1,049
Views
0
CrossRef citations to date
0
Altmetric
Review

The functional role and the clinical application of periostin in chronic rhinosinusitis

, &
Pages 857-866 | Received 03 Jan 2023, Accepted 15 Mar 2023, Published online: 30 Mar 2023

ABSTRACT

Introduction

Chronic rhinosinusitis (CRS) comprises several heterogenous groups, now classified based on endotype more often than on phenotype. A number of studies aimed at finding a useful biomarker for type 2 CRS suggest that periostin is a promising surrogate.

Areas covered

A comprehensive overview of the clinical significance of tissue periostin expression and serum periostin in CRS patients is provided. The effects of comorbid asthma on serum periostin and samples other than serum in which periostin can be detected in CRS patients are also discussed. Moreover, the functional roles of periostin in CRS pathogenesis are summarized.

Expert opinion

The position of periostin as a signature biomarker of type 2 CRS has been well established, enabling us to classify CRS patients by endotyping. Serum periostin is useful not only for endotyping CRS patients, but also for estimating disease severity, comorbidity, prognosis, and response to treatment, and in particular, predicting recurrence after surgery. However, it remains to be addressed how we apply serum periostin to using biologics for CRS patients. Further studies aimed at showing periostin to be a therapeutic target for CRS are awaited.

1. Introduction

Chronic rhinosinusitis (CRS) is defined as inflammation of the mucosa and paranasal sinuses persisting for at least 12 weeks [Citation1,Citation2]. Common complaints among CRS patients include hyposmia/anosmia, nasal obstruction and/or congestion, nasal discharge, and facial pain/pressure. The incidence of CRS is high; more than 10% of adults in Europe and the US are assumed to be affected with CRS. However, geographic differences do exist in the incidence of CRS. It is known that CRS is composed of heterogenous groups [Citation2]. CRS has historically been classified based on phenotypes with or without nasal polyps (NPs: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP)). However, this phenotypical classification of CRS was generally unhelpful for treatment of CRS patients. Therefore, recently stratification by endotypes, type 2 and non-type 2, has been proposed as the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS2020) [Citation3]. Endotypical classification of CRS is helpful in clinical practice, yielding information about disease severity, comorbidity, prognosis, and response to treatment. In particular, it offers us a direction in which to apply several molecularly targeted drugs for CRS that have recently become available. Thus, a paradigm shift in the classification of CRS is in progress, moving from one based on phenotype to one based on endotype.

To establish a way of endotyping CRS, it is crucial to find an appropriate biomarker for it. Many type 2 biomarkers have been described, and periostin has been established as one of them. It is thought to play an important role in the pathogenesis of CRS. In this article, we summarize and explain its functional role and the clinical application of periostin to CRS.

2. From phenotyping to endotyping of CRS

Historically, CRS has been classified into CRSwNP and CRSsNP, based on endoscopic findings. CRSwNP and CRSsNP have different clinical characteristics; the prevalence of asthma is higher in CRSwNP than CRSsNP (56% vs. 36%) [Citation4] and hyposmia/anosmia is more common in CRSwNP compared to CRSsNP [Citation5]. It has been generally accepted that type 2 inflammation is dominant in CRSwNP, whereas non-type 2 inflammation is relatively dominant in CRSsNP [Citation1,Citation2].

In type 2 inflammation of CRS, inhaled allergens microorganisms, or irritants, act on nasal epithelial cells inducing epithelial cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) [Citation1](). These cytokines activate dendritic cells followed by activation of TH2 cells and do type 2 innate lymphoid cells (ILC2s). Activated TH2 cells and ILC2s produce signature type cytokines such as IL-4, IL-15, and IL-13. IL-5 activates eosinophils, whereas IL-4 and IL-13 induce production of mucins by epithelial cells, contraction of smooth muscle cells, and production of fibrotic components, which leads to remodeling in CRS. IL-4 and IL-13 also cause IgE synthesis by B cells and IgE-bound mast cells and basophils release various mediators including prostaglandin D2 that causes recruitment of ILC2s and TH2 cells.

Figure 1. Type 2 inflammation in CRS. Cells and mediators involved in type 2 inflammation in CRS are depicted. The results of type 2 inflammation (mucin production, eosinophil activation, fibrosis, contraction of smooth muscle cells, and IgE synthesis) are also depicted.

Figure 1. Type 2 inflammation in CRS. Cells and mediators involved in type 2 inflammation in CRS are depicted. The results of type 2 inflammation (mucin production, eosinophil activation, fibrosis, contraction of smooth muscle cells, and IgE synthesis) are also depicted.

CRSwNP patients more predominantly exhibiting type 2 inflammation show different disease severity, comorbidity, and prognosis compared to patients relatively predominantly exhibiting non-type 2 inflammation. CRSwNP patients with high total/enterotoxin IgE and/or eosinophil cationic protein (ECP) have highly comorbid asthma [Citation6], whereas CRSwNP patients with persistent asthma complain more of olfactory dysfunction [Citation7]. Moreover, high type 2 biomarkers – tissue eosinophil, eosinophil mucin, total/enterotoxin IgE, ECP, IL-5-are correlated with high recurrence of nasal polyps after surgery [Citation8,Citation9].

Although the importance of type 2 inflammation in CRS has been already established, comprehensive analyses of gene expression in tissues from CRSwNP and CRSsNP patients have revealed that inflammatory endotypes of CRS are more diverse and heterogenous among individuals [Citation10–12]. Particularly, there exist ethnic and geographic differences in the expression of type 1/type 2/type 17 cytokines in both CRSwNP and CRSsNP patients [Citation13]. Wang et al. have recently reported that CRS patients can be classified into five clusters based on 16 inflammatory and remodeling factors. These clusters (clusters 1 and 2: non-type 2, cluster 3: low type 2, cluster 4: moderate type 2, and cluster 5: high type 2) can predict clinical phenotypes in that type 2 clusters are well correlated with the existence of nasal polyps, high comorbid asthma, high anosmia, high recurrence, and high CR score, compared to non-type 2 clusters [Citation14]. Therefore, the paradigm shift in the classification of CRS is moving from the phenotype-based to the endotype-based.

