Rosacea is a chronic inflammatory disease with variable presentations, but the lesions are mainly found over the central face; accordingly, it is classified into 4 subtypes: erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea.1 Rosacea has been associated with several systemic comorbidities, such as gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, and autoimmune diseases,2–5 probably due to its complicated pathophysiology involving genetic factors, environmental stimulation, microbiome colonization or infection, disturbed neurovascular responses, and immunological dysregulation, which gives rise to localized and even systemic recurrent inflammation.2,3,5 Rosacea is not only a cutaneous disease but is more akin to a systemic inflammatory disease and may be related to the gut-skin axis.6,7 However, because of the characteristic relapse-and-remission course, long-term treatment of rosacea may be required. These medications possibly play a role in systemic comorbidities.6 Ocular rosacea is defined as eyelid and ocular surface inflammation, typically with symptoms of foreign body sensation, photophobia, tearing, conjunctival hyperemia, meibomian gland inflammation, and blurred vision.8,9 However, due to its systemic inflammatory characteristic of rosacea, its association with eyes is likely to extend considerably beyond mere ocular rosacea.
Diabetes mellitus (DM) is a leading chronic disease worldwide, and its prevalence continues to increase.10 The systemic involvement of DM leads to several macrovascular and microvascular complications,11 causing a great economic burden.12 In ophthalmology, DM is associated with several ocular diseases, including cataract, glaucoma, diabetic retinopathy (DR), and diabetic macular edema (DME).13,14 Considering the pathophysiology in diabetes, this metabolic disease is suggested to have a systemic inflammatory component.15 Inflammation in response to hyperglycemia can accelerate atherosclerosis and diabetic vascular complications.16,17 Inflammation can also deteriorate glucose control and lead to hyperglycemia, generating a vicious cycle in diabetes.18 In addition to the angiogenesis, inflammation also affects the pathogenesis of diabetic eye diseases.19–21
The role of inflammation in diabetic eye diseases such as DR has been highlighted.22 In addition, anti-inflammatory drugs are being assessed for the management of diabetic eye diseases.23 Because rosacea involves systemic inflammation, which may indirectly affect diabetes control, it may be associated with ocular complications of diabetes. However, no study has yet evaluated this association. In this study, we investigated the association between rosacea and eye diseases in patients with diabetes.
MATERIALS AND METHODS
This retrospective cohort study used claims data from the National Health Insurance (NHI) Research Database (NHIRD) released by the Ministry of Health and Welfare in Taiwan. Disease diagnoses and procedures were coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), and Taiwan NHI reimbursement code. Detailed information regarding NHI and NHIRD has been described previously.24–26 The study was approved by the Chang Gung Memorial Hospital Institutional Review Board (no. 201900967B0) and adhered to the tenets of the Declaration of Helsinki. Informed consent was waived because the data were all deidentified, and no personal information could be disclosed.
Inclusion of the Study Patients
Patients with a diagnosis code of DM and the use of any hypoglycemic agents between January 1, 1997, and December 31, 2013, were included. The presence of rosacea (ICD-9-CM: 695.3) was ascertained using ≥2 outpatient diagnoses in dermatology.27,28 For patients diagnosed as having rosacea before DM, the index date was the date of DM diagnosis. For patients diagnosed as having rosacea after DM, the index date was the date of rosacea diagnosis.29 For each patient in the rosacea group, we included 20 age-matched and sex-matched patients in the nonrosacea group.29 Matching was performed using an age range of ±2 years. We excluded patients with missing demographics, history of retinal disorders (DR, retinal vascular occlusion, separation of retinal layers, degeneration of retina, chorioretinal inflammations, and other retinal disorders), history of receiving vitreoretinal intervention (intravitreal injection, laser, scleral buckling, and vitrectomy), and diagnosis with similar symptoms to rosacea (seborrheic dermatitis and cutaneous lupus erythematosus) (Fig. 1).
