Introduction

Chronic rhinosinusitis (CRS) is a common and multifactorial inflammatory disease of the nasal cavity and paranasal sinus mucosa, involving complex interactions between environmental, genetic, and immune factors.1,2 CRS manifests with typical symptoms such as nasal congestion, purulent nasal discharge, olfactory dysfunction, and headaches.3–5 CRS can be divided into two phenotypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). As a unique CRS phenotype, CRSwNP has more obvious symptoms, a higher postoperative recurrence rate, and significantly impaired olfactory function than CRSsNP, which are clinical features that attract more attention from clinicians.6–8 Increasing evidence suggests that the histopathological features of CRSwNP are highly heterogeneous, and accompanying diseases further exacerbate the complexity of its pathological mechanisms.9–11 Recently, functional endoscopic sinus surgery (FESS) has become the favored surgical approach for CRSwNP patients who responded poorly to pharmacological treatments, owing to its effectiveness and safety.12,13 However, despite advancements in surgical techniques, postoperative recurrence remains high and continues to be a significant challenge in managing CRSwNP. This challenge is primarily driven by the unclear etiology of the disease, high tissue heterogeneity, and the complexity introduced by comorbid conditions.14–16 Several potential risk factors have been identified, including disease duration, eosinophilic inflammation, nasal microbiota dysbiosis, and comorbidities such as allergic rhinitis (AR), hyperuricemia, and metabolic syndrome, all of which have been linked to an increased risk of CRSwNP recurrence.17–21

Understanding the additional factors that contribute to postoperative recurrence in CRSwNP is critical for improving patient prognosis and optimizing treatment strategies. Recent studies have increasingly highlighted the connection between CRSwNP and systemic inflammatory conditions, such as rheumatoid arthritis (RA). Furthermore, both conditions are thought to share common immune pathways, involving cytokines and immune cells, which may contribute to similar pathogenic mechanisms.22 RA is an autoimmune disease characterized by systemic inflammation and extra-articular manifestations, including those affecting the respiratory system.23 It is well-established that RA can lead to systemic inflammation and immune dysregulation, potentially impacting various organ systems beyond the joints, including complications like pleuritis, valvular heart disease, interstitial lung disease, and nasal and paranasal sinus impairments.24,25 A recent study reported a higher incidence of CRS in patients with RA, suggesting that RA may contribute to nasal mucosal damage and play a role in the pathogenesis of CRS.26 Another publication found an increased prevalence of Staphylococcus aureus nasal carriage in rheumatoid arthritis patients, which may contribute to the development of CRS.27 However, the influence of RA on the clinical and histopathological features of CRSwNP patients remains unexplored, and knowledge about the interrelation between RA and CRSwNP recurrence is sparse. The presence of RA in CRSwNP patients raises concerns about potentially more complicated disease progressions and challenges in managing postoperative outcomes. Identifying the clinical and histopathological characteristics of CRSwNP patients with concurrent RA as a distinct disease subgroup and assessing whether RA contributes to increased tissue heterogeneity and postoperative CRSwNP recurrence are crucial.

This study is designed to rigorously assess the potential association between RA and eosinophilic inflammation, as well as postoperative recurrence, in patients with CRSwNP. Our objective is to analyze the clinical features and outcomes of FESS in CRSwNP patients who also suffer from RA, to deepen our understanding of how these conditions interact. By exploring the relationship between RA and both eosinophilic inflammation and postoperative recurrence in CRSwNP, this research could significantly influence the optimization of treatment approaches and enhance the management of postoperative outcomes for this patient group.

Materials and MethodsEthical Statement

This retrospective cohort study was approved by the Human Ethical Committee in Xiangya Hospital of Central South University (2021091148). As the study did not involve any private patient information or commercial interests, the Ethics Committee waived the requirement for informed consent. This study complies with the Declaration of Helsinki.

Participants, Study Design, and Data Collection

This study included CRSwNP patients who underwent FESS at our medical center between January 1, 2019, and December 31, 2021. The inclusion criteria of CRSwNP patients were as follows:1 adherence to the guidelines for diagnosis and treatment of CRSwNP;28 (2) age between 18 and 70 years old; (3) complete clinical data; (4) no previous history of FESS; (5) no comorbidity with other autoimmune diseases other than RA. The exclusion criteria of CRSwNP patients included the follows: (1) with fungal sinusitis, allergic fungal rhinosinusitis, sinus benign or malignant tumor; (2) with severe systemic organic disease or current acute inflammation; (3) previous radiotherapy history; (4) loss of follow-up; (6) RA in the acute status; (7) received immunomodulatory drugs or biologics treatment within one month before FESS. All patients underwent detailed medical history inquiries and records, nasal endoscopy examinations, laboratory examinations, and sinus computed tomography.