Based on the usefulness of endotyping rather than phenotyping in the treatment of CRS, EPOS2020, the updated guideline of EPOS, has been published [Citation3]. In EPOS2020, the existence of nasal polyps was no longer at the center of CRS, but primary CRS, even though it is either the localized (unilateral) type or the diffuse (bilateral) type, was differentiated into either the ‘type 2’ type or the ‘non-type 2’ type, based on endotyping [Citation15]. EPOS2020 also proposed indications for biological treatments in CRSwNP [Citation3]; biologics were indicated in a patient with bilateral polyps who had had sinus surgery or was not fit for surgery and who had at least three of the following characteristics: (1) evidence of type 2 inflammation, (2) need for systemic corticosteroids or contraindication to systemic steroids, (3) significantly impaired quality of life, (4) significant loss of smell, and (5) diagnosis of comorbid asthma. At present, three biologics – dupilumab (anti-IL-4Rα Ab), omalizumab (anti-IgE Ab), and mepolizumab (anti-IL-5 Ab) – have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treating CRSwNP patients, and several drugs are expected to be available soon [Citation16,Citation17]. Thus, the endotype diagnosis is important for application of biologics for CRS as well.

In Japan, based on the observation that nasal polyps from CRSwNP patients exhibiting high rate of recurrence after surgery show eosinophil-dominant inflammatory cell infiltration, the concept of eosinophilic CRS (ECRS) was proposed [Citation18]. Although this concept had been widely accepted, the diagnostic criteria were vague [Citation19]. Therefore, Prof. Fujieda’s group established the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score, composed of four items: side affected, existence of nasal polyps, CT changes, and peripheral blood eosinophil count [Citation20]. ECRS is mapped as an example of primary/diffuse/type 2 CRS (eCRS) in the updated classification of CRS, adapted from EPOS2020 [Citation3].

3. Identification of periostin as a surrogate marker of type 2 inflammation in CRS

Because of the significance of type 2 inflammation as an endotype for treating CRS patients, a number of studies have been carried out aimed at finding a useful biomarker for type 2 inflammation in CRS [Citation21,Citation22]. Many potential type 2 biomarkers have been listed, of which tissue/blood eosinophils are representative. Among these biomarkers, periostin has emerged as a promising surrogate biomarker of type 2 inflammation for many allergic diseases, including CRS [Citation23,Citation24].

We found that IL-4 and IL-13, signature type 2 cytokines, have the ability to induce periostin in airway epithelial cells and lung fibroblasts [Citation25,Citation26], suggesting that periostin can be a surrogate biomarker of type 2 inflammation. We examined the expression mechanism of periostin by IL-4/IL-13 using lung fibroblasts, finding that activated STAT6 downstream of the IL-4/IL-13 signals induces periostin in both Cis- and Trans-regulated manners via SOX11, a transcriptional gene belonging to the SOX (SRY-related HMG box) family [Citation27]. Because IL-4/IL-13 can induce periostin, we were able to show that in asthma patients, periostin is deposited in the thickened basement membrane [Citation26]. Subsequently, it was reported that periostin is a signature molecule of ‘Th2-high’ asthma patients in whom expression of IL-5 and IL-13 is high [Citation28]. Thus, the position of periostin as a surrogate biomarker of type 2 inflammation has been established in asthma. This concept has now been extended into other allergic diseases – atopic dermatitis [Citation29], eosinophilic esophagitis [Citation30], allergic conjunctivitis [Citation31], eosinophilic otitis media [Citation32] as well as CRS, as discussed below – because IL-4 and IL-13 are commonly expressed in these allergic diseases.

In addition to type 2 biomarker, periostin has a characteristic of a biomarker reflecting fibrosis. We found that TGF-β, a cytokine important to induce collagen from fibroblasts, also induces periostin from fibroblasts [Citation26]. Accordingly, we and others found that tissue and serum periostin is upregulated in TGF-β-related fibrotic diseases such as pulmonary fibrosis [Citation33,Citation34] and scleroderma [Citation35,Citation36]. Periostin is correlated with collagen production and epithelial-mesencymal transition. These results suggest that periostin has a characteristic distinct from other type 2 biomarkers such as blood eosinophils, total IgE, and moreover, exhaled fraction of NO (FeNO) in that periostin and FeNO are produced in fibroblasts and epithelial cells, respectively.

Stankovic et al. have reported that gene expression of periostin is high in nasal polyps from CRS patients, demonstrating for the first time the correlation between periostin and CRS [Citation37]. We and others confirmed high gene expression of periostin in nasal polyps in CRS patients [Citation38–41]. Histochemical analyses showed that periostin is deposited in the subepithelial areas of nasal polyps [Citation38,Citation40,Citation42]. Moreover, Ohta et al. found, for the first time, that serum periostin is high in CRSwNP patients compared to control subjects and that periostin in nasal lavage fluid is higher than that in allergic rhinitis patients [Citation43]. Kim et al. analyzed aspirin-exacerbated respiratory disease (AERD) patients, reporting that patients complicated with CRSwNP show higher serum periostin than AERD patients without CRS or complicated with CRSsNP [Citation44]. Thus, periostin has emerged as a biomarker of CRSwNP as well as of other allergic diseases.