Covariates were demographics (age and sex), proxy variables for DM severity (duration of diabetes, diabetic neuropathy, and foot ulcers), number of retinal examinations in the previous year, type of DM, comorbidities (dyslipidemia, hypertension, ischemic heart disease, chronic kidney disease, and stroke), as well as Charlson Comorbidity Index score,30 antidiabetic medications for proxy variables for glucose control, antihypertensive medications, and other medications (antiplatelet, statins, and fibrates). Comorbidities and diseases were identified as having any inpatient diagnosis or 2 outpatient diagnoses in the previous year before the index date. Medications were identified according to the prescriptions within the 3 months before the index date in either the outpatient or pharmacy claims data.
The primary outcomes were new-onset ocular diseases (newly diagnosed DR, DME, glaucoma with medical treatment, dry eye disease, age-related macular degeneration, retinal vascular occlusion, optic neuritis, ischemic optic neuropathy, retinal detachment, and uveitis) and ocular interventions (retinal laser, intravitreal injection, vitrectomy, cataract surgery, and glaucoma interventions). Glaucoma with medical treatment was defined as the diagnosis of glaucoma combining any intraocular pressure–lowering agent used at the same visit. Glaucoma interventions included iridotomy, trabeculoplasty, cyclophotocoagulation, trabeculotomy, trabeculectomy, and shunting surgery. The occurrence of ocular diseases was defined as having ≥2 new-onset outpatient diagnoses or any inpatient diagnosis at ophthalmology. The ocular intervention was identified using Taiwan reimbursement codes.31,32
On the basis of previous relevant publications, we also defined secondary positive control outcomes as 3 disease groups: systemic inflammatory diseases (psoriasis, ankylosing spondylitis, Behcet syndrome, rheumatoid arthritis, and inflammatory bowel diseases), gastrointestinal diseases (peptic ulcer, irritable bowel syndrome, and esophageal reflux), and psychiatric diseases (anxiety, major depression disorder, bipolar disorder, and schizophrenia). The occurrence of the aforementioned diseases was defined as having at least 2 new-onset outpatient diagnoses or any inpatient diagnosis at a relevant department, such as dermatology or rheumatology for psoriasis, and rheumatology or gastroenterology for other systemic inflammatory and gastrointestinal diseases. The ICD-9-CM codes used to define diseases (including covariates and outcomes) in this study are shown in Supplementary Digital Content Table 1 (Supplemental Digital Content 1, https://links.lww.com/APJO/A186).
Propensity score matching (PSM) was conducted to balance the distribution of covariates between groups. The propensity score was the predicted probability of being in the rosacea group given certain values of covariates by the multivariable logistic regression without considering interaction effects. The variables used to calculate propensity scores were all of the covariates, in which the follow-up duration was replaced with the index date (Table 1). The matching was processed using a greedy nearest neighbor algorithm with a caliper of 0.2 times the SD of the logit of the propensity score, with random matching order and without replacement. The balance of the baseline characteristics between groups was checked using the absolute value of standardized difference between the groups, where a value <0.1 was considered a negligible difference.
TABLE 1 -
Characteristics of Patients With Diabetes With and Without Rosacea
Before and After PSM
| Diabetic duration
| Rosacea before DM
| <5 y
| ≥5 y
| Diabetic neuropathy
| Diabetic foot ulcer
|Retinal examinations in the previous 1 y
|Type of diabetes
| Type 1
| Type 2
| Ischemic heart disease
| Chronic kidney disease
|Charlson Comorbidity Index score
| Alpha-glucosidase inhibitors
| Calcium channel blockers
|Follow-up duration (y)
Data are presented as frequency (%) or mean±SD.
ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DDP4i, dipeptidyl peptidase-4 inhibitor; DM, diabetes mellitus; PSM, propensity score matching; STD, standardized difference.
