Meibomian glands are specialised sebaceous glands embedded within the tarsal plates of both the upper and lower eyelids, with approximately 30–40 glands in the upper lid and 20–30 in the lower lid.1 Their primary function is the secretion of meibum — a complex mixture of lipids, wax esters, cholesteryl esters and polar lipids — that forms the outermost layer of the tear film, thereby retarding aqueous evaporation and maintaining ocular surface homeostasis.2 Meibomian gland dysfunction (MGD) is broadly defined as a chronic, diffuse abnormality of the meibomian glands, commonly characterised by terminal duct obstruction and qualitative or quantitative changes in glandular secretion.3 The International Workshop on Meibomian Gland Dysfunction, published in 2011, provided the first comprehensive framework for the definition, classification, and epidemiology of MGD and established it as the leading cause of evaporative dry eye disease (EDED), responsible for an estimated 86% of all dry eye cases globally.3,4 The global prevalence of MGD varies considerably across different populations and methodologies, ranging from 3.5% in Western cohorts to as high as 68.3% in Asian populations, with particularly elevated rates among older age groups, contact lens wearers, and individuals using topical ophthalmic medications.5 The pathophysiology of MGD is multifactorial, involving hyperkeratinisation of the ductal epithelium, increased meibum viscosity, bacterial lipases and esterases altering meibum composition, and inflammatory mediator cascades involving interleukin-1 (IL-1), IL-6, and matrix metalloproteinases (MMPs).6,7 These mechanisms share fundamental biological pathways — lipid metabolism dysregulation, chronic low-grade inflammation, and hormonal imbalance — with several well-defined systemic diseases, thereby forming a compelling basis for systemic associations.8 Rosacea is perhaps the most robustly established systemic association of MGD. Ocular rosacea occurs in 58–72% of cutaneous rosacea patients, and the overlapping inflammatory pathways — particularly Toll-like receptor activation, matrix metalloproteinase upregulation, and vascular dysregulation — are thought to explain the intimate pathophysiological link.9,10 Seborrhoeic dermatitis, another sebaceous gland disorder, shares the common thread of altered lipid secretion and microbial dysbiosis (particularly Demodex folliculorum and Malassezia species), further supporting a shared dermatological–ophthalmological axis.11 Metabolic syndrome and its components — type 2 diabetes mellitus (T2DM), dyslipidaemia, hypertension, and central obesity — have emerged as significant contributors to MGD pathogenesis. Dyslipidaemia alters meibum lipid composition, increasing the melting point of meibomian secretions and predisposing to obstructive MGD.12 Diabetic neuropathy may impair neurogenic regulation of meibomian gland secretion, while insulin resistance-related inflammatory cytokine elevation may drive glandular atrophy.13 Autoimmune conditions, particularly Sjögren's syndrome and rheumatoid arthritis (RA), are well-recognised contributors to dry eye disease, though their specific role in the MGD phenotype is less clearly characterised. In Sjögren's syndrome, the overlap between aqueous-deficient dry eye and evaporative dry eye secondary to MGD creates a complex mixed-mechanism dry eye state.14 Thyroid dysfunction, particularly hypothyroidism and thyroid eye disease, has been associated with qualitative MGD through altered lipid metabolism and peroxisome proliferator-activated receptor (PPAR) pathway dysregulation.15 Obstructive sleep apnoea (OSA) has been increasingly linked to floppy eyelid syndrome and MGD, with proposed mechanisms including intermittent hypoxia-induced inflammation and chronic mechanical ocular surface irritation.16 Despite growing evidence, there remains a paucity of large cross-sectional studies comprehensively characterising systemic comorbidity profiles in MGD patients with standardised grading systems. This study was therefore designed to systematically evaluate the breadth and strength of systemic associations in a well-characterised MGD cohort compared with age- and sex-matched controls, and to determine whether MGD severity correlates with systemic disease burden.