4. Tissue expression of periostin and its clinical significance in CRS patients

It is very reproducible that periostin is highly deposited in the subepithelial areas of nasal polyps in CRS patients [Citation38,Citation40,Citation42]. A systematic review recently published also showed that periostin is consistently and significantly higher in CRSwNP than CRSsNP and controls at both protein and mRNA levels [Citation45]. However, it has been pointed out that the deposition levels are diverse, differing among individuals [Citation40,Citation42]. Since the pathological backgrounds of CRS patients are thought to be heterogenous [Citation5,Citation10,Citation11], this is a reasonable finding. Shiono et al. have proposed three types of periostin deposition in nasal polyps – negative, superficial, and diffuse [Citation42]. In the superficial type, periostin is detected only in the subepithelial portion beneath the basement membrane, whereas in the diffuse type, periostin is expressed throughout the lamina propria ().

Figure 2. Tissue expression of periostin in CRS patients. Two deposition types of periostin in nasal polyps (superficial type and diffuse type) are depicted (cited from Ref. 52). In the superficial type, periostin is detected only in the subepithelial portion beneath the basement membrane (panel A), whereas in the diffuse type, periostin is expressed throughout the lamina propria (panel B).

Figure 2. Tissue expression of periostin in CRS patients. Two deposition types of periostin in nasal polyps (superficial type and diffuse type) are depicted (cited from Ref. 52). In the superficial type, periostin is detected only in the subepithelial portion beneath the basement membrane (panel A), whereas in the diffuse type, periostin is expressed throughout the lamina propria (panel B).

Many studies have investigated the correlation between the deposition levels of periostin in nasal polyps in CRS patients taken during surgery and the clinical parameters, finding that the deposition levels are positively associated with tissue eosinophilia [Citation46–50], tissue remodeling (e.g. basement thickness, fibrosis [Citation51], goblet cell hyperplasia) [Citation46,Citation48], olfactory dysfunction [Citation50], CT score estimated by the Lund-Mackay method [Citation48], clinical severity estimated by the JESREC or SNOT-22 score [Citation49,Citation50,Citation52,Citation53], complication of asthma [Citation48], and TSLP expression [Citation48] (). These results support the notions that periostin is a surrogate biomarker of type 2 CRS and that type 2 CRS is clinically more severe compared to non-type 2 CRS.

Table 1. Clinical parameters correlated with periostin deposited in nasal polyps of CRS patients.

5. Periostin in serum and its clinical significance in CRS patients

Since serum periostin has several advantages as a biomarker [Citation24], it has been applied to many diseases – allergic diseases, fibrotic diseases, and cancers – including CRS [Citation24,Citation54,Citation55]. After the initial discovery of high serum periostin in CRSwNP patients by Ohta et al [Citation43]. (), it has been revealed that serum periostin is positively associated with the existence of nasal polyps [Citation50,Citation56–59], tissue/blood eosinophilia [Citation50,Citation52,Citation57,Citation60], CT score as estimated by the Lund-Mackay method [Citation57,Citation61], clinical severity as estimated by the JESREC or SNOT-22 score [Citation50,Citation52,Citation57,Citation60], IL-5–positivity [Citation56], efficacy of drugs including methylprednisolone, dupilumab, omalizumab, and mepolizumab [Citation62–64], and recurrence after surgery [Citation52,Citation60,Citation65] (). These results may suggest that serum periostin is thought to reflect not only type 2 inflammation, but also fibrosis, in CRS patients. Tajiri et al. have shown that serum periostin can predict omalizumab’s efficacy for CRS patients, although the investigated number was very small [Citation66,Citation67]. Yilmaz et al. found that tissue expression of periostin is well correlated with serum periostin, suggesting that serum periostin is a good indicator of periostin expression in the lesion sites [Citation50]. Asano et al. have reported that serum periostin together with tissue/blood eosinophils and FeNO, but not total IgE or serum eotaxin, can distinguish the existence or absence of CRSwNP in asthma patients [Citation57]. It was reported in the phase 3 clinical trials for dupilumab (SINUS-24 and SINUS-52 studies) that dupilumab downregulates serum periostin [Citation63,Citation64]. The decline was very rapid; it was obvious within two or four weeks of administration [Citation63]. It is of note that Ninomiya et al. and Sato et al. have proposed that using the cutoff values for serum periostin (115.5 ng/mL and 130 ng/mL, respectively), slightly higher than the cutoff value aimed at diagnosing CRSwNP (95 ng/mL), as estimated by the periostin kit provided by Shino-Test Corporation, is appropriate to predict the risk of recurrence after surgery [Citation52,Citation60]. It has been also recently reported that neutrophil inflammation is another factor to predict recurrence after surgery [Citation68]. These results suggest that serum periostin is a type 2 biomarker with many potential uses for treating CRS patients.

Figure 3. Periostin in serum of CRS patients. Serum periostin is high in CRSwNP patients compared to control subjects (modified from Ref. 43). The mean values (116.6 ng/mL vs. 39.1 ng/mL, respectively) and the cutoff value (95 ng/mL) are depicted.

Figure 3. Periostin in serum of CRS patients. Serum periostin is high in CRSwNP patients compared to control subjects (modified from Ref. 43). The mean values (116.6 ng/mL vs. 39.1 ng/mL, respectively) and the cutoff value (95 ng/mL) are depicted.

Table 2. Clinical parameters correlated with serum periostin in CRS patients.

6. Effects of comorbid asthma on serum periostin in CRS patients

Asthma is a common comorbidity of CRS, and up to 60% of CRSwNP patients have asthma [Citation2]. Since it is known that some asthma patients show elevated serum periostin [Citation24], it is no surprise that some patients in whom asthma and CRS coexist show higher serum periostin. Moreover, the existence of type 2 inflammation as the underlying mechanism of comorbid asthma for CRS, rather than a mass effect of the source of periostin, would be more important for higher elevation of serum periostin in CRS patients with comorbid asthma.