The baseline characteristics and clinical data were obtained from the electronic medical records. The Lund-MacKay score and Lund-Kennedy score were used to assess the severity of CRSwNP patients’ preoperative symptoms as previously described.11 Preoperative data including age, gender, smoking, alcohol, duration of disease, body mass index (BMI), RA, diabetes mellitus, hypertension, AR, and asthma were collected. In addition, laboratory data, specifically erythrocyte sedimentation rate, hypersensitive C-reactive protein, anti-cyclic citrulline peptide antibody, rheumatoid factor, systolic blood pressure, diastolic blood pressure, and fasting blood glucose, were measured in the hospital biochemistry department. A diagnosis of RA was performed based on the 2010 classification criteria of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR 2010).23

Follow-Up and Postoperative Recurrence Definition

All FESS surgical procedures were carried out by the same medical team. A uniform postoperative care protocol was adhered to for all patients, which included daily nasal saline irrigations, antibiotics, topical corticosteroids, and routine endoscopic cleanings. Postoperative evaluations were conducted using nasal endoscopy at one month, three months, six months, and subsequently every six months to one year to monitor patient outcomes. All patients were followed up for more than two years, with the endpoint being either the recurrence of the disease or the end of the follow-up interval. Recurrence was determined by the reappearance of clinical symptoms along with endoscopic and computed tomography findings, persisting for at least two months despite a treatment intervention involving antibiotics and oral steroids as previously outlined.20,29

Tissue Eosinophil Quantification

Nasal polyp tissues were obtained during surgery and subsequently preserved in 4% paraformaldehyde. Post-fixation, these samples were embedded in paraffin wax and sectioned into 4 μm slices. The sections were then stained using hematoxylin and eosin (HE). Each stained sample was examined at a high-power field (HPF) magnification of ×400 to evaluate the infiltration of inflammatory cells, with a specific focus on eosinophils. The eosinophil count was calculated by averaging the counts from five HPF chosen at random, and the eosinophil percentage was determined by computing the ratio of eosinophils to the total number of inflammatory cells observed.

Statistical Analysis

Categorical variables were presented as percentages and numbers, and compared utilizing the chi-squared test. Quantitative variables with normal distribution were shown as mean ± standard deviation and compared with the Student’s t-test between the two groups. Those data without normal distribution were presented as median and interquartile ranges (IQRs), and the Mann–Whitney U-test was utilized in the comparison between the two groups. CRSwNP patients were categorized into non-recurrent and recurrent CRSwNP groups, and logistic regression analysis was performed to identify factors that affect the recurrence of CRS postoperatively. Additionally, the association between RA and the risk of CRS recurrence was further analyzed using various adjusted models. Kaplan-Meier survival curves and multivariate regression analysis were performed and explore RA association with the risk of CRSwNP recurrence. Statistical significance was regarded as a two-tailed P < 0.05.

ResultsCharacteristics and Baseline Data of the Study Subjects

In the original cohort, 558 CRSwNP patients were initially included. After exclusion criteria were applied, 41 patients were excluded, leaving 517 patients available for analysis. These subjects were divided based on the presence of RA into two groups: CRSwNP patients with RA (n = 78) and CRSwNP patients without RA (n = 439). Furthermore, based on the outcomes observed during follow-up, patients were also categorized into the recurrent CRSwNP group (n = 117) and the non-recurrent CRSwNP group (n = 400). Figure 1 shows the flowchart of CRSwNP recruitment and grouping.

Figure 1 The flowchart of CRSwNP recruitment and grouping.

Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyps; RA, rheumatoid arthritis.