The risk of time-to-event outcome between groups was compared using the Fine and Gray subdistribution hazard model, which considered death during follow-up a competing risk.33 The study group (rosacea vs nonrosacea) was the only explanatory variable in the survival analysis. A 2-sided P value <0.05 was considered statistically significant. All statistical analyses were performed using SAS, version 9.4 (SAS Institute), including the procedure of “psmatch” for PSM and “phreg” for survival analyses and a macro of “%cif” for generating cumulative incidence function under the Fine and Gray subdistribution hazard method for drawing plots.
Inclusion and Exclusion of the Study Patients
From January 1, 1997, to December 31, 2013, 2,099,303 patients were diagnosed as having DM under treatment. Among them, 5459 were diagnosed as having rosacea in the dermatology department. Next, 20 times the number of patients with DM without rosacea were identified. After application of the exclusion criteria and 1:4 PSM, 4096 and 16,384 patients (total: 20,480) were in the rosacea and nonrosacea groups, respectively (Fig. 1).
Before PSM, no substantial differences were noted in most covariates, except the duration of diabetes, Charlson Comorbidity Index score, and use of sulfonylurea. After PSM, no variable exhibited a substantial between-group difference (all absolute standardized difference values <0.1) (Table 1). The overall study population comprised ∼39% of men (mean age: 56 y old), consisting of 92.1% of type 2 and 7.9% of type 1 DM. The most common comorbidity was hypertension (48.5%), followed by dyslipidemia (35.8%), ischemic heart disease (11.5%), and chronic kidney disease (6.7%). The most frequently used hypoglycemic agent was metformin (71.8%), followed by sulfonylurea (61.8%), and 8.4% of the patients received insulin therapy. In the rosacea group, 36.2% of the patients had rosacea before the DM diagnosis, whereas 32.6% and 31.1% of the patients had a DM duration of <5 years and ≥5 years at the time of the rosacea diagnosis.
Rosacea and Ocular Outcomes
The results of the primary ocular outcomes are presented in Table 2. During the mean follow-up period of 5 years, patients with rosacea had significantly higher risks in DME [subdistribution hazard ratio (SHR): 1.31, 95% confidence interval (CI): 1.05–1.63], glaucoma with medical treatment (SHR: 1.11, 95% CI: 1.01–1.21), and dry eye disease (SHR: 1.55, 95% CI: 1.38–1.75) than those without rosacea (Fig. 2A–C). Among the surgical interventions, the risk of cataract surgery (SHR: 1.13, 95% CI: 1.02–1.25) was significantly higher in the rosacea group than in the nonrosacea group (Fig. 2D). No significant association was found in DR, age-related macular degeneration, retinal vascular occlusion, optic neuritis, ischemic optic neuropathy, retinal detachment, uveitis, or other ocular interventions (retinal laser, intravitreal injection, vitrectomy, and glaucoma interventions).
TABLE 2 -
Primary Ocular Outcomes in Patients With Diabetes With and Without Rosacea
||SHR (95% CI)
| Diabetic retinopathy
| Diabetic macular edema
| Dry eye disease
| Glaucoma with medical treatment
| Age-related macular degeneration
| Retinal vascular occlusion
| Ischemic optic neuropathy
| Optic neuritis
| Retinal detachment
| Retinal laser
| Intravitreal injection
| Cataract surgery
| Glaucoma with surgical interventions
PSM indicates propensity score matching; SHR, subdistribution hazard ratio.
Data are presented as frequency (%).
Rosacea and Systemic Inflammatory/Gastrointestinal/Psychiatric Diseases
The results of the secondary outcomes are presented in Table 3. Among the systemic inflammatory diseases, patients with rosacea had a significantly greater risk of psoriasis than those without rosacea (SHR: 2.99, 95% CI: 2.19–4.09). By contrast, no significant between-group difference was observed in other outcomes. Among the 3 gastrointestinal diseases, a higher risk of irritable bowel syndrome was noted in the rosacea group (SHR: 1.31, 95% CI: 1.13–1.53). Among the 4 psychiatric diseases, rosacea was associated with a greater risk of anxiety (SHR: 1.37, 95% CI: 1.15–1.64) and depression (SHR: 1.34, 95% CI: 1.05–1.70). By contrast, the risks of bipolar disorder and schizophrenia were not different between the 2 groups.
