Publication
Article
Advances in the Treatment of Demodex Blepharitis: Strategies for Improving Patient Outcomes
INTRODUCTION
Demodex blepharitis is a common disease that affects the skin, eyelashes, lash follicles, and sebaceous glands but is often underdiagnosed.1,2 This disease occurs in up to 57.7% of all patients who visit eye clinics in the US.3 Previously, limited options were available for treating this condition. These approaches often involved incorporating tea tree oil (TTO) or its primary component, terpinen-4-ol, into eyelid cleansers.4 In July 2023, the first therapeutic for the treatment of Demodex blepharitis, lotilaner ophthalmic solution, 0.25%, was approved by the FDA.5,6
This article highlights clinical and economic factors associated with Demodex blepharitis as well as diagnostic complexities, limitations of traditional therapies, the safety and efficacy of the 1 FDA-approved treatment, and developments in management over the past year; it also emphasizes the role of education, training, and evidence-based treatment in improving patient outcomes.
OVERVIEW
Demodex mites are typically present on the eye margin in individuals without health concerns and contribute to blepharitis only in specific cases.7,8 Demodex blepharitis is associated with several symptoms that are not exclusive to the disease such as eyelid swelling and irritation, burning sensation, itching, foreign body sensation, crusting, matting, and eyelash loss.2,3,9-11 Secondary complications can also occur, including dry eye disease (DED), meibomian gland dysfunction (MGD), inflammatory conjunctivitis, rosacea, blepharoconjunctivitis, punctate keratitis, chalazion, and trichiasis.2,3,9-15
Limited data are available regarding the prevalence of Demodex blepharitis within the US population. In a retrospective analysis of a subgroup of patients (n = 1032) who visited 1 of 6 US eye clinics, Trattler et al found that 57.7% of patients had Demodex-induced collarettes, leading to a diagnosis of Demodex blepharitis.3 Although several studies have found Demodex blepharitis to be particularly prevalent among the elderly population,7,12,16-20 the Trattler study did not identify age as a significant predictor of disease (odds ratio, 1.001; 95% CI, 0.994-1.008).3
Risk Factors
Demodex blepharitis occurs more frequently in patients with immune system–related conditions than in the general population. Facial rosacea frequently coexists with Demodex infestation, and the results of 1 study showed a correlation between seborrheic dermatitis and elevated Demodex proliferation.21,22 Demodex blepharitis occurs more commonly among patients using immunosuppressive agents such as steroids, and in those with certain diseases affecting the immune system such as HIV or leukemia.23-26 It remains unclear whether a relationship exists between immune alterations and Demodex infestation risk.27 Various modifiable factors are thought to increase Demodex proliferation, including poor hygiene, alcohol use disorder, and specific skin properties (eg, oily or dry skin).28,29
Whether sex, age, and race are independent risk factors for Demodex blepharitis requires further research. For example, in the US-based Trattler study, the incidence of collarettes was found to be only slightly higher in males (62.9%) than in females (54.5%).3 However, the results of studies conducted outside the US have been mixed. Although some studies reported similar patterns, most have found no significant differences in the incidence of Demodex blepharitis between sexes.7,17-19,30-32 Similarly, although a higher prevalence of Demodex in older adults was reported in previous studies,7,12,16-20 findings of a study published in 2021 showed no correlation between age and the prevalence of Demodex infestation.33 Study findings regarding Demodex blepharitis and race are also mixed. The Trattler study reported that the prevalence of Demodex blepharitis was similar among individuals with diverse racial backgrounds.3 These results depart from the findings of previous studies.17 Additional research is needed to determine whether Demodex infestation rates differ between patients from different racial, ethnic, and geographic groups.
