Patient-Reported Outcomes Reveal Distinct Sinonasal Phenotype in Vitiligo-Associated Chronic Rhinosinusitis

Introduction

Vitiligo is a chronic, immune-mediated depigmentation disorder resulting from the targeted destruction of melanocytes by autoreactive CD8+ T cells. It affects approximately 0.5-2% of the global population and it often carries substantial psychosocial consequences disproportionate to its visible extent.¹˒² While historically classified as a purely cutaneous disease, vitiligo is now recognized as a systemic autoimmune condition associated with a range of comorbid immune-mediated disorders, including thyroid disease, alopecia areata, rheumatoid arthritis, and inflammatory bowel disease.³˒⁴ Its immunological profile is predominantly driven by a T1-skewed cytokine environment, with interferon (IFN)-gamma serving as the central pathogenic mediator, promoting CXCL9 and CXCL10 chemokine expression that recruits cytotoxic T cells to pigmented skin.⁵˒⁶ Additional pro-inflammatory signals including interleukin (IL)-17, tumor necrosis factor (TNF)-alpha, and IL-6 have also been identified in lesional and perilesional skin, suggesting diffuse immune dysregulation extending beyond zones of active depigmentation.⁷

Chronic rhinosinusitis (CRS) is an inflammatory condition affecting the paranasal sinuses and nasal mucosa, defined by the continuation of hallmark sinonasal symptoms for a minimum of 12 uninterrupted weeks. The condition is broadly subdivided based on the presence or absence of nasal polyposis. CRS with nasal polyps (CRSwNP) is most often characterized by a type 2 (T2) inflammatory milieu mediated by cytokines such as IL-4, IL-5, and IL-13, a pattern that can occur independent of systemic allergic sensitization but associated with atopy; whereas CRS without nasal polyps (CRSsNP) more frequently demonstrates a neutrophil-predominant T1/T3 immune pattern not driven by atopy.⁸˒⁹ These distinct immunologic underpinnings carry meaningful clinical consequences, shaping symptom expression, disease trajectory, and therapeutic decision-making. Given this heterogeneity, the present study evaluates vitiligo-associated CRS within these recognized phenotypic categories rather than treating CRS as a homogeneous entity.¹⁰

Although the incidence of CRS is higher in patients with vitiligo than in the general population, the relationship between vitiligo and impact on sinonasal pathology has not been characterized in the literature. However, CRS prevalence and severity have been shown to be altered when in the presence of other dermatological and autoimmune conditions (e.g. atopic dermatitis, and psoriasis).¹¹–¹³ Whether this phenotypic modification reflects a process specific to vitiligo’s T1-dominant immune signature or a more general feature of systemic autoimmune disease remains unclear, as similar alterations in CRS phenotype have been observed in other autoimmune populations, including Sjogren syndrome and psoriasis.¹⁰˒¹¹ Systemic immune dysregulation observed in vitiligo, particularly its T1-predominant cytokine signature, may plausibly influence the inflammatory environment of the sinonasal mucosa and modulate CRS presentation. The shared immunological profile between vitiligo and CRS subtypes, as well as the documented impact of vitiligo on psychosocial functioning and quality of life, makes this population clinically important.¹⁴˒¹⁵

Methods

We compared CRS phenotypic characteristics in patients with coexisting vitiligo to those observed in patients with CRS alone, stratified by CRS subtype (CRSsNP and CRSwNP) and without other autoimmune comorbidities. Electronic medical records were reviewed to identify individuals with CRS who also carried a dermatologist-confirmed diagnosis of vitiligo. CRS diagnoses were established by otolaryngologists and required persistent sinonasal symptoms along with objective confirmation on both nasal endoscopy and sinus computed tomography (CT).

Eligible patients were identified between 2019 and 2025, corresponding to the interval during which the Sino-Nasal Outcome Test (SNOT-22) was routinely documented at initial CRS encounters within the UVA Health System. Disease severity was assessed at the initial clinical evaluation, prior to initiation of biologic therapies or functional endoscopic sinus surgery. Use of topical sinonasal treatments, including saline irrigations and intranasal corticosteroids, was permitted.