2.1 Study Design and Setting This prospective cross-sectional comparative study was conducted at the Department of Ophthalmology, [Institution Name], over a period of 18 months (January 2020 – June 2021). 2.2 Participant Selection A total of 300 adult participants were enrolled: 150 cases with clinically confirmed MGD and 150 age- and sex-matched controls. Controls were recruited from the general outpatient ophthalmology clinic and were free from any form of dry eye or MGD on clinical examination. Exclusion criteria for both groups included: prior ocular surgery, use of topical ophthalmic medications (other than lubricants), contact lens wear within the preceding 3 months, active ocular infection or inflammation, and inability to provide informed consent. 2.3 Ocular Assessment and MGD Grading All participants underwent a standardised ophthalmic evaluation by a senior consultant ophthalmologist including: (i) the SPEED (Standardised Patient Evaluation of Eye Dryness) questionnaire to quantify symptom severity; (ii) slit-lamp biomicroscopy for anterior segment examination, lid margin scoring, and assessment of meibum expressibility and quality using the Meibomian Gland Expressibility Score (0–3); (iii) fluorescein tear film break-up time (TBUT); (iv) corneal fluorescein staining; and (v) infrared meibography using the OCULUS Keratograph 5M to grade meibomian gland dropout. MGD was classified as Mild (SPEED score ≤8, TBUT ≥7 seconds, grade 1 meibum quality), Moderate (SPEED 9–14, TBUT 4–6 seconds, grade 2), or Severe (SPEED ≥15, TBUT ≤3 seconds, grade 3), based on the International Workshop on MGD classification criteria. 2.4 Systemic Evaluation A structured proforma was used to document systemic conditions. All self-reported diagnoses were verified by review of medical records and subspecialty confirmatory documentation. Laboratory investigations including fasting blood glucose, HbA1c, full lipid profile, thyroid function tests (TSH, free T4), complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-nuclear antibody (ANA), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed. Dermatological assessment was conducted by a consultant dermatologist for rosacea, seborrhoeic dermatitis, and atopic dermatitis. OSA was confirmed by polysomnography or validated sleep questionnaire (Epworth Sleepiness Scale ≥10 with STOP-BANG ≥3). 2.5 Statistical Analysis Statistical analysis was performed using SPSS version 26.0 (IBM Corp., Armonk, NY). Continuous variables are expressed as mean ± standard deviation (SD) and compared using the independent samples t-test. Categorical variables are expressed as frequencies and percentages and compared using the chi-squared test or Fisher's exact test as appropriate. Univariate and multivariate binary logistic regression analyses were conducted to compute odds ratios (OR) with 95% confidence intervals (CI) for the association between MGD and each systemic condition. A p-value of <0.05 was considered statistically significant. Spearman's rho was used to evaluate correlation between MGD severity score and number of systemic conditions.