Many studies have pointed out the usefulness of serum periostin in these patients (). It has been reported that CRSwNP patients with asthma show higher periostin than CRSwNP patients without asthma [Citation59,Citation69], whereas inversely, asthma patients with CRS show higher periostin than asthma patients without CRS [Citation44,Citation61,Citation69]. Matsusaka et al. have listed olfactory function, but not CRSwNP, as a factor upregulating serum periostin in asthma patients [Citation70]. Hinks et al. have performed multidimensional endotyping in severe asthma patients, showing that the existence of nasal polyps is a characteristic of asthma patients with high periostin, together with high eosinophils and neutrophils in sputum, airway obstruction, and sensitivity to aspirin [Citation71]. Kanemitsu et al. investigated the ability of several type 2 biomarkers to identify the existence of asthma in CRS patients, finding that serum periostin has the highest ability, together with blood eosinophils and FeNO [Citation72]. Moreover, they found that patients with high serum periostin before surgery show low incidence of exacerbations after surgery, suggesting that serum periostin is useful for predicting the preventive effect of endoscopic sinus surgery for asthma exacerbations in CRS patients having comorbid asthma. These results suggest that serum periostin would be useful not only for diagnosing comorbid asthma, but also for choosing treatments in patients having both CRS and asthma.

Table 3. Usefulness of serum periostin as a biomarker for CRS patients having comorbid asthma.

7. Other samples detecting periostin in CRS patients

It is known that periostin can be detected in many body fluids other than blood (). In samples from CRS patients, it has been reported that periostin can potentially be detected in nasal discharge, sputum, and exhaled breath condensate. Ohta et al. found that periostin in nasal discharge in CRS patients is higher than in those of allergic rhinitis patients [Citation43]. It has also been reported that periostin in nasal discharge is downregulated by surgery [Citation73] or drugs – methylprednisolone, omalizumab, and mepolizumab – [Citation63] in CRSwNP patients. Kanemitsu et al. have reported that periostin in sputum is higher in CRS patients having comorbid asthma than in CRSwNP patients without asthma [Citation74]. Moreover, Wardzynska et al. have shown that periostin in exhaled breath condensate is higher in asthma patients having comorbidity with CRS than in those with asthma only [Citation75]. Since periostin in nasal discharge, sputum, and exhaled breath directly reflects local inflammation – in contrast to in blood – periostin derived from these samples may prove to be useful as a biomarker for CRS, different from serum periostin.

Figure 4. Body fluids and periostin. Periostin is detected in many body fluids, including blood, and these samples can be used to detect periostin as a biomarker for many diseases. In case of CRS, periostin can be detected in nasal discharge, sputum, and exhaled breath condensate, in addition to blood.

Figure 4. Body fluids and periostin. Periostin is detected in many body fluids, including blood, and these samples can be used to detect periostin as a biomarker for many diseases. In case of CRS, periostin can be detected in nasal discharge, sputum, and exhaled breath condensate, in addition to blood.

8. Functional roles of periostin in CRS

Given that periostin is highly expressed in the inflamed sites of CRS patients, several underlying mechanisms in which periostin contributes to the pathogenesis of CRS have been proposed (). It has been well investigated how periostin is involved in fibrosis of CRS. However, the functional mechanism of how periostin is involved in tissue remodeling or clinical severity has not been enough understood. Periostin is a matricellular protein that activates or modulates cell function by binding its receptor, several integrins, on cell surfaces [Citation23]. Therefore, several cells either constitutively or infiltratively existing in the inflamed sites of CRS can be targets of periostin.

Figure 5. Functional roles of periostin in CRS. the possible underlying mechanisms in which periostin contributes to the pathogenesis of CRS are depicted. The target cells of periostin and its actions on the target cells are shown.

Figure 5. Functional roles of periostin in CRS. the possible underlying mechanisms in which periostin contributes to the pathogenesis of CRS are depicted. The target cells of periostin and its actions on the target cells are shown.

8.1. Fibroblasts

In vitro analyses have found that periostin acts on fibroblasts derived from nasal polyps, inducing several cytokines/chemokines such as VEGF, RANTES, and eotaxin-2 [Citation47]; several matrix metalloproteinases (MMPs) such as MMP-3/7/8/9 [Citation76]; fibrosis-relating molecules such as α-SMA; fibronectin; and collagen type 1 [Citation49]. Yang et al. have reported that periostin activates the Src/AKT/mTOR pathway in these fibroblasts and induces migration, invasion, and collagen gel contraction of these fibroblasts [Citation49]. These in vitro effects would contribute to type 2 inflammation, remodeling, and angiogenesis in CRS. We have shown that periostin enhances proliferation of lung fibroblasts by modulating cell-cycle-related genes such as cyclin, CDK, E2F families, and transcriptional factors (B-MYB and FOXM1), followed by shifting the G0/G1 phase to the G2/M phase, which may contribute to hyperproliferation of nasal fibroblasts in CRS as well [Citation77].

8.2. Epithelial cells

We have previously and recently shown, using both in vitro and in vivo systems, that periostin derived from fibroblasts acts on keratinocytes, activating NF-κB, followed by inducing NF-κB-related mediators including TSLP [Citation29,Citation78,Citation79]. These results suggest that activation of keratinocytes by periostin is important for the onset of NF-κB-related inflammation in atopic dermatitis. Wei et al. have demonstrated, using an air-liquid interface method, that activation of NF-κB molecules by periostin also occurs in human nasal epithelial cells [Citation48]. Their results suggest that activation of NF-κB molecules in epithelial cells is a common underlying mechanism among atopic dermatitis and CRS via periostin.