The baseline characteristics and clinical data between non-RA and RA groups are detailed in Table 1. The mean age of the participants was 45.0 years, and the cohort comprised predominantly males (338 or 65.4%). Among these, 78 patients also had a diagnosis of comorbid RA. The average duration of postoperative follow-up was 31.4 months. By the end of this period, postoperative recurrence had been identified in 117 (22.6%) of the CRSwNP patients. After categorizing the patients based on RA status, we analyzed the postoperative recurrence rates between the RA and non-RA groups. As shown in Table 1, patients with RA exhibited significantly higher rates of postoperative recurrence compared to those without RA (P < 0.05). Additionally, the RA group displayed a greater proportion of female patients, a higher prevalence of diabetes mellitus, and significantly elevated values for BMI, Lund-MacKay score, Lund-Kennedy score, and both the count and percentage of tissue eosinophils compared to the non-RA group (P < 0.05).

Table 1 Baseline Clinical Characteristics of CRSwNP Patients

RA and the Risk of Postoperative Recurrence in CRSwNP

To investigate the association between RA and the risk of CRSwNP recurrence, we further categorized study subjects into the non-recurrent CRSwNP group and the recurrent CRSwNP group. As presented in Table 2, The tissue eosinophil count and percentage, and the rate of AR and RA were significantly elevated in the recurrent CRSwNP group compared to the non-recurrent CRSwNP group (P < 0.05). However, there was no significant difference in other variables between the two groups (P > 0.05).

Table 2 Baseline Clinical Characteristics Between Non-Recurrent and Recurrent CRSwNP Groups

We conducted a multivariate logistic regression analysis to explore potential risk factors for recurrence of CRSwNP. According to the results presented in Table 3, there was a significant association between higher risks of CRSwNP recurrence and factors such as tissue eosinophil count and percentage, RA, and AR (P < 0.05). Additionally, RA was evaluated as a standalone variable in both unadjusted and adjusted logistic regression analyses to further assess its impact on CRSwNP recurrence. The findings, displayed in Table 4, indicated that RA significantly elevated the risk of postoperative recurrence (P < 0.05), even when adjusting for various potential confounders across different models. Moreover, Kaplan-Meier survival curves, illustrated in Figure 2, showed that the non-RA group had a lower recurrence risk compared to the RA group (P < 0.05).

Table 3 Multivariate Analysis of Risk Factors for CRSwNP Recurrence

Table 4 Unadjusted and Adjusted Logistic Regression Analysis for CRSwNP Recurrence According to RA

Figure 2 Kaplan–Meier survival curves stratified by RA and non-RA in predicting the postoperative recurrence of CRSwNP.

Abbreviations: RA, rheumatoid arthritis; CRSwNP, chronic rhinosinusitis with nasal polyps.

Discussion

To our knowledge, this study is the first to investigate the effects of RA on eosinophilic inflammation in tissue and postoperative recurrence among CRSwNP patients, using a relatively large retrospective cohort. We discovered that RA significantly increases the risk of postoperative recurrence and intensifies tissue eosinophil inflammation. Notably, RA was identified as an independent risk factor for postoperative recurrence, even when controlling for other potential variables. Our findings shed light on the clinical features of CRSwNP patients with comorbid RA, providing a detailed overview of postoperative recurrence rates within this group. This study highlights the role of RA in promoting eosinophilic infiltration in tissue and its detrimental effects on symptom severity and recurrence post-surgery in these patients.

RA is characterized as a chronic, progressive autoimmune inflammatory disease that prominently features systemic inflammation and immune cell reactivity towards joint tissues.23 RA also significantly influences the development and prognosis of various extra-articular inflammatory conditions, impacting systems such as the nervous, respiratory, and cardiovascular systems.24,25,30 Recent literature has found that RA can influence the nasal microbiome profile.31 A study analyzed the prevalence of nasal Staphylococcus aureus in RA patients and reported an increased prevalence of Staphylococcus aureus nasal carriage in these individuals.27 Staphylococcus aureus is also considered one of the common pathogens in CRSwNP, and it is commonly used as an inducer in establishing animal models.32,33 These studies suggest a potential role for certain microorganisms in the pathogenesis of both RA and CRSwNP. Existing epidemiological survey study examining the link between CRSwNP and RA has been limited but indicative. For instance, one cross-sectional study highlighted a higher prevalence of RA among CRS patients than in controls,34 and another found an increased incidence of CRS in patients with RA.26 Furthermore, Shih et al35 demonstrated a significant association between RA and various CRS phenotypes in a case-control study, noting an elevated incidence of both CRSwNP and CRSsNP among patients with pre-existing RA. Conversely, Tan et al36 found no significant correlation between RA and subsequent CRS diagnoses, reporting that the incidence of CRS and CRSwNP in RA patients was comparable to that observed in hypertensive patients.37 Notably, recent Mendelian randomization studies have suggested a causal relationship between RA and nasal polyps, partially mediated by the “BAFF-R for IgD+ B cells” pathway,38,39 further underscoring RA’s role in exacerbating CRSwNP conditions. Despite these insights, research into RA’s impact on the histopathology and postoperative recurrence of CRSwNP remains unexplored.

