Comorbidities in Rosacea: Considerations for Diagnosis and Treatment

Rosacea affects an estimated 16 million people in the United States, a substantial proportion of whom likely have one or more of the comorbidities that are more prevalent in patients with rosacea than in the general population.

Its cause is not well understood, but like most autoimmune diseases, rosacea involves dysregulation of the inflammatory response and may share pathogenesis with several common comorbidities, including cardiovascular, psychiatric, gastrointestinal, autoimmune, and neurologic conditions.

“A growing body of evidence suggests that rosacea, in addition to being a distinct disease of the skin, may have a systemic origin or [may] be a marker for increased risk of systemic disease,” wrote Holmes et al in a 2017 review of the evidence in the Journal of the American Academy of Dermatology.¹

“Reports have shown increased levels of C-reactive protein, a marker of systemic inflammation, and unbalanced oxidative mediators in serum of patients with rosacea; however, direct mechanistic evidence remains elusive.”

Clinicians should therefore consider screening people with rosacea for common comorbidities, ideally before considering treatment options.

“If rosacea is shown to have high predictive value for the development of serious hidden systemic disorders, its presence might provide a valuable early warning, especially in settings where access to health care is limited,” wrote Gallo et al in a 2017 update on rosacea comorbidities by the National Rosacea Society Expert Committee.²

All research to date is epidemiologic and cannot suggest causation, and most studies report relative risk without stratifying by rosacea severity or subtype (erythematotelangiectatic, papulopustular, phymatous, or ocular). The association of many comorbidities with rosacea might be “explained by shared environmental or lifestyle factors rather than by a common genetic disposition or pathophysiologic pathways,” wrote Haber and Gemayel in a systematic review of 29 studies.³

“The current retrospective evidence associating rosacea with other diseases must be interpreted conservatively, because observed relative risks do not translate into large absolute numbers or a clinically relevant increased risk of disease,” wrote Holmes and colleagues.¹ “Although rosacea is not a life-threatening condition, the awareness of possible systemic comorbidity associations and early [identification] may be life-extending.”

Psychiatric Conditions

Depression is among the most common comorbidities identified in the research, followed closely by anxiety. Multiple studies have founder a higher than average prevalence of depression and anxiety in patients with rosacea.

“Since the psychosocial impact of rosacea tends to be underestimated by physicians, this issue should be raised with every patient and considered in the therapeutic plan,” wrote Rainer et al in a review in Dermato-Endocrinology.⁴ Younger patients with low socioeconomic status appear most at risk.

At least one study⁵ found no greater risk for rosacea among those who already had clinical depression, but the association may be bidirectional given that stress can trigger rosacea flare-ups. Rainer et al reported⁴ that a National Rosacea Society survey of more than 400 respondents found “75% of [people with] rosacea feel low self-esteem, 70% feel embarrassed, and 69% feel frustrated.” In those with severe symptoms, “88% cited the disorder as adversely affecting their professional interactions and 51% had missed work because of their condition.” Prevalence of anxiety about the condition was present in 41%, and 25% reported having depression related to their disease.

Cardiovascular Disease

Although several cardiovascular-related conditions have been very clearly associated with rosacea, existing evidence does not suggest an increased risk for heart attack, stroke, or other cardiovascular events in patients with rosacea. More commonly, patients with rosacea have a higher incidence of hypertension and dyslipidemia, which increases with severity of rosacea symptoms, than the general population.

Patients also have higher rates of peripheral artery disease, heart failure, diabetes mellitus, and coronary artery disease — the latter even after controlling for hypertension and dyslipidemia. Recent data have suggested the risk for vascular events increases with tetracycline treatment.

Haber and Gemayal³ recommend screening with family history, body mass index calculation, blood pressure, fasting lipid panel, fasting glucose, or hemoglobin A1c level at least once in patients 45 years or older. They also recommend 81 mg of aspirin daily for patients with at least 2 risk factors.

Neurologic Disorders

Researchers have identified increased risk for Parkinson disease, dementia (particularly Alzheimer disease), and migraine in those with rosacea, although risk levels vary. Two Danish cohort studies, for example, revealed a 71% greater risk for Parkinson disaese⁶ and a 36% greater risk for dementia.⁷ Migraine, more often seen in female patients, involves vascular abnormality as rosacea does, and both conditions can be triggered by stress or alcohol.

Cancer

The only cancers linked with rosacea are a weak association with thyroid cancer in women and glioma in men, plus a stronger association with basal cell carcinoma.³ The latter is least surprising given the contribution of ultraviolet exposure to both skin cancers and worsened rosacea symptoms.