8.3. Eosinophils and mast cells

It has been reported that periostin acts on eosinophils and mast cells, enhancing adhesion, superoxide anion generation, TGF-β production, and migration in eosinophils [Citation30,Citation80,Citation81], as well as IgE-dependent degranulation in mast cells [Citation82], which would contribute to activation/recruitment of eosinophils and mast cells in CRS.

8.4. Nerve cells

We and others have found that periostin links the immuno- and neuro-systems in atopic dermatitis in that periostin produced as a downstream mediator of type 2 inflammation acts on sensory nerve cells in skin, causing itching [Citation79,Citation83]. It remains undetermined whether periostin excessively produced in the inflamed sites of CRS acts on olfactory nerves and/or sensory nerve cells, leading to their dysfunction. In LIBERTY NP SINUS-24 and LIBERTY NPSINUS-52, dupilumab showed a good efficacy for loss of smell in CRS wNP patients, which may suggest that IL-4/IL-13 or their mediators including periostin cause olfactory dysfunction [Citation84]. Future studies aimed at this point are needed.

9. Expert opinion

Along with the discovery of periostin as a downstream molecule of IL-4 and IL-13 – the signature of type 2 cytokines – the position of periostin as a signature mediator and biomarker of type 2 CRS has been well established. CRS patients more dominantly exhibiting type 2 inflammation show higher tissue expression of periostin and elevated serum periostin. It is expected that by using periostin as a type 2 biomarker, we can estimate the contribution of type 2 inflammation in CRS patients whose pathogenesis is heterogenous and diverse. Alternatively, it would be better to combine periostin with other type 2 biomarkers to diagnose type 2 CRS. Such a classification would lead to realization of classification of CRS patients by endotyping, as has recently been proposed [Citation3]. One of the limitations of the present knowledge is the role of periostin in CRSsNP patients. For example, it should be clarified what biologic would be effective for CRS patients with high periostin and low eosinophils, although serum periostin and blood eosinophils are well correlated.

Many studies have suggested that serum periostin is useful not only for endotyping CRS patients, but also for estimating disease severity, comorbidity, prognosis, and response to treatment. It is clear that serum periostin is useful for predicting recurrence after surgery [Citation52,Citation60,Citation64,Citation65]; this information is very important to both CRS patients and their physicians to predict prognosis of surgery. In contrast, many questions remain to be addressed with regard to the use of serum periostin in selecting biologics for CRS patients. It has been reported that serum periostin is downregulated by dupilumab, omalizumab, and mepolizumab [Citation62–64]; however, so far only one study, very small, has shown the ability of serum periostin to predict the efficacy of omalizumab among these biologics [Citation66,Citation67]. This point awaits clarification, for omalizumab as well as for other biologics, not only with regard to efficacy, but also concerning the discontinuation or tapering of these drugs. Furthermore, the usefulness of periostin found in samples other than serum – nasal discharge, sputum, and exhaled breath condensate – should be clarified. Periostin in these non-serum samples may prove useful as a biomarker for CRS. Since we have found that periostin in sputum is cleaved, probably by proteases in sputum [Citation85], we would need to use an appropriate assay system for these samples, particularly with the cleaved type of periostin. Another problem for using periostin as a biomarker is that periostin cannot be measured in hospitals as a routine laboratory test but can be measured only by a research reagent at this moment. Development of an in-vitro diagnostic agent for periostin has been hoped.

The functional mechanism of how periostin is involved in tissue remodeling or clinical severity has not been enough understood. One of the reasons would be that it is difficult to confirm using animal models the functional significance of periostin in the formation of nasal polyps. However, a lot of evidence based on mouse models of other periostin-related diseases supports its significance, and several underlying mechanisms involving periostin have been proposed. These results suggest that periostin is a promising therapeutic target for CRS. Thus far, several periostin inhibitors, including cilengitide, have been administered to mice, showing efficacy sufficient to improve periostin-related pathogenesis [Citation83,Citation86–91]. We have already administered CP4715, a low-molecular compound to inhibit the interaction between periostin and its receptor, αVβ3 integrin, to mouse models of both pulmonary fibrosis and atopic dermatitis, showing good efficacies [Citation77,Citation79,Citation92]. CP4715, which was developed as an integrin inhibitor, has a tetrahydropyrimidin-2-yl-amino moiety at the N terminus and a benzoyl moiety at the center [Citation93–96]. Further studies aimed at establishing periostin as a therapeutic target for CRS are hoped for soon.

Article highlights

  • The basis for classifying CRS has shifted from phenotype to endotype.

  • The position of periostin as a signature biomarker of type 2 CRS has been well established, which enables us to classify CRS patients by endotyping.

  • Serum periostin is useful not only for endotyping also for treating CRS patients, in particular the prediction of recurrence after surgery.

  • It remains to be addressed how we apply serum periostin to using biologics for CRS patients.

  • Periostin is a promising therapeutic target for CRS.

Declaration of interest

Kenji Izuhara has received honoraria and grants from Shino-test Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We thank Dr. Dovie R. Wylie for the critical review of this manuscript.

Additional information

Funding

This paper was not funded.