It is well established that the complex interactions between immune cells, inflammatory cells, and the cytokine composition in the immune microenvironment, along with nasal microbiota dysbiosis, are the fundamental causes of the high tissue heterogeneity and postoperative recurrence in CRSwNP.40,41 The underlying the influence of RA on CRSwNP result from a multifaceted interplay of factors, and the potential mechanisms may involve autoimmune dysregulation, systemic inflammation, particularly eosinophilic inflammation, and the impact of RA treatments. RA is characterized by systemic autoimmune dysregulation, where the immune system erroneously targets the body’s own tissues, leading to chronic inflammation and tissue damage that often extend beyond the joints to affect various other tissues.42,43 Notably, studies in molecular biology and immunology have demonstrated elevated levels of anti-dsDNA antibodies in nasal polyp tissues,22 suggesting a potential mechanism of pathology in CRSwNP. It is highly plausible that in CRSwNP patients with comorbid RA, the presence of high levels of autoantibodies could damage nasal epithelial cells. This damage is likely to manifest locally within the sinonasal tract, further exacerbating chronic inflammation and compromising mucosal barrier function. Consequently, the persistent immune dysregulation in these patients may result in delayed postoperative wound healing, impaired tissue remodeling, prolonged eosinophilic inflammatory responses, and recurrent sinonasal infections. Excessive inflammatory cytokines and immune cells are central to the pathophysiology of both RA and CRSwNP.44,45 It has been shown that synovial tissue and circulating immune cells in RA patients produce substantial amounts of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1, interleukin-17A, interleukin-5, and interleukin-6.46 These cytokines play a critical role in mediating the inflammatory cascade, facilitating the recruitment of eosinophils, exacerbating tissue damage in affected areas, and sustaining ongoing eosinophilic inflammation and tissue remodeling.47 The elevated levels of these cytokines can circulate systemically and potentially impact sinonasal tissues, thereby perpetuating inflammation in nasal and sinus passages even postoperatively. Our findings indicate that RA significantly enhances eosinophils infiltration in CRSwNP tissues, and eosinophilia is considered a major risk factor for the recurrence of CRSwNP.11,16 Moreover, the systemic increase in pro-inflammatory cytokines due to RA can prolong inflammation and impair nasal tissue repair, creating conditions favorable for recurrent infections and inflammation. This disruption in the normal healing process is a key contributor to the recurrence of CRSwNP. Furthermore, RA can lead to nasal microbiota dysbiosis, particularly causing a significant increase in the infection and level of Staphylococcus aureus. Staphylococcus aureus infection and persistence in CRSwNP can perpetuate nasal inflammation, especially by promoting eosinophilic recruitment and general Th2 polarization, both of which play a crucial role in the pathophysiological mechanisms underlying CRSwNP recurrence.48,49

Treatment of RA with immunosuppressive medications and non-biologic disease-modifying anti-rheumatic drugs can disrupt immune regulation and diminish the immune system’s capacity to combat infections in the sinonasal tract. These treatments can also alter immune responses both systemically and locally, potentially influencing immune cell activity within sinonasal tissues and affecting postoperative outcomes.50 It is crucial to comprehend these complex mechanisms to refine postoperative care and improve outcomes for CRSwNP patients with comorbid RA. Additionally, further investigation is needed to better understand and address these immunological factors to minimize the risk of recurrence in this patient group.

This study has several limitations. Firstly, the participants were recruited from a single medical center, and the cohort of RA patients was relatively small, potentially introducing selection bias and limiting the generalizability of the results to a broader population. Secondly, the presence of confounding variables and unmeasured factors could influence the associations observed, complicating the interpretation of the results. Thirdly, the disease severity and treatment specifics of RA patients were not clearly documented, obscuring any direct effects these factors might have on CRSwNP recurrence. Additionally, this study was unable to establish a temporal relationship between RA exposure and the development of CRSwNP, further limiting the conclusions that can be drawn.