Patient-reported symptom burden was measured using the SNOT-22.¹⁶ Objective measures of disease severity included radiographic involvement assessed by the Lund-Mackay score on sinus CT imaging, endoscopic severity graded using the Lund-Kennedy scoring system, and markers of type 2 inflammation, including serum immunoglobulin E (IgE) levels, absolute eosinophil counts (AEC), and the presence of nasal polyps. Group comparisons were conducted using ANOVA or the Kruskal-Wallis test, as appropriate. Statistical significance was defined as p < 0.05, with p values between 0.05 and 0.10 considered indicative of trends toward significance.

Results

A total of 13 patients with comorbid vitiligo and CRS were identified and compared to 137 patients with CRSsNP and 49 patients with CRSwNP without autoimmune comorbidity (Table 1). Baseline demographics, including age at presentation and gender distribution were similar across groups. Notably, 46.1% of patients in the vitiligo cohort harbored nasal polyps.

Peripheral markers of type 2 inflammation differed significantly across groups. AEC was significantly higher in the CRSwNP cohort and intermediate in vitiligo-CRS compared to CRSsNP (p < 0.001). Serum IgE levels were numerically highest in CRSwNP compared to vitiligo-CRS and CRSsNP, with a trend toward significance (p = 0.08). Objective sinonasal disease burden followed expected patterns: LMS was highest in CRSwNP and lowest in CRSsNP, with the vitiligo cohort demonstrating intermediate radiographic involvement (p < 0.001). Endoscopic severity mirrored this pattern, with LKS highest in CRSwNP and lowest in CRSsNP, and vitiligo-CRS again falling in between (p < 0.001).

Despite carrying intermediate objective disease burden, the vitiligo cohort reported the highest total SNOT-22 scores (p = 0.04). Item-level analysis revealed significantly elevated scores in vitiligo-associated CRS for need to blow the nose (p = 0.04), sneezing (p = 0.03), ear fullness (p = 0.05), dizziness (p = 0.01), ear pain (p = 0.003), facial pain/pressure (p = 0.04), fatigue (p = 0.04), and lack of a good night's sleep (p = 0.10). Trends toward significance were observed for runny nose (p = 0.10), waking up at night (p = 0.07), and feelings of frustration/irritability (p = 0.10).

Discussion

This study provides the first characterization of CRS clinical phenotype in patients with comorbid vitiligo. Our central finding is that vitiligo-associated CRS is defined not by the greatest objective sinonasal burden, but by a markedly amplified subjective symptom experience. Patients in the vitiligo cohort reported the highest total SNOT-22 scores across groups, with significant elevations spanning rhinologic, otologic, sleep, and systemic domains, despite carrying intermediate scores on CT and endoscopic staging. This dissociation between objective and subjective disease measures points to a vitiligo-driven phenotypic modification of CRS.

The pattern of symptom elevation observed in the vitiligo cohort spans multiple symptom clusters that are not traditional markers of sinonasal inflammatory severity, though given the exploratory nature of these item-level comparisons, this pattern should be viewed as hypothesis generating and not definitive. Significant elevations in dizziness, ear fullness, ear pain, and fatigue raise the possibility of systemic or neuroinflammatory contributions to symptom generation, though this study was not designed to establish such a mechanism. IFN-gamma, the central cytokine in vitiligo pathogenesis, has well-documented effects on central and peripheral nervous system function, including modulation of nociception and sensory processing.¹⁷˒¹⁸ Upregulation of IFN-gamma, attributed to the upregulation of CXCL9 and CXCL10, has been identified in neuroinflammatory contexts, raising the possibility that the systemic immune environment of vitiligo primes an amplified sensorineural response to sinonasal inflammation; this remains speculative and was not directly tested in the current study.¹⁹

Particularly noteworthy is the absence of significant differences in nasal obstruction and loss of smell or taste between groups. These symptoms are classically associated with the degree of polyp burden and mucosal edema, objective features more directly tied to local type 2 inflammation. Their lack of elevation in the vitiligo cohort, despite this group having the highest SNOT-22 total, reinforces the notion that the symptom amplification is not mechanistically driven by T2 mucosal pathology but rather by a systemic immune-neurological interaction characteristic of vitiligo's T1-dominant environment.