References

  • Bachert C, Marple B, Schlosser RJ, et al. Adult chronic rhinosinusitis. Nat Rev Dis Primers. 2020;6:86.
  • Hopkins C, Solomon CG. Chronic rhinosinusitis with nasal polyps. N Engl J Med. 2019;381:55–63.
  • Fokkens WJ, Lund VJ, Hopkins C, et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(Suppl S29):1–464. DOI:10.4193/Rhin20.401.
  • Benjamin MR, Stevens WW, Li N, et al. Clinical characteristics of patients with chronic rhinosinusitis without nasal polyps in an academic setting. J Allergy Clin Immunol Pract. 2019;7:1010–1016.
  • Litvack JR, Fong K, Mace J, et al. Predictors of olfactory dysfunction in patients with chronic rhinosinusitis. Laryngoscope. 2008;118:2225–2230.
  • Bachert C, Zhang N, Holtappels G, et al. Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J Allergy Clin Immunol. 2010;126:962–968.
  • Alobid I, Cardelus S, Benitez P, et al. Persistent asthma has an accumulative impact on the loss of smell in patients with nasal polyposis. Rhinology. 2011;49:519–524.
  • Van Zele T, Holtappels G, Gevaert P, et al. Differences in initial immunoprofiles between recurrent and nonrecurrent chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2014;28:192–198.
  • Vlaminck S, Vauterin T, Hellings PW, et al. The importance of local eosinophilia in the surgical outcome of chronic rhinosinusitis: a 3-year prospective observational study. Am J Rhinol Allergy. 2014;28:260–264.
  • Tomassen P, Vandeplas G, Van Zele T, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016;137:1449–1456.
  • Tan BK, Klingler AI, Poposki JA, et al. Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois. J Allergy Clin Immunol. 2017;139:699–703.
  • Stevens WW, Peters AT, Tan BK, et al. Associations between inflammatory endotypes and clinical presentations in chronic rhinosinusitis. J Allergy Clin Immunol Pract. 2019;7:2812–2820.
  • Wang X, Zhang N, Bo M, et al. Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania. J Allergy Clin Immunol. 2016;138:1344–1353.
  • Wang X, Sima Y, Zhao Y, et al. Endotypes of chronic rhinosinusitis based on inflammatory and remodeling factors. J Allergy Clin Immunol. 2023;151:458–468.
  • Xu X, Reitsma S, Wang Y, et al. Highlights in the advances of chronic rhinosinusitis. Allergy. 2021;76:3349–3358.
  • Mullol J, Azar A, Buchheit KM, et al. Chronic rhinosinusitis with nasal polyps: quality of life in the biologics era. J Allergy Clin Immunol Pract. 2022;10:1434–1453.
  • Brzost J, Czerwaty K, Dzaman K, et al. Perspectives in therapy of chronic rhinosinusitis. Diagnostics (Basel). 2022;12:2301.
  • Haruna S, Nakanishi M, Otori N, et al. Histopathological features of nasal polyps with asthma association: an immunohistochemical study. Am J Rhinol. 2004;18:165–172.
  • Fujieda S, Imoto Y, Kato Y, et al. Eosinophilic chronic rhinosinusitis. Allergol Int. 2019;68:403–412.
  • Tokunaga T, Sakashita M, Haruna T, et al. Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study. Allergy. 2015;70:995–1003.
  • Lou H, Wang C, Zhang L. Endotype-driven precision medicine in chronic rhinosinusitis. Expert Rev Clin Immunol. 2019;15:1171–1183.
  • Guo CL, Wang CS, Liu Z. Clinical and biological markers in disease and biologics to treat chronic rhinosinusitis. Curr Opin Allergy Clin Immunol. 2022;22:16–23.
  • Izuhara K, Arima K, Ohta S, et al. Periostin in allergic inflammation. Allergol Int. 2014;63:143–151.
  • Izuhara K, Nunomura S, Nanri Y, et al. Periostin: an emerging biomarker for allergic diseases. Allergy. 2019;74:2116–2128. .
  • Yuyama N, Davies DE, Akaiwa M, et al. Analysis of novel disease-related genes in bronchial asthma. Cytokine. 2002;19:287–296.
  • Takayama G, Arima K, Kanaji T, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol. 2006;118:98–104.
  • Mitamura Y, Nunomura S, Nanri Y, et al. Hierarchical control of interleukin 13 (IL-13) signals in lung fibroblasts by STAT6 and SOX11. J Biol Chem. 2018;293:14646–14658.
  • Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180:388–395.
  • Masuoka M, Shiraishi H, Ohta S, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. 2012;122:2590–2600. .
  • Blanchard C, Mingler MK, McBride M, et al. Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol. 2008;1:289–296.
  • Fujishima H, Okada N, Matsumoto K, et al. The usefulness of measuring tear periostin for the diagnosis and management of ocular allergic diseases. J Allergy Clin Immunol. 2016;138:459–467.
  • Nishizawa H, Matsubara A, Nakagawa T, et al. The role of periostin in eosinophilic otitis media. Acta Otolaryngol. 2012;132:838–844.
  • Okamoto M, Hoshino T, Kitasato Y, et al. Periostin, a matrix protein, is a novel biomarker for idiopathic interstitial pneumonias. Eur Respir J. 2011;37:1119–1127.
  • Uchida M, Shiraishi H, Ohta S, et al. Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2012;46:677–686.
  • Yang L, Serada S, Fujimoto M, et al. Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma. PLoS ONE. 2012;7:e41994.
  • Yamaguchi Y, Ono J, Masuoka M, et al. Serum periostin levels are correlated with progressive skin sclerosis in patients with systemic sclerosis. Br J Dermatol. 2013;168:717–725.
  • Stankovic KM, Goldsztein H, Reh DD, et al. Gene expression profiling of nasal polyps associated with chronic sinusitis and aspirin-sensitive asthma. Laryngoscope. 2008;118:881–889.
