Rosacea Linked to Increased Parkinson's Risk

Pauline Anderson

March 29, 2016

Patients with rosacea are at significantly increased risk for new-onset Parkinson's disease (PD), a new study shows.

A chronic, inflammatory facial skin condition characterized by flushing and/or skin papules and pustules, rosacea has an estimated prevalence of 5% to 10% among whites. The study also showed an inverse association between treatment of rosacea using tetracycline and PD.

"While [rosacea was] previously believed to be limited to the skin, these new results could suggest that rosacea may have systemic implications, including risk of neurologic diseases," said lead author Alexander Egeberg, MD, PhD, Department of Dermatology and Allergology, Herlev and Gentofte Hospital, Copenhagen, Denmark.

"Rosacea should be considered more than just a cosmetic disorder," he told Medscape Medical News.

The study was published online March 21 in JAMA Neurology.

Linking national administrative registers, researchers examined the entire Danish population aged 18 years or older over a 15-year period: January 1, 1997, to December 31, 2011.

The cohort consisted of 5,472,745 persons. This included 68,053 patients with rosacea (38,305 with mild and 29,748 with moderate to severe rosacea) and 5,404,692 in the reference population.

The researchers determined rosacea severity by treatment type: Topical metronidazole indicated mild rosacea, while oral tetracycline denoted moderate to severe rosacea.

The incidence rate (IRR, per 10,000 person-years) of PD among those with rosacea was 7.62 (95% confidence interval [CI], 6.78 - 8.57) compared with 3.54 (95% CI, 3.49 - 3.59) among the reference population. Furthermore, PD occurred about 2.4 years earlier in patients with rosacea compared with the reference population.

The crude incidence rate ratio (IRR) of PD per 10,000 person-years was 2.15 (95% CI, 1.91 - 2.42) in the rosacea group compared with the reference population. After adjustment for age, sex, socioeconomic status, smoking, alcohol abuse, comorbidity, and medications, the IRR was 1.71 (95% CI, 1.52 - 1.92). Results were similar for men and women.

The adjusted IRR with treatment with antiparkinson dopaminergic agents was 1.59 (95% CI, 1.50 - 1.69) in patients with rosacea compared with the reference population.

The IRR for PD was about the same for those with mild rosacea as for those with moderate or severe rosacea.

Ocular Rosacea

Sensitivity analyses showed a tendency toward an increased PD risk among patients with ocular rosacea. "Rosacea should be considered an umbrella term that covers several subtypes of the disease; it's possible that patients with ocular rosacea may constitute a particular high-risk group," said Dr Egeberg.

However, he emphasized that this finding is "speculative" given the available data.

To avoid misclassification or misdiagnosis, researchers did an analysis that excluded patients with rosacea who had ever filled a prescription for ketoconazole or topical corticosteroids, the most common treatments for seborrheic dermatitis in Denmark. The results showed essentially the same IRR of PD.

The researchers observed a slightly decreased risk for PD in patients treated with tetracycline-class drugs. These agents, said Dr. Egeberg, have been used for decades to treat rosacea.

A potential neuroprotective effect of tetracycline has been suggested both in animal models and a phase 2 randomized double-blinded clinical trial of minocycline (a tetracycline) in patients with early PD.

"The observed reduced occurrence of Parkinson's disease in patients treated with tetracyclines is intriguing and supports a call for more definitive randomized trials of this drug class in patients with Parkinson's disease," said Dr Egeberg.

A plausible pathophysiologic mechanism connecting rosacea with PD involves the matrix metalloproteinases (MMPs), which are enzymes involved in tissue remodeling, organ development, and regulation of inflammatory processes.

"Rosacea skin shows an upregulation of various cytokines, which are small proteins that are important in cell signalling, and displays increased activation and expression of MMPs," explained Dr. Egeberg.

"Importantly, MMPs have also been implicated in the pathogenesis of Parkinson's disease and other neurodegenerative disorders, and MMPs contribute to loss of dopamine producing brain cells."

But Dr Egeberg emphasized that the observed effect of tetracycline on PD is "hypothesis generating" and needs to be confirmed in randomized trials before a causal link can be established.

There may be other common mechanisms. For example, both rosacea and PD have been associated with small intestine bacterial overgrowth and Helicobacter pylori infection, said Dr Egeberg.

It's not clear from this study whether patients with PD are at higher risk for rosacea, although it's "an interesting thought" according to Dr Egeberg. He noted that a German study that examined 70 patients with PD found that 18.6% of them had rosacea. "But whether rosacea preceded Parkinson's disease or vice versa was not known."

Timely Referral

Dr Egeberg stressed that just because a patient has rosacea doesn't mean he or she will develop PD. "However, we have noticed an increased frequency of patients with neurological diseases in rosacea patients at our hospital, and if patients develop neurological symptoms, timely referral to experienced neurologists may be appropriate."

In an accompanying editorial by Thomas S. Wingo, MD, Department of Neurology, Emory University, Atlanta, Georgia, said that one limitation of the study was that patients with rosacea might see doctors more often, prompting earlier recognition of PD. However, he pointed out that dermatologists and general practitioners are usually not particularly focused on neurologic illnesses.

"Furthermore, symptoms of PD are well recognized by patients themselves, making it doubtful that their findings were unduly influenced by surveillance bias."

Another "minor concern" is that facial flushing associated with rosacea may be viewed as evidence for dysautonomia when considering the diagnosis for PD, although it's doubtful that any diagnosis of PD hinged on that feature, said Dr Wingo.

The "intriguing finding" that increased tetracycline use is associated with reduced PD risk should be further explored, he said. "Of particular interest would be to understand the temporal association between the use of tetracycline and effect on PD risk."

The co-occurrence of PD and rosacea should also be explored by investigating whether there's evidence for genetic pleiotropy between the two diseases, he said.

Dr Egeberg reported being employed by Pfizer Inc at the time of the study. Dr Wingo has disclosed no relevant financial relationships.

JAMA Neurol. Published online March 21, 2016. Abstract Editorial

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