Pathophysiology
In both healthy and asymptomatic individuals hosting Demodex mites, these ectoparasites can cause tissue damage leading to inflammation.7,8 Symptomatic and asymptomatic individuals host 2 separate species of Demodex mites: D folliculorum and D brevis (Figure 1).34 Both species consume cellular components and oils for nutrition.1,30,35 During feeding, the mites are thought to release lipases that help digest sebum; the subsequent release of fatty acids may irritate the infested tissue.36 The mites’ claws also cause minor abrasions that are thought to result in epithelial hyperplasia and keratinization around the base of the eyelashes. This results in the formation of collarettes, or cylindrical dandruff (CD), along the upper lid margin (Figure 2).1,37 All patients with Demodex blepharitis exhibit these waxy CD plugs.3,38 In patients with Demodex blepharitis, Demodex mites may also obstruct the openings of the meibomian glands, potentially leading to MGD and disruptions in the tear film.1,11,23 Finally, Demodex mites can function as vectors for harmful bacteria that can cause blepharitis.23,39
CLINICAL IMPACT
Demodex blepharitis is associated with eye itching and redness.7 Ocular dryness, pain, burning, irritation, matted or crusty lashes, loss of lashes, a foreign body sensation, blurry vision, increased tearing, and purulence are also common among patients with the disease.2,7,9-11 Disease-induced inflammation can influence the health of the lid margin and may lead to MGD and ocular surface conditions including DED, corneal melting, inflammatory conjunctivitis, rosacea, blepharoconjunctivitis, punctate keratitis, chalazion, and trichiasis.2,3,10,11,13,15,23
The symptoms and signs of Demodex blepharitis can also impact the psychosocial well-being of patients.40 In the Atlas study, 524 patients with Demodex blepharitis were surveyed to explore this impact.40 Patients were recruited between June 2020 and October 2021 at 20 US optometric and ophthalmic practices involved in the Saturn-1 clinical trial (NCT04475432).40,41 Of 505 patients responding to a questionnaire about how Demodex blepharitis affected their daily lives overall, 391 respondents (77.4%) reported that the condition negatively impacted their daily lives, 202 (42.0%) stated that they were aware of their eyes throughout the day, 117 (23.2%) thought that their eyes or eyelids had a negative appearance to others, and 101 (20%) reported constant worry about their eyes or eyelids. Demodex blepharitis also affected their ability to perform daily activities, with 214 patients (42.4%) struggling with nighttime driving and 153 (30.3%) reporting a prolonged daily hygiene regimen. Further, 95 of 287 women (33.1%) encountered challenges with wearing makeup. Of 14 patients who wore contact lenses, 9 (64.3%) experienced vision changes or discomfort.40
ECONOMIC IMPACT
Although there are no dedicated economic analyses specifically addressing Demodex blepharitis, economic data related to DED are available. Demodex blepharitis has been identified in most patients with DED and may precede the onset of DED.3,14
Results of a 2011 study of the economic impact of DED in the US showed that DED was associated with annual direct and indirect overall costs of approximately $3.84 billion and $55.4 billion, respectively.42 Adjusted for inflation, these figures amount to a total of $82.8 billion in direct and indirect costs in 2024.43 (Note: These costs were adjusted for inflation only and do not incorporate other factors such as advancements in therapies.)
Although Demodex blepharitis accounted for only some of the DED cases in the Trattler study, costs associated with Demodex blepharitis may still be high.3
DIAGNOSIS AND RELATED CHALLENGES
Demodex blepharitis is conclusively diagnosed based on visual inspection. Mites can be detected by extracting several eyelashes and mounting them in oil on a microscope slide for examination. If adult mites, larvae, or eggs are observed, this is considered diagnostic of Demodex mite infestation.7,31 Although this method is commonly used, it has limitations, such as the tendency to underestimate the actual mite count; mites may drift away in the oil or remain in the collarettes that persist in the eyelid after lash removal.44 The collarettes can be dissolved and expanded using sodium fluorescein, which can improve microscopic detection of the mites and more accurately reflect the population of mites present in the sample.44
Slit-lamp examination can be used to detect collarettes at the base of the lashes at the lid margin. This routine eye care procedure serves as a straightforward method for identifying Demodex mites and assessing overall eye health.3,45
Underdiagnosis and Misdiagnosis
As the mites are present on both healthy people and those with Demodex blepharitis, diagnosis and study of this disease are challenging.8 Universally accepted criteria for defining the threshold of mite infestation that triggers blepharitis symptoms are not available. However, diagnosed patients show clinical improvement even with a reduction in 1 mite per lash.7,46