  • Ishida A, Ohta N, Suzuki Y, et al. Expression of pendrin and periostin in allergic rhinitis and chronic rhinosinusitis. Allergol Int. 2012;61:589–595.
  • Daines SM, Wang Y, Orlandi RR. Periostin and osteopontin are overexpressed in chronically inflamed sinuses. Int Forum Allergy Rhinol. 2011;1:101–105.
  • Zhang W, Hubin G, Endam LM, et al. Expression of the extracellular matrix gene periostin is increased in chronic rhinosinusitis and decreases following successful endoscopic sinus surgery. Int Forum Allergy Rhinol. 2012;2:471–476.
  • Milonski J, Zielinska-Blizniewska H, Przybylowska K, et al. Significance of CYCLOOXYGENASE-2(COX-2), PERIOSTIN (POSTN) and INTERLEUKIN-4(IL-4) gene expression in the pathogenesis of chronic rhinosinusitis with nasal polyps. Eur Arch Otorhinolaryngol. 2015;272:3715–3720.
  • Shiono O, Sakuma Y, Komatsu M, et al. Differential expression of periostin in the nasal polyp may represent distinct histological features of chronic rhinosinusitis. Auris Nasus Larynx. 2015;42:123–127.
  • Ohta N, Ishida A, Kurakami K, et al. Expressions and roles of periostin in otolaryngological diseases. Allergol Int. 2014;63:171–180.
  • Kim MA, Izuhara K, Ohta S, et al. Association of serum periostin with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2014;113:314–320.
  • Danielides G, Lygeros S, Kanakis M, et al. Periostin as a biomarker in chronic rhinosinusitis: a contemporary systematic review. Int Forum Allergy Rhinol. 2022;12:1535–1550.
  • Ebenezer JA, Christensen JM, Oliver BG, et al. Periostin as a marker of mucosal remodelling in chronic rhinosinusitis. Rhinology. 2017;55:234–241.
  • Xu M, Chen D, Zhou H, et al. The role of periostin in the occurrence and progression of eosinophilic chronic sinusitis with nasal polyps. Sci Rep. 2017;7(1):9479. DOI:10.1038/s41598-017-08375-2
  • Wei Y, Ma R, Zhang J, et al. Excessive periostin expression and Th2 response in patients with nasal polyps: association with asthma. J Thorac Dis. 2018;10:6585–6597.
  • Yang HW, Park JH, Shin JM, et al. Glucocorticoids ameliorate periostin-induced tissue remodeling in chronic rhinosinusitis with nasal polyps. Clin Exp Allergy. 2018. DOI:10.1111/cea.13267
  • Yilmaz GO, Cetinkaya EA, Eyigor H, et al. The diagnostic importance of periostin as a biomarker in chronic rhinosinusitis with nasal polyp. Eur Arch Otorhinolaryngol. 2022;279:5707–5714.
  • Zhang Z, Liu J, Xie L, et al. Tissue eosinophils and mucous inflammatory cytokines for the evaluation of olfactory recovery after endoscopic sinus surgery in patients with nasal polyposis. Am J Otolaryngol. 2022;43:103561.
  • Ninomiya T, Noguchi E, Haruna T, et al. Periostin as a novel biomarker for postoperative recurrence of chronic rhinosinitis with nasal polyps. Sci Rep. 2018;8:11450.
  • Kim DK, Kang SI, Kong IG, et al. Two-track medical treatment strategy according to the clinical scoring system for chronic rhinosinusitis. Allergy Asthma Immunol Res. 2018;10:490–502.
  • Izuhara K, Nunomura S, Nanri Y, et al. Periostin in inflammation and allergy. Cell Mol Life Sci. 2017;74:4293–4303.
  • Cui D, Huang Z, Liu Y, et al. The multifaceted role of periostin in priming the tumor microenvironments for tumor progression. Cell Mol Life Sci. 2017;74:4287–4291.
  • Jonstam K, Westman M, Holtappels G, et al. Serum periostin, IgE, and SE-IgE can be used as biomarkers to identify moderate to severe chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2017;140:1705–1708.
  • Asano T, Kanemitsu Y, Takemura M, et al. Serum periostin as a biomarker for comorbid chronic rhinosinusitis in patients with asthma. Ann Am Thorac Soc. 2017;14:667–675.
  • Xu M, Zhang W, Chen D, et al. Diagnostic significance of serum periostin in eosinophilic chronic sinusitis with nasal polyps. Acta Otolaryngol. 2018;138:387–391.
  • Maxfield AZ, Landegger LD, Brook CD, et al. Periostin as a biomarker for nasal polyps in chronic rhinosinusitis. Otolaryngol Head Neck Surg. 2018;158:181–186.
  • Sato T, Ikeda H, Murakami K, et al. Periostin is an aggravating factor and predictive biomarker of eosinophilic chronic rhinosinusitis. Allergol Int. 2023;72:161–168.
  • Kimura H, Konno S, Nakamaru Y, et al. Sinus computed tomographic findings in adult smokers and nonsmokers with asthma. Analysis of clinical indices and biomarkers. Ann Am Thorac Soc. 2017;14:332–341.
  • De Schryver E, Derycke L, Calus L, et al. The effect of systemic treatments on periostin expression reflects their interference with the eosinophilic inflammation in chronic rhinosinusitis with nasal polyps. Rhinology. 2017;55:152–160.
  • Hamilton JD, Harel S, Swanson BN, et al. Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases. Clin Exp Allergy. 2021;51:915–931.
  • Mullol J, Laidlaw TM, Bachert C, et al. Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: results from two randomized placebo-controlled phase 3 trials. Allergy. 2022;77:1231–1244.
  • Oka A, Ninomiya T, Fujiwara T, et al. Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis. Allergol Int. 2020;69:417–423.
  • Tajiri T, Matsumoto H, Hiraumi H, et al. Efficacy of omalizumab in eosinophilic chronic rhinosinusitis patients with asthma. Ann Allergy Asthma Immunol. 2013;110:387–388.
