs 200.7±13.3 pg/mL, P=0.001, Fig. 1B). However, IL-13 levels were not significantly different between the presence and the absence of angioedema, dermographism, atopy, antinuclear antibody, thyroid autoantibody, or the positivity of ASST. IL-13 levels were not significantly correlated with serum total IgE levels or blood eosinophil count. When we analyzed an association of IL-13 levels with treatment level of CSU patients, there were no significant differences in IL-13 levels between treatment levels.

In this study, we demonstrated that IL-13 levels in serum were significantly increased in CSU patients compared to NCs (P=0.001), while serum periostin levels were decreased in CSU patients compared to NCs with borderline significance (P=0.04). Furthermore, serum periostin levels were significantly lower in the severe to very severe group than in the mild to moderate group of CSU patients (P=0.04).

Although CSU is a complex idiopathic disease that may be triggered by various etiologic factors, it has been indicated that cutaneous mast cells are major effector cells in most cases. However, mast cell degranulation is followed by many cellular infiltrations that are responsible for changes in vasopermeability, upregulation of adhesion molecules on endothelial cells, and rolling and attachment of blood leukocytes.5 CD4+ T-lymphocytes of the Th2 subclass particularly affect late-phase responses, such as tender, deep, erythematous, or poorly demarcated areas of swelling that persist for up to 24 hours.6 Elevation in the Th2-initiating cytokines, such as IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), was recently demonstrated in the lesional skin of CSU patients.14

Periostin is an intrinsic mediator of the amplification and chronicity of allergic skin inflammation.9 A positive correlation between periostin and key Th2 cytokines, such as IL-4 and IL-13, has been well established in bronchial asthma and atopic dermatitis.7, 8, 9 Caproni et al.6 showed that serum IL-13 levels were significantly higher in CSU patients than healthy controls and even higher in the ASST-positive group than in the ASST-negative group. They also found that CSU patients with higher IL-13 levels have more frequent and diffuse exacerbations and severe itch, suggesting that IL-13 might be a serologic marker of disease activity. However, we could not find any association between IL-13 levels and clinical manifestation. Serum IL-4 levels did not show any consistency among studies.5, 6 Moreover, periostin has not yet been investigated in chronic urticaria.

It is noteworthy that the two Th2 markers behaved independently in CSU patients. Although periostin expression may be upregulated by Th2 cytokines, other unknown factors that suppress or downregulate periostin expression could be present in CSU patients. Unlike in atopic dermatitis or asthma, more complicated cellular infiltrates, followed by the release of various inflammatory cytokines, are involved in CSU pathogenesis, although Th2 immune responses might be critical in the development and maintenance of CSU. As it is well established that fibroblasts are major producers of periostin and that periostin contributes to the development of fibrosis of the airways and skin, the activity of dermal fibroblast may be decreased in chronic urticaria. Further studies are needed to elucidate fibroblast activity in CSU patients to support our findings.

Recently, Yang et al.15 reported that histamine was found to directly induce periostin expression whereas the expression levels of IL-4 and IL-13 were not altered by histamine stimulation. Lower periostin levels in CSU patients in this study might be influenced by antihistamine treatment. This might be another explanation for the discrepancy between periostin and IL-13 levels in CSU patients in this study. In addition, they also demonstrated that periostin induction was inhibited by H1 antagonist treatment in vitro and was attenuated in histamine receptor 1 knock-out mice. It could be the reason periostin levels were further decreased in severe CSU patients taking more antihistamines.

Our study has two limitations. One is the relatively small number of study subjects. In addition, the number of the severe to very severe group patients (n=12) was much smaller than the mild to moderate group patients (n=71) during data analyses according to the disease severity. The comparison between these 2 groups does not seem appropriate. The other is that the urticaria activity score was not assessed. The severity and long-term prognosis of the disease can also be estimated based on the treatment level for disease control. Therefore, the association between the serum biomarker and treatment level could have clinical implications as a prognostic factor of the disease. In the present study, periostin levels were significantly lower in the severe to very severe group than in the mild to moderate group. However, caution is needed before concluding that periostin levels may be a prognostic indicator or a severity marker of CSU and further studies with a larger sample size are required to confirm our results.