Gastrointestinal and Autoimmune Disease

The gastrointestinal disorder with the highest prevalence among patients with rosacea is inflammatory bowel disease, which some researchers have suggested may be related to a shared pathogenesis from Helicobacter pylori or small intentional bacterial overgrowth, both also more prevalent in rosacea. One small study found that 21.6% of patients with rosacea had H pylori and 25% had small intentional bacterial overgrowth.⁸

Evidence also supports an association between rosacea and celiac disease, ulcerative colitis, rheumatoid arthritis, and allergies. For example, a small case-control study published in 2015⁹ found higher odds of airborne and food allergies, plus other systemic diseases, in patients with rosacea.

Although male patients show higher risk for glioma, the associations linking rosacea with rheumatoid arthritis, celiac disease, type 1 diabetes, migraines, multiple sclerosis, and hormone imbalances are stronger in females.

Treatment Options

Because of different subtypes and their overlapping symptoms, no single treatment can meet the needs of all patients with rosacea adequately. However, in addition to avoiding triggers and maintaining a consistent skin care routine with sun protection and hydrating lotion, several topical and systematic therapies have shown benefits.

The US Food and Drug Administration (FDA) has approved topical metronidazole 0.75%, azelaic acid 15%, and ivermectin 1% to treat inflammatory lesions, and all have been shown to improve symptoms of papulopustular rosacea, Rainer et al reported.⁴ Topical brimonidine tartrate 0.33% is FDA approved and effective for persistent facial erythema but may be associated with risk for depression, cerebral or coronary artery insufficiency, Raynaud phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma, Sjögren syndrome, and severe or unstable cardiovascular disease.

Low-dose doxycycline is the only FDA-approved oral drug for rosacea; however, oral tetracycline has also shown efficacy, although caution is advised in those with cardiovascular risk factors. Oral azithromycin may be helpful, although data are scarce. Isotretinoin has improved severe or persistent papulopustular rosacea and early or mild rhinophyma, although serious cases require surgery or carbon dioxide laser therapy.

Potentially useful off-label drugs include sodium sulfacetamide 10%, macrolide, macrolide analogs, permethrin, retinoids, and topical calcineurin inhibitors. No topical or systemic agents are approved for telangiectasia, but vascular lasers or intense pulse light therapy have moderately good evidence of effectiveness.

Shared Pathogenesis or Underlying Risk Factors?

Just as the pathogenesis of rosacea itself is not well understood, it is unclear which comorbidities may have a shared pathogenesis with the skin disease or whether rosacea may be a biomarker for certain systematic conditions. The only clearly identified shared risk factor is ultraviolet light exposure, which is correlated with both rosacea and basal cell carcinoma.

The other environmental risk factors under investigation for shared pathogenesis with rosacea and other comorbidities are H pylori infections, small intentional bacterial overgrowth, and differences in gut microbiomes, which are also implicated in celiac disease, diabetes, depression, and cardiovascular disease.

Other research into possible shared mechanisms includes shared alleles showing susceptibility to rosacea and other autoimmune diseases, other genetic biomarkers, and similar inflammatory elements or pathways.

“The pathophysiologic connections are complex, remain unclear, and probably involve mechanisms that underlie chronic inflammatory conditions in addition to metabolic, immune, and endocrine changes,” Haber and Gemayel concluded.

References

1. Holmes AD, Spoendlin J, Chien AL, Baldwin H, Chang ALS. Evidence-based update on rosacea comorbidities and their common physiologic pathways. J Am Acad Dermatol. 2018;78(1):156-166.
2. Gallo RL, Granstein RD, Kang S, et al. Rosacea comorbidities and future research: the 2017 update by the National Rosacea Society Expert Committee.  J Am Acad Dermatol. 2018;78:167-170.
3. Haber R, El Gemayel M. Comorbidities in rosacea: a systematic review and update.  J Am Acad Dermatol. 2018;78(4):786-792.
4. Rainer BM, Kang S, Chien AL. Rosacea: epidemiology, pathogenesis, and treatment. Dermatoendocrinol. 2017;9(1):e1361574.
5. Spoendlin J, Bichsel F, Voegel JJ, Jick SS, Meier CR. The association between psychiatric diseases, psychotropic drugs and the risk of incident rosacea.  Br J Dermatol. 2014;170(4):878-883.
6. Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Exploring the association between rosacea and Parkinson disease: a Danish nationwide cohort study.  JAMA Neurol. 2016;73:529-534.
7. Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Patients with rosacea have increased risk of dementia. Ann Neurol. 2016;79:921-928.
8. Agnoletti AF, De Col E, Parodi A, et al. Etiopathogenesis of rosacea: a prospective study with a three-year follow-up. G Ital Dermatol Venereol. 2017;152(5):418-423.
9. Rainer BM, Fischer AH, Luz Felipe da Silva D, Kang S, Chien AL. Rosacea is associated with chronic systemic diseases in a skin severity-dependent manner: results of a case-control study. J Am Acad Dermatol. 2015;73(4):604-608.