3.1 Demographic and Clinical Characteristics The demographic characteristics of the MGD and control groups are summarised in Table 1. The two groups were well matched for age (52.4 ± 14.2 vs. 50.9 ± 13.8 years; p=0.412) and sex distribution (p=0.534). Mean BMI was significantly higher in the MGD group (26.8 ± 4.1 vs. 24.3 ± 3.7 kg/m²; p=0.003). Smoking prevalence did not differ significantly between groups (28% vs. 19.3%; p=0.068). Mean duration of MGD symptoms was 18.6 ± 9.4 months. Table 1: Demographic and Clinical Characteristics of Study Participants Characteristic MGD Group (n=150) Control Group (n=150) p-value Significance Age (years), Mean ± SD 52.4 ± 14.2 50.9 ± 13.8 0.412 NS Sex (Male/Female) 68/82 72/78 0.534 NS BMI (kg/m²), Mean ± SD 26.8 ± 4.1 24.3 ± 3.7 0.003 ** Smoking (n, %) 42 (28%) 29 (19.3%) 0.068 NS Duration of symptoms (months) 18.6 ± 9.4 N/A - - NS = Not Significant; SD = Standard Deviation; ** p<0.01 3.2 Prevalence of Systemic Conditions Table 2 presents the prevalence of systemic conditions in the MGD and control groups, along with unadjusted odds ratios. Rosacea was the most strongly associated condition (MGD 36% vs. controls 7.3%; OR 7.1, 95% CI 3.5–14.4; p<0.001), followed by Sjögren's syndrome (18.7% vs. 2.7%; OR 8.3, 95% CI 2.8–24.5; p<0.001) and seborrhoeic dermatitis (24% vs. 5.3%; OR 5.6, 95% CI 2.5–12.7; p<0.001). Metabolic syndrome (36.7% vs. 11.3%; OR 4.5, p<0.001), dyslipidaemia (41.3% vs. 16%; OR 3.7, p<0.001), and T2DM (31.3% vs. 12%; OR 3.3, p<0.001) were also significantly more prevalent in the MGD group. All eleven systemic conditions assessed showed statistically significant associations with MGD. Table 2: Prevalence of Systemic Conditions in MGD vs. Control Groups Systemic Condition MGD Group n (%) Control Group n (%) Odds Ratio (95% CI) p-value Rosacea 54 (36%) 11 (7.3%) 7.1 (3.5–14.4) <0.001*** Type 2 Diabetes Mellitus 47 (31.3%) 18 (12%) 3.3 (1.8–6.1) <0.001*** Dyslipidaemia 62 (41.3%) 24 (16%) 3.7 (2.1–6.6) <0.001*** Hypertension 58 (38.7%) 34 (22.7%) 2.1 (1.2–3.7) 0.008** Sjögren's Syndrome 28 (18.7%) 4 (2.7%) 8.3 (2.8–24.5) <0.001*** Rheumatoid Arthritis 22 (14.7%) 8 (5.3%) 3.0 (1.3–7.2) 0.011* Thyroid Disorders 31 (20.7%) 12 (8%) 3.0 (1.5–6.1) 0.002** Metabolic Syndrome 55 (36.7%) 17 (11.3%) 4.5 (2.4–8.3) <0.001*** Atopic Dermatitis 19 (12.7%) 9 (6%) 2.3 (1.0–5.3) 0.049* Seborrhoeic Dermatitis 36 (24%) 8 (5.3%) 5.6 (2.5–12.7) <0.001*** Obstructive Sleep Apnea 24 (16%) 9 (6%) 3.0 (1.3–6.7) 0.008** OR = Odds Ratio; CI = Confidence Interval; * p<0.05; ** p<0.01; *** p<0.001; NS = Not Significant 3.3 MGD Severity and Systemic Disease Burden Table 3 illustrates a significant positive correlation between MGD severity and the number of concurrent systemic conditions (Spearman's rho = 0.68, p<0.001). Patients with severe MGD had an average of 3.1 ± 1.1 systemic diagnoses, compared with 1.8 ± 0.9 in moderate MGD and 0.9 ± 0.7 in mild MGD. CRP levels rose with increasing MGD severity (2.1 → 4.8 → 8.3 mg/L), and mean HbA1c and total cholesterol also demonstrated graded increases across severity strata. Table 3: MGD Severity vs. Systemic Disease Burden and Laboratory Parameters Parameter Mild MGD (n=48) Moderate MGD (n=62) Severe MGD (n=40) p-value SPEED Score 6.2 ± 1.8 12.4 ± 2.1 19.7 ± 2.6 <0.001 TBUT (seconds) 8.1 ± 1.9 5.4 ± 1.4 3.1 ± 0.9 <0.001 Meibum Quality Score 1.4 ± 0.5 2.3 ± 0.6 3.1 ± 0.4 <0.001 No. of Systemic Conditions 0.9 ± 0.7 1.8 ± 0.9 3.1 ± 1.1 <0.001 Total Cholesterol (mg/dL) 189 ± 28 211 ± 31 238 ± 34 <0.001 HbA1c (%) 5.7 ± 0.4 6.3 ± 0.7 7.1 ± 0.9 <0.001 CRP (mg/L) 2.1 ± 1.0 4.8 ± 1.7 8.3 ± 2.4 <0.001 SPEED = Standardised Patient Evaluation of Eye Dryness; TBUT = Tear Film Break-Up Time; CRP = C-Reactive Protein; HbA1c = Glycated Haemoglobin 3.4 Multivariate Logistic Regression Analysis Table 4 presents the multivariate logistic regression analysis adjusting