Conclusion

This retrospective cohort study revealed that RA might promote tissue eosinophil infiltration, potentially increasing the risk of postoperative CRSwNP recurrence. Tissue eosinophil count, percentage, and AR were identified as possible risk factors for recurrence. Patients with both CRSwNP and RA may benefit from a multidisciplinary approach that addresses both autoimmune factors and surgical challenges.

Funding

This research was supported by the Natural Science Foundation of Hunan Province (2022JJ40831).

Disclosure

There are no patents, products in development, or marketed products to declare. Authors of this manuscript have no relevant financial or other relationships to disclose.

References

1. Kato A, Schleimer RP, Bleier BS. Mechanisms and pathogenesis of chronic rhinosinusitis. J Allergy Clin Immunol. 2022;149(5):1491–1503. doi:10.1016/j.jaci.2022.02.016

2. Kariyawasam HH, Chandrasekharan DP, Jacques T, et al. Biologic treatment for severe chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis. Rhinology. 2023;61(2):98–107. doi:10.4193/Rhin22.412

3. Rank M, Mullol J. Chronic Rhinosinusitis: forward! J Allergy Clin Immunol Pract. 2022;10(6):1472–1473. doi:10.1016/j.jaip.2022.01.017

4. Boscke R, Heidemann M, Bruchhage KL. Dupilumab for chronic rhinosinusitis with nasal polyps: real-life retrospective 12-month effectiveness data. Rhinology. 2023;61(3):203–213. doi:10.4193/Rhin22.469

5. Boechat JL, Sousa-Pinto B, Delgado L, Silva D. Biologicals in severe chronic rhinosinusitis with nasal polyps: translation to clinical practice while waiting for head-to-head studies. Rhinology. 2023;61(3):283–286. doi:10.4193/Rhin22.436

6. Chapurin N, Wu J, Labby AB, Chandra RK, Chowdhury NI, Turner JH. Current insight into treatment of chronic rhinosinusitis: phenotypes, endotypes, and implications for targeted therapeutics. J Allergy Clin Immunol. 2022;150(1):22–32. doi:10.1016/j.jaci.2022.04.013

7. Shen KH, Jiang JY, Hsu PY, et al. Can serum IgE or blood eosinophil count predict postoperative oral corticosteroid response in chronic rhinosinusitis with nasal polyps? Rhinology. 2024;62(2):192–201. doi:10.4193/Rhin23.124

8. Kemp P, van der Lans RJL, Otten JJ, et al. Hypereosinophilia during dupilumab treatment in patients with chronic rhinosinusitis with nasal polyps. Rhinology. 2024;62(2):202–207. doi:10.4193/Rhin23.357

9. Giri S, Schneider AL, Tan BK. Chronic rhinosinusitis: future treatments and unmet needs. J Allergy Clin Immunol. 2022;150(2):287–290. doi:10.1016/j.jaci.2022.05.016

10. Xu X, Seet JE, Yap QV, et al. Latent class analysis of structured histopathology in prognosticating surgical outcomes of chronic rhinosinusitis with nasal polyps in Singapore. Rhinology. 2023;61(4):358–367. doi:10.4193/Rhin22.455

11. Wu PW, Chiu CH, Huang YL, et al. Tissue eosinophilia and computed tomography features in paediatric chronic rhinosinusitis with nasal polyps requiring revision surgery. Rhinology. 2023;61(3):348–357. doi:10.4193/Rhin22.435

12. Simmonds JC, Paz-Lansberg M, Scangas G, Metson R. Endoscopic sinus surgery for chronic rhinosinusitis: 22-item sino-nasal outcome test 5-year results. Int Forum Allergy Rhinol. 2022;12(3):257–265. doi:10.1002/alr.22886

13. de Loos DAE D, Cornet ME, Hopkins C, Fokkens WJ, Reitsma S. Measuring control of disease in chronic rhinosinusitis; assessing the correlation between sinonasal outcome test-22 and visual analogue scale item scores. Rhinology. 2023;61(1):39–46. doi:10.4193/Rhin21.275