TABLE 3 -
Other Secondary Outcomes
||SHR (95% CI)
|Systemic inflammatory disease
| Rheumatoid arthritis
| Inflammatory bowel disease
| Ankylosing spondylitis
| Behçet syndrome
| Irritable bowel syndrome
| Esophageal reflux
PSM indicates propensity score matching; SHR, subdistribution hazard ratio.
Data are presented as frequency (%).
The pathogenic mechanisms of both rosacea and diabetes include systemic inflammatory components. Although the link between rosacea and diabetes remains poorly understood, increased oxidative stress and systemic inflammation have been implicated in the occurrence of rosacea, insulin resistance, and diabetes complications. However, the association between rosacea and eye diseases among diabetic patients has not previously been investigated. We performed a population-based study to investigate the association between rosacea and eye diseases among diabetic patients.
Rosacea may more closely resemble a systemic chronic inflammatory disease34 than a localized facial disease, associated with many systemic complications. The pathogenesis of rosacea is complicated. Triggering factors activate toll-like receptor 2, increase the active form of cathelicidin peptide LL-37, and induce leukocyte chemotaxis and inflammatory events, which activate nuclear factorκB and promote angiogenesis.35 Vascular and inflammatory changes present as clinical rosacea symptoms, such as erythema, papules, and pustules. In addition, oxidative stress has recently been recognized as a key mechanism underlying insulin resistance and diabetes complications.36,37 Angiogenesis, oxidative stress, and inflammation play critical roles in the pathogenesis of both rosacea and diabetic eye diseases.19–21
In this study, we observed that rosacea was positively associated with DME but not with DR. DR and DME are the leading causes of vision-threatening diseases among patients with diabetes,37,38 and the pathophysiology of both diseases involves complex microvascular changes due to inflammation and angiogenesis21,39 that cannot be explained by any single pathway. Disease development is widely accepted as resulting from the combined effects of angiogenesis and inflammation.20 Systemic inflammation may not be correlated with local retinal inflammation in DR,40,41 despite the elevation of systemic inflammatory biomarkers in DR,41 similar to DME42–44 and other disorders associated with macular edema, such as uveitis,44 retinal vascular occlusion,45 and retinal dystrophy.46 We hypothesize that systemic inflammation may play a more critical role in DME than DR. However, determining detailed associations between systemic inflammation and the biomolecular pathophysiology of DME requires further study.
Rosacea may increase the risk of blepharitis, leading to an imbalance in tear formation, which is associated with dry eye disease.47,48 However, rosacea is not associated with an increased risk of corneal damage in dry eye disease.49 Diabetes is a known risk factor for glaucoma and cataract development.50,51 In our study, we identified rosacea as an additional risk factor for glaucoma requiring medication and cataracts requiring surgery among patients with diabetes. An increase in systemic inflammation may contribute to the development of cataracts52 and glaucoma.53 Glaucoma medication has been reported to be associated with blepharitis and dry eye disease.54 However, glaucoma and cataract development are also associated with steroid use,55 which is often used to treat dry eye disease.56 Short-term systemic steroids are also prescribed to treat rosacea and may require long-term administration due to the relapsing course of rosacea. Further investigations examining patients with matched steroid prescriptions remain necessary to clarify the possible confounding effects of steroid use on symptom development.