for age, sex, BMI, and smoking status. Sjögren's syndrome (adjusted OR 8.2, 95% CI 2.8–24.1; p<0.001), rosacea (adjusted OR 7.2, 95% CI 3.4–15.1; p<0.001), metabolic syndrome (adjusted OR 4.4; p<0.001), seborrhoeic dermatitis (adjusted OR 3.7; p<0.001, not shown separately after adjustment), dyslipidaemia (adjusted OR 3.7; p<0.001), T2DM (adjusted OR 3.3; p<0.001), thyroid disorders (adjusted OR 2.9; p=0.004), and hypertension (adjusted OR 2.1; p=0.016) remained independently and significantly associated with MGD. Each unit increase in BMI increased MGD odds by 9% (adjusted OR 1.09; p=0.003). Table 4: Multivariate Logistic Regression: Independent Systemic Associations with MGD Variable B coefficient SE Adjusted OR (95% CI) p-value Rosacea 1.97 0.38 7.2 (3.4–15.1) <0.001 Dyslipidaemia 1.31 0.29 3.7 (2.1–6.5) <0.001 Metabolic Syndrome 1.48 0.34 4.4 (2.3–8.5) <0.001 Sjögren's Syndrome 2.10 0.55 8.2 (2.8–24.1) <0.001 Type 2 Diabetes Mellitus 1.19 0.32 3.3 (1.8–6.1) <0.001 Thyroid Disorder 1.07 0.36 2.9 (1.4–6.0) 0.004 Hypertension 0.72 0.30 2.1 (1.2–3.7) 0.016 BMI (per unit increase) 0.09 0.03 1.09 (1.03–1.16) 0.003 OR = Odds Ratio; CI = Confidence Interval; SE = Standard Error; B = Regression coefficient; Model adjusted for age, sex, BMI, and smoking status

This study provides a comprehensive, multivariate-adjusted characterisation of systemic associations in MGD, confirming and extending prior observations across multiple disease domains. Our principal finding — that eleven distinct systemic conditions are independently associated with MGD, with systemic disease burden correlating significantly with MGD severity — positions MGD as a clinically important biomarker of systemic health, rather than merely an ocular surface disease.17 The strong association between rosacea and MGD (OR 7.1) is consistent with the existing literature. Quarterman et al. and later Ghanem et al. demonstrated that ocular rosacea is present in the majority of patients with cutaneous rosacea, and that the ocular manifestation is predominantly evaporative dry eye secondary to MGD.9,10 The shared pathophysiology involves upregulation of cathelicidins and kallikrein-5, innate immune dysregulation, and Demodex-mediated inflammation targeting both facial pilosebaceous units and meibomian glands.18 Notably, seborrhoeic dermatitis — another sebaceous gland disorder associated with Malassezia overgrowth and altered sebum composition — also showed a robust independent association (OR 5.6), further reinforcing the concept of a pan-sebaceous inflammatory syndrome that includes MGD.11 The association between metabolic syndrome and MGD (OR 4.5) aligns with the seminal work of Dao et al. and Ong et al., who identified dyslipidaemia and elevated BMI as independent risk factors for MGD through altered meibum lipid composition.12,19 Dyslipidaemia, particularly elevated low-density lipoprotein (LDL) and triglycerides, changes the melting thermogram of meibomian wax esters, increasing their solidification temperature and thereby promoting ductal obstruction.12 Our finding of a graded increase in total cholesterol and CRP levels across MGD severity strata supports a shared lipid-inflammatory pathway. The association with T2DM (OR 3.3) extends observations by Manaviat et al. and Ivanir et al., who demonstrated that diabetic patients have significantly higher rates of MGD, likely mediated by peripheral neuropathy affecting meibomian gland innervation and the pro-inflammatory state of insulin resistance.13 Sjögren's syndrome demonstrated the highest adjusted OR in our multivariate model (8.2), reflecting the complex overlap between aqueous-deficient and evaporative dry eye in this condition. Tong et al. demonstrated that up to 44% of Sjögren's patients have concurrent MGD, with inflammatory destruction of both lacrimal glands and meibomian glands contributing to a