From a clinical standpoint, the intermediate polyp prevalence (46.1%) in the vitiligo cohort presents an intriguing phenotypic portrait. This finding may reflect a mixed inflammatory endotype in vitiligo-associated CRS; one in which the baseline T1 skew of vitiligo partially suppresses the T2-predominant polyp-forming presentation. The elevated AEC and intermediate IgE in this cohort, though not reaching the levels seen in CRSwNP, suggest that some residual type 2 activity persists, potentially in a modified or attenuated form. Future tissue-level inflammatory analysis of nasal mucosa in vitiligo patients would be valuable to resolve this endotype question. Comparison across these autoimmune-associated CRS cohorts may help clarify whether symptom amplification is driven by disease-specific cytokine profiles or represents a shared consequence of systemic immune dysregulation more broadly.¹⁰˒¹¹

The psychosocial dimension of vitiligo must also be considered as a contributor to the observed symptom burden. Vitiligo has a well-documented and often underappreciated impact on psychological wellbeing, with high rates of depression, anxiety, social stigma, and diminished quality of life, particularly in individuals with visible facial or acral depigmentation.¹⁴˒¹⁵˒²⁰ Psychological distress and heightened symptom vigilance, potentially reinforced by the visible nature of vitiligo, are known to amplify somatic symptom reporting through central sensitization mechanisms, including heightened activity in limbic and prefrontal circuits involved in interoceptive processing.²¹ In patients already experiencing significant psychosocial burden from their skin disease, even moderate sinonasal inflammation may be experienced and reported with disproportionate intensity.²²˒²³ It is also possible that the persistent visibility of vitiligo, in contrast to the more episodic or fluctuating course of many other autoimmune conditions, keeps patients in a heightened state of bodily awareness that extends beyond the skin, potentially increasing attentiveness to and reporting of sinonasal symptoms independent of any underlying neuroimmune process.

These findings carry practical implications for clinicians managing CRS in patients with vitiligo. Standard objective measures may substantially underestimate the true disease impact in this population. Patient-reported outcome instruments such as the SNOT-22 are therefore particularly valuable in this context and should be weighted heavily in treatment decision-making. A multidisciplinary approach involving otolaryngology, allergy/immunology, and dermatology is advisable. Additionally, screening for depression, anxiety, sleep disorders, and fatigue should be routine in this population, and psychological support integrated into the broader management plan.²⁰˒²²⁻²⁴

This study has several limitations. The vitiligo cohort is small, reflecting the relative rarity of this comorbid combination in a tertiary care referral population, and the retrospective single-center design introduces potential referral bias. Tissue-level inflammatory analysis was not available, limiting our ability to definitively characterize the sinonasal endotype in vitiligo-associated CRS. Peripheral biomarkers such as AEC and IgE, while useful, do not fully capture local mucosal inflammatory patterns.¹⁰˒¹⁵ SNOT-22 scores represent a single cross-sectional time point, precluding conclusions about longitudinal symptom trajectories or treatment responsiveness. Additionally, because nearly half of the vitiligo cohort carried nasal polyps, this group likely represents a heterogenous mixture of CRS subtypes rather than a single phenotype; the small sample size precluded meaningful subgroup analysis by polyp status, and this distinction should be examined in future studies with larger vitiligo cohorts.

This study represents the first description of CRS symptom burden in patients with comorbid vitiligo. The dissociation between objective sinonasal measures and patient reported outcomes raises the possibility of a distinct vitiligo associated CRS phenotype, potentially driven by systemic neuroimmune amplification rather than local mucosal disease alone. These findings support expanded investigation into the neuroinflammatory mechanisms by which systemic immune diseases may reshape sinonasal symptom experience.

Statement of Ethics

Study approval statement: This study protocol was reviewed and approved by the University of Virginia IRB, approval number 21482.

Consent to participate statement: Study was granted exemption from requiring written informed consent by the University of Virginia IRB, approval number 21482.

Conflict of Interest/Disclosures

LB reports investigator-initiated research grants from Regeneron (all funds are awarded to the University of Virginia).  LB serves on advisory boards for GSK, Sanofi/Genzyme, Regeneron, and Astra Zeneca.  All other authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

AS: Conceptualization; writing – original draft; methodology; validation; investigation; writing- review and editing; data curation; visualization; resources; formal analysis; supervision. CL: Writing – review and editing; validation. FA: Writing – review and editing; validation. MS: Writing – review and editing; validation.  LB: Conceptualization; investigation; writing – original draft; methodology; validation; writing – review and editing; data curation; supervision; resources; project administration.