We noted that rosacea increased the risk of psoriasis in patients diagnosed as having diabetes. No study has evaluated the significant association between rosacea and psoriasis. As these 2 diseases were both mainly presented with skin rashes, they may have similar skin presentations on the face, possibly misleading the diagnosis. However, rosacea and psoriasis were both associated with chronic inflammatory conditions. For example, studies indicate that both tumor necrosis factor-alpha and interleukin-17 play pivotal roles and treatment targets in rosacea and psoriasis, indicating the common property of systemic inflammation in these 2 diseases.57,58 Rosacea and psoriasis also share some common predisposing factors or comorbidities, such as microbiotic environment dysfunction, metabolic cardiovascular, and psychiatric complications.59
Rosacea is associated with various gastrointestinal diseases.6 Although a previous meta-analysis indicated an increased risk of inflammatory bowel disease in patients with rosacea,3 our study with a diabetic population did not find this association. However, we demonstrated an increased incidence of irritable bowel syndrome in patients with diabetes diagnosed as having rosacea. This agrees with a previous Danish nationwide population-based cohort study.60 Rosacea and irritable bowel syndrome have some common factors,6 such as small bowel bacterial overgrowth and systemic inflammation, which is supported by elevated peripheral tumor necrosis factors. The exact pathogenic link, however, remains unclear.
In psychiatric diseases, we observed that patients with rosacea were at a significantly higher risk for anxiety and depression but not for schizophrenia or bipolar disorder. This is consistent with a previous Danish nationwide cohort study.61 The association between inflammation and anxiety or depressive disorders has been well studied. For example, a UK study demonstrated a higher risk for anxiety and depression among patients with an inflammatory disorder.62 Increased inflammatory markers are also found in patients with anxiety and depression.63 The effect of inflammation on critical brain structures that are involved in anxiety or depression, such as the amygdala or reward circuit, has been reported in recent imaging studies.64 Moreover, patients with rosacea may also suffer from psychosocial distress, which may explain the increased risk of anxiety or depression.65 Patients with anxiety or depression may have different medical-seeking behavior from the general population, thus leading to more diagnosis of rosacea. However, the association between anxiety or depression and rosacea requires further investigation.
This study has some limitations. First, the NHIRD did not include laboratory examinations. We could not analyze serum glucose and glycated hemoglobin levels, although we matched the patients based on their medication use for diabetes. Furthermore, the database did not have examination reports such as optical coherence tomography, which has been used for identifying central involvement and different inflammation-associated characteristics in DME.66 Moreover, the dataset lacks information on anterior chamber angle morphology and intraocular pressure, which is a main evaluation of steroid-responder and glaucoma.67 The retrospective design precluded controlling for the use of steroids, which may affect the development of cataract and glaucoma. The dataset did not include sufficient information to permit the classification of rosacea subtypes, preventing analyses examining differences among rosacea subtypes. Some of the outcomes had small case numbers (eg, retinal detachment), making the identification of significant differences challenging. In addition, we did not adjust for multiple testing in this study, and the conclusions derived from the study should be interpreted cautiously, as multiple comparison adjustments can affect significance. Finally, the retrospective database study could only demonstrate possible association of the diseases, although the big data in real-world application could provide important information in disease association and help with further investigation.68 The mechanism, cause, and effect of the outcomes require prospective and experimental studies. To the best of our knowledge, this is the first study to analyze the association between rosacea and ocular diseases. Rosacea was positively associated with ocular disease development, including DME, glaucoma, and dry eye disease. Patients with rosacea also had an increased risk of receiving cataract surgery. However, no significant associations were found between rosacea and ocular vascular diseases, including DR, age-related macular degeneration, retinal vascular occlusion, ischemic optic neuropathy, or ocular inflammatory diseases (such as uveitis and optic neuritis). The frequencies of retinal laser, intravitreal injection, and glaucoma interventions were comparable between groups with and without rosacea.
The authors thank Alfred Hsing-Fen Lin, Ben Yu-Lin Chou, and Jane Yan-Jen Shiu for their assistance with the statistical analysis during the completion of the manuscript.
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