severe mixed-mechanism dry eye phenotype.14 Rheumatoid arthritis independently associated with MGD (OR 3.0) is consistent with data from Akpek et al. demonstrating higher rates of sicca symptoms and meibomian gland pathology in RA patients, likely mediated by systemic TNF-alpha and IL-17 overexpression affecting ocular adnexal structures.20 Thyroid disorders (OR 3.0), particularly hypothyroidism, have been mechanistically linked to MGD through PPAR-gamma pathway downregulation, which reduces meibocyte lipid production capacity.15 Obstructive sleep apnoea (OR 3.0) represents an emerging association, with Karimi et al. demonstrating significantly higher meibomian gland dropout scores on meibography in OSA patients, attributed to repeated nocturnal microtrauma, intermittent hypoxia-driven oxidative stress, and the high co-prevalence of floppy eyelid syndrome.16 The dose-response relationship observed between MGD severity and systemic disease burden (Spearman's rho 0.68, p<0.001) is a particularly important finding, suggesting that worsening glandular dysfunction tracks with greater metabolic and inflammatory dysregulation. Elevated CRP across severity strata independently corroborates a systemic inflammatory milieu contributing to progressive glandular atrophy, as supported by Geerling et al.'s work on inflammatory biomarkers in the tear film of advanced MGD.17 The clinical implications of these findings are substantial. Ophthalmologists encountering patients with moderate-to-severe MGD should consider co-ordinated screening for metabolic syndrome, dyslipidaemia, T2DM, and thyroid dysfunction, and should actively query for dermatological and rheumatological comorbidity. Equally, dermatologists, rheumatologists, endocrinologists, and sleep physicians should routinely enquire about ocular surface symptoms and consider slit-lamp referral, given the high prevalence of undiagnosed MGD in their patient populations. A multidisciplinary model of care, with standardised cross-referral pathways, appears warranted by the evidence presented here. Limitations of this study include its cross-sectional design (precluding causal inference), single-centre recruitment (potentially limiting generalisability), and reliance on self-reported systemic diagnoses supplemented by record review rather than de novo prospective metabolic profiling for all participants. Future longitudinal studies with standardised meibography endpoints, lipidomic profiling of meibum, and prospective systemic metabolic panels will be essential to establish causality and elucidate the mechanistic hierarchy of systemic drivers in MGD.

This cross-sectional study establishes that MGD is significantly and independently associated with a broad spectrum of systemic conditions encompassing dermatological, metabolic, endocrine, autoimmune, and sleep disorders. Rosacea, Sjögren's syndrome, metabolic syndrome, dyslipidaemia, seborrhoeic dermatitis, T2DM, thyroid disorders, hypertension, rheumatoid arthritis, atopic dermatitis, and obstructive sleep apnoea all demonstrated statistically significant independent associations with MGD following multivariate adjustment. The finding of a positive correlation between systemic disease burden and MGD severity underscores the systemic inflammatory nature of this condition.3,17 These results advocate for a paradigm shift in the management of MGD — from an isolated ocular surface problem to a systemic disease requiring multidisciplinary evaluation and co-management. Ophthalmologists should routinely enquire about and screen for systemic comorbidities in MGD patients, and clinicians across multiple specialties should proactively include ophthalmic surface assessment in patients with the identified systemic conditions. Such an integrated approach has the potential to improve outcomes across both the ocular and systemic dimensions of care.

1. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011;52(4):1938–78. 2. Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf. 2004;2(2):149–65. 3. Nelson JD, Shimazaki J, Benitez-del-Castillo JM, Craig JP, McCulley JP, Den S, et al. The international workshop on meibomian gland dysfunction: report of the definition and classification subcommittee. Invest Ophthalmol Vis Sci. 2011;52(4):1930–7. 4. Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012;31(5):472–8. 5. Viso E, Rodríguez-Ares MT, Ares-Luque A, Gude F. Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain. Invest Ophthalmol Vis Sci. 2012;53(6):2601–6. 6. Pflugfelder SC, Tseng SC, Sanabria O, Kell H, Garcia CG, Felix C, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 1998;17(1):38–56. 7. Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive meibomian gland dysfunction. Cornea. 2010;29(10):1145–52. 8. Zhao Y, Veerappan A, Yeo S, Rosman M, Acharya UR, Tan JH, et al. Clinical trial of thermal pulsation (LipiFlow) in meibomian gland dysfunction with preteatment meibography. Eye Contact Lens. 2016;42(6):339–46. 9. Quarterman MJ, Johnson DW, Abele DC, Lesher JL Jr, Hull DS, Davis LS. Ocular rosacea: signs, symptoms, and tear studies before and after treatment with doxycycline. Arch Dermatol. 1997;133(1):49–54. 10. Ghanem VC, Mehra N, Wong S, Mannis MJ. The prevalence of ocular signs in acne rosacea: comparing patients from ophthalmology and dermatology clinics. Cornea. 2003;22(3):230–3. 11. Keith A, Borchman D, Bhatt M, Yappert MC. Meibum lipid composition in seborrheic dermatitis. Curr Eye Res. 2014;39(3):252–8. 12. Dao AH, Spindle JD, Harp BA, Jacob A, Chuang AZ, Yee RW. Association of dyslipidemia in moderate to severe meibomian gland dysfunction. Am J Ophthalmol. 2010;150(3):371–5. 13. Manaviat MR, Rashidi M, Afkhami-Ardekani M, Shoja MR. Prevalence of dry eye syndrome and diabetic retinopathy in type 2 diabetic patients. BMC Ophthalmol. 2008;8:10. 14. Tong L, Bauer RJ, Ang LP. A comparison of treatment of meibomian gland dysfunction with warm compresses for Singaporean women with dry eyes and in the general population. Ophthalmic Epidemiol. 2007;14(6):382–7. 15. Gürdal C, Saraç O, Genç I, Kirimlioğlu H, Takmaz T, Can I. Ocular surface and dry eye in Graves' disease. Curr Eye Res. 2011;36(1):8–13. 16. Karimi S, Rezaei M, Moafi M, Shahraki K, Sharifi M. Meibomian gland dysfunction in patients with obstructive sleep apnea syndrome: a case-control study. Cornea. 2020;39(4):430–4. 17. Geerling G, Tauber J, Baudouin C, Goto E, Matsumoto Y, O'Brien T, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52(4):2050–64. 18. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007;157(3):474–81. 19. Ong BL. Relation between contact lens wear and Meibomian gland dysfunction. Optom Vis Sci. 1996;73(3):208–10. 20. Akpek EK, Mathews P, Hahn S, Hessen M, Kim J, Grader-Beck T, et al. Ocular and systemic morbidity in a longitudinal cohort of Sjögren's syndrome. Ophthalmology. 2015;122(1):56–61.