14. Soler ZM, Jones R, Le P, et al. Sino-Nasal outcome test-22 outcomes after sinus surgery: a systematic review and meta-analysis. Laryngoscope. 2018;128(3):581–592. doi:10.1002/lary.27008

15. Yilmaz G, Eyigor H, Gur OE, et al. The role of TAS2R38 genotype in surgical outcomes and culturable bacteria in chronic rhinosinusitis with or without nasal polyps. Rhinology. 2023;61(1):54–60. doi:10.4193/Rhin22.118

16. Jo S, Lee SH, Jo HR, et al. Eosinophil-derived TGFβ1 controls the new bone formation in chronic rhinosinusitis with nasal polyps. Rhinology. 2023;61(4):338–347. doi:10.4193/Rhin22.439

17. Yip J, Hao W, Eskander A, Lee JM. Wait times for endoscopic sinus surgery influence patient-reported outcome measures in patients with chronic rhinosinusitis who fulfill appropriateness criteria. Int Forum Allergy Rhinol. 2019;9(4):396–401. doi:10.1002/alr.22257

18. Shin S-H, M-K Y, Park J, Geum S-Y. Immunopathologic role of eosinophils in eosinophilic chronic rhinosinusitis. Int J Mol Sci. 2022;23(21):13313. doi:10.3390/ijms232113313

19. Zhang C, Zhang H, Tang Q, et al. Allergic rhinitis as an independent risk factor for postoperative recurrence of children chronic sinusitis. Children. 2023;11(1):10. doi:10.3390/children11010010

20. Xie S, Zhang C, Xie Z, Zhang J, Zhang H, Jiang W. Serum metabolomics identifies uric acid as a possible novel biomarker for predicting recurrence of chronic rhinosinusitis with nasal polyps. Rhinology. 2023;61(6):541–551. doi:10.4193/Rhin23.236

21. Jiang T, Yu T, Jiang L, Qin M, Tong Z. Metabolic syndrome facilitates histopathological changes and the risk of postoperative recurrence in chronic rhinosinusitis with nasal polyps. Int Immunopharmacol. 2024;128:111540. doi:10.1016/j.intimp.2024.111540

22. Kato A, Peters A, Suh L, et al. Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2008;121.

23. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheumatic Dis. 2010;69(9):1580–1588. doi:10.1136/ard.2010.138461

24. Figus FA, Piga M, Azzolin I, McConnell R, Iagnocco A. Rheumatoid arthritis: extra-articular manifestations and comorbidities. Autoimmunity Rev. 2021;20(4):102776. doi:10.1016/j.autrev.2021.102776

25. Wu D, Luo Y, Li T, et al. Systemic complications of rheumatoid arthritis: focus on pathogenesis and treatment. Front Immunol. 2022;13:1051082. doi:10.3389/fimmu.2022.1051082

26. Lee IH, Yang HG, Ha -S-S, Son GM, Kim DW, Kim D-K. Effect of chronic rhinosinusitis on the risk of development of rheumatoid arthritis. Allergy Asthma Immunol Res. 2023;15(5):647–658. doi:10.4168/aair.2023.15.5.647

27. Asai S, Takahashi N, Kishimoto K, et al. Increased prevalence of staphylococcus aureus nasal carriage in rheumatoid arthritis patients with moderate/high disease activity. J Orthop Sci. 2023;28(6):1400–1406. doi:10.1016/j.jos.2022.09.014

28. Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg. 2015;153(1):152. doi:10.1177/0194599815580981

29. Brescia G, Contro G, Giacomelli L, Barion U, Frigo AC, Marioni G. Blood eosinophilic and basophilic trends in recurring and non-recurring eosinophilic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2021;35(3):296–301. doi:10.1177/1945892420953960

30. Conforti A, Di Cola I, Pavlych V, et al. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmunity Rev. 2021;20(2):102735. doi:10.1016/j.autrev.2020.102735

31. Goodman SM, Nocon AA, Selemon NA, et al. Increased staphylococcus aureus nasal carriage rates in rheumatoid arthritis patients on biologic therapy. J Arthroplasty. 2019;34(5):954–958. doi:10.1016/j.arth.2019.01.025

32. Shaghayegh G, Cooksley C, Bouras G, et al. S. aureus biofilm properties correlate with immune B cell subset frequencies and severity of chronic rhinosinusitis. Clin Immunol. 2024;263:110221. doi:10.1016/j.clim.2024.110221

33. Houtak G, Nepal R, Bouras G, et al. Staphylococcus aureus biofilm-secreted factors cause mucosal damage, mast cell infiltration, and goblet cell hyperplasia in a rat rhinosinusitis model. Int J Mol Sci. 2024;25.