  • Matsumoto H. Roles of periostin in asthma. Adv Exp Med Biol. 2019;1132:145–159.
  • Yu H, Kim DK. Neutrophils play an important role in the recurrence of chronic rhinosinusitis with nasal polyps. Biomedicines. 2022;10:2911.
  • Kanemitsu Y, Matsumoto H, Izuhara K, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132:305–312.
  • Matsusaka M, Kabata H, Fukunaga K, et al. Phenotype of asthma related with high serum periostin levels. Allergol Int. 2015;64:175–180.
  • Hinks TS, Brown T, Lau LC, et al. Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1. J Allergy Clin Immunol. 2016;138:61–75.
  • Kanemitsu Y, Kurokawa R, Ono J, et al. Increased serum periostin levels and eosinophils in nasal polyps are associated with the preventive effect of endoscopic sinus surgery for asthma exacerbations in chronic rhinosinusitis patients. Int Arch Allergy Immunol. 2020;181:862–870.
  • Mueller SK, Wendler O, Nocera A, et al. Escalation in mucus cystatin 2, pappalysin-A, and periostin levels over time predict need for recurrent surgery in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2019;9:1212–1219.
  • Kanemitsu Y, Suzuki M, Fukumitsu K, et al. A novel pathophysiologic link between upper and lower airways in patients with chronic rhinosinusitis: association of sputum periostin levels with upper airway inflammation and olfactory function. World Allergy Organ J. 2020;13:100094.
  • Wardzynska A, Makowska JS, Pawelczyk M, et al. Periostin in exhaled breath condensate and in serum of asthmatic patients: relationship to upper and lower airway disease. Allergy Asthma Immunol Res. 2017;9:126–132.
  • Du K, Wang M, Zhang N, et al. Involvement of the extracellular matrix proteins periostin and tenascin C in nasal polyp remodeling by regulating the expression of MMPs. Clin Transl Allergy. 2021;11:e12059.
  • Yoshihara T, Nanri Y, Nunomura S, et al. Periostin plays a critical role in the cell cycle in lung fibroblasts. Respir Res. 2020;21:38.
  • Shiraishi H, Masuoka M, Ohta S, et al. Periostin contributes to the pathogenesis of atopic dermatitis by inducing TSLP production from keratinocytes. Allergol Int. 2012;61:563–572.
  • Nunomura S, Uta D, Kitajima I, et al. Periostin activates distinct modules of inflammation and itching downstream of the type 2 inflammation pathway. Cell Rep. 2023;42:111933.
  • Noguchi T, Nakagome K, Kobayashi T, et al. Periostin upregulates the effector functions of eosinophils. J Allergy Clin Immunol. 2016;138:1449–1452.
  • Johansson MW, Khanna M, Bortnov V, et al. IL-5-stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8-dependent migration. Clin Exp Allergy. 2017;47:1263–1274.
  • Nunomura S, Ejiri N, Kitajima M, et al. Establishment of a mouse model of atopic dermatitis by deleting Ikk2 in dermal fibroblasts. J Invest Dermatol. 2019;139:1274–1283.
  • Mishra SK, Wheeler JJ, Pitake S, et al. Periostin activation of integrin receptors on sensory neurons induces allergic itch. Cell Rep. 2020;31:107472.
  • Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019;394:1638–1650.
  • Ono J, Takai M, Kamei A, et al. A novel assay for improved detection of sputum periostin in patients with asthma. PLoS ONE. 2023;18:e0281356.
  • Mikheev AM, Mikheeva SA, Trister AD, et al. Periostin is a novel therapeutic target that predicts and regulates glioma malignancy. Neuro Oncol. 2015;17:372–382.
  • Wu Z, Dai W, Wang P, et al. Periostin promotes migration, proliferation, and differentiation of human periodontal ligament mesenchymal stem cells. Connect Tissue Res. 2018;59:108–119.
  • Chen G, Wang Y, Zhao X, et al. A positive feedback loop between periostin and TGFbeta1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2a activation. J Exp Clin Cancer Res. 2021;40:218.
  • Liu Y, Luan Y, Guo Z, et al. Periostin attenuates oxygen and glucose deprivation-induced death of mouse neural stem cells via inhibition of p38 MAPK activation. Neurosci Lett. 2022;774:136526.
  • Liu GX, Xi HQ, Sun XY, et al. Role of periostin and its antagonist PNDA-3 in gastric cancer metastasis. World J Gastroenterol. 2015;21:2605–2613.
  • Um JE, Park JT, Nam BY, et al. Periostin-binding DNA aptamer treatment attenuates renal fibrosis under diabetic conditions. Sci Rep. 2017;7:8490.
  • Nanri Y, Nunomura S, Terasaki Y, et al. Cross-talk between transforming growth factor-b and periostin can be targeted for pulmonary fibrosis. Am J Respir Cell Mol Biol. 2020;62:204–216.
  • Kubota D, Ishikawa M, Yamamoto M, et al. Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 1: design and synthesis of a lead compound exhibiting αvβ3/αIIbβ3 dual antagonistic activity. Bioorg Med Chem. 2006;14:2089–2108 .
  • Ishikawa M, Kubota D, Yamamoto M, et al. Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 2: synthesis of potent αvβ3/αIIbβ3 dual antagonists. Bioorg Med Chem. 2006;14:2109–2130.
  • Ishikawa M, Hiraiwa Y, Kubota D, et al. Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: synthesis of potent antagonists with αvβ3/αIIbβ3 dual activity and improved water solubility. Bioorg Med Chem. 2006;14:2131–2150.
  • Kubota D, Ishikawa M, Yahata N, et al. Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: preliminary control of αvβ3 selectivity by meta-oriented substitution. Bioorg Med Chem. 2006;14:4158–4181.