34. Chung S-D, Chen P-Y, Lin H-C, Hung S-H. Comorbidity profile of chronic rhinosinusitis: a population-based study. Laryngoscope. 2014;124(7):1536–1541. doi:10.1002/lary.24581

35. Shih L-C, Hsieh -H-H, Tsay GJ, et al. Chronic rhinosinusitis and premorbid autoimmune diseases: a population-based case-control study. Sci Rep. 2020;10(1):18635. doi:10.1038/s41598-020-75815-x

36. Tan BK, Chandra RK, Pollak J, et al. Incidence and associated premorbid diagnoses of patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2013;131(5):1350–1360. doi:10.1016/j.jaci.2013.02.002

37. Chandra RK, Lin D, Tan B, et al. Chronic rhinosinusitis in the setting of other chronic inflammatory diseases. Am J Otolaryngol 2011;32(5):388–391. doi:10.1016/j.amjoto.2010.07.013

38. Chen S, Tan L, Qin D, et al. The causal relationship between multiple autoimmune diseases and nasal polyps. Front Immunol. 2023;14:1228226. doi:10.3389/fimmu.2023.1228226

39. Xiao Q, Wang H, Song J, et al. Impaired local vitamin D3 metabolism contributes to IL-36g overproduction in epithelial cells in chronic rhinosinusitis with nasal polyps. Rhinology. 2024;62(2):236–249. doi:10.4193/RhinRhin23.123

40. Fokkens WJ, Viskens AS, Backer V, et al. EPOS/EUFOREA update on indication and evaluation of biologics in chronic rhinosinusitis with nasal polyps 2023. Rhinology. 2023;61(3):194–202. doi:10.4193/Rhin22.489

41. Zhao Y, Chen J, Hao Y, et al. Predicting the recurrence of chronic rhinosinusitis with nasal polyps using nasal microbiota. Allergy. 2022;77(2):540–549. doi:10.1111/all.15168

42. Gravallese EM, Firestein GS. Rheumatoid arthritis - common origins, divergent mechanisms. New Engl J Med. 2023;388(6):529–542. doi:10.1056/NEJMra2103726

43. Cutolo M, Campitiello R, Gotelli E, Soldano S. The role of m1/m2 macrophage polarization in rheumatoid arthritis synovitis. Front Immunol. 2022;13:867260. doi:10.3389/fimmu.2022.867260

44. Li P, Sheng Q, Huang LC, Turner JH. Epithelial innate immune response to Pseudomonas aeruginosa– derived flagellin in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2023;13(10):1937–1948. doi:10.1002/alr.23164

45. Brock J, Basu N, Schlachetzki JCM, Schett G, McInnes IB, Cavanagh J. Immune mechanisms of depression in rheumatoid arthritis. Nat Rev Rheumatol. 2023;19(12):790–804. doi:10.1038/s41584-023-01037-w

46. Middleton FM, McGregor R, Webb RH, Wilson NJ, Moreland NJ. Cytokine imbalance in acute rheumatic fever and rheumatic heart disease: mechanisms and therapeutic implications. Autoimmun Rev. 2022;21(12):103209. doi:10.1016/j.autrev.2022.103209

47. Sverrild A, Cerps S, Nieto-Fontarigo JJ, et al. Tezepelumab decreases airway epithelial IL-33 and T2-inflammation in response to viral stimulation in patients with asthma. Allergy. 2024;79(3):656–666. doi:10.1111/all.15918

48. Poddighe D, Brambilla I, Licari A, Marseglia GL. Pediatric rhinosinusitis and asthma. Respir Med. 2018;141:94–99. doi:10.1016/j.rmed.2018.06.016

49. Poddighe D, Vangelista L, Moss J. Staphylococcus aureus infection and persistence in chronic rhinosinusitis: focus on leukocidin ED. Toxins. 2020;13(1):12. doi:10.3390/toxins13010012

50. Liu S, Ma H, Zhang H, Deng C, Xin P. Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis. Clin Immunol. 2021;230:108793. doi:10.1016/j.clim.2021.108793