Demodex blepharitis has symptoms that are similar to those of other eye conditions, which contributes to misdiagnosis of the disease. Additionally, clinicians rarely screen for Demodex mite infestation.3,9 A high rate of underdiagnosis and misdiagnosis was evident in the US-based Trattler study, in which 44% of patients with collarettes were not diagnosed with Demodex blepharitis.3 In the Atlas study, 46.5% of patients displayed signs of blepharitis for a minimum of 4 years, and 56.3% experienced symptoms frequently or all the time in the prior month; 32.3% of patients visited their doctor at least twice to address disease symptoms.40 Despite these high rates of signs, symptoms, and physician visits and despite all patients having confirmed Demodex blepharitis, 59% of all study participants had not been diagnosed with Demodex blepharitis prior to participating in the study.40
Efforts are needed to improve misdiagnosis and underdiagnosis rates of Demodex blepharitis, as a lack of treatment can result in punctate keratitis and corneal melting.3,15 A missed diagnosis of Demodex infestation can also lead to the use of ineffective management options, which may lead to disease progression and increased costs.3,9 For example, if more severe Demodex blepharitis develops, microblepharoexfoliation may be required. This procedure is performed 2 to 4 times per year at a cost of approximately $180 per session (2024 US$).9,43,47
LIMITATIONS OF TRADITIONAL MANAGEMENT OPTIONS
Traditional therapies for Demodex blepharitis such as TTO application have not shown lasting efficacy and are poorly tolerated.3,4,9,11,48-52 Moreover, few randomized clinical trials have been performed to evaluate traditional treatments other than TTO.53-57
In the Atlas study, although 32.3% of patients sought medical attention from a physician on at least 2 occasions, a notable proportion of patients (45.9%) discontinued traditional treatment because of concerns regarding effectiveness or tolerability.40 The Trattler study outcomes demonstrated that Demodex blepharitis persisted among patients employing TTO and lid wipes in 75% and 57% of cases, respectively.3 Findings from clinical investigations involving commercial cleansers containing TTO or linalool also showed incomplete resolution of blepharitis symptoms and incomplete elimination of Demodex mites.4,50,51
TTO is also associated with ocular irritation, dermatitis, and allergies.3,9,11,48,49,58 Strategies to reduce irritation from TTO include counseling patients to be gentler when cleansing their eyelids, diluting TTO with another oil, or considering in-office treatments to receive treatment with higher concentration TTO scrubs and saline rinses.9,52,59 Although potential solutions to these challenges are available, adherence to treatment remains suboptimal, resulting in unfavorable outcomes for patients.48,52,59 Lack of adherence is exacerbated by the need for ongoing treatment with lid hygiene measures aimed at alleviating symptoms.9,52
The unmet need for a safe, effective, and well-tolerated therapy was described by a panel of experts on Demodex blepharitis in early 2023.34 The expert panel was comprised of 9 ophthalmologists and 3 optometrists who were experts in external disease, blepharitis, and ocular surface disease.34 The Delphi panel process was used to reach consensus on the diagnosis, treatment, pathophysiology, and signs and symptoms of Demodex blepharitis.34 Most panelists stated that Demodex blepharitis is chronic and recurrent.34 However, at that time, there was no consensus on the most effective over-the-counter treatment, and the panelists also noted a lack of FDA-approved therapies.34
LOTILANER OPHTHALMIC SOLUTION
In July 2023, lotilaner ophthalmic solution, 0.25%, was the first treatment for Demodex blepharitis to receive FDA approval.5,6,60 The agent exerts its effects by inhibiting γ-aminobutyric acid (GABA) chloride channels in mites, inducing paralysis and death. In mammalian cells tested in vitro, lotilaner did not inhibit GABA-mediated chloride channels even when tested at approximately 1100 times the recommended ophthalmic dosage recommended for use in humans (30 μM).60 Lotilaner ophthalmic solution, 0.25%, is administered by applying 1 drop in each eye twice daily for 6 weeks. To prevent contamination, the tip of the dispensing container should not come into contact with the fingers, eyes, or other surfaces.60
The decision by the FDA to approve lotilaner ophthalmic solution, 0.25%, for treatment of Demodex blepharitis was based on results of the Saturn-1 and Saturn-2 (NCT04784091) trials, which were 6-week, multicenter, randomized, double-masked, and vehicle-controlled trials.60-62
Saturn-1
The phase 2b/3 Saturn-1 trial was performed to evaluate the efficacy and safety of treatment with lotilaner ophthalmic solution, 0.25%, in adults with Demodex blepharitis.61 Patients meeting the following criteria were eligible to participate in the study: aged 18 years or older, average mite density of at least 1.5 mites per lash, collarettes present on at least 11 lashes of the upper eyelid, and mild or more severe erythema on the upper eyelid margin. Patients were recruited from 15 US clinical sites.61 Exclusion criteria included use of any lid hygiene product within the previous 2 weeks, use or change in use of a prostaglandin analog (PGA) to induce eyelash growth within the previous 30 days or planned change to PGA use during the treatment phase, or unwillingness to stop using contact lenses, artificial eyelashes, or eyelash extensions during the study.61
The study involved 421 patients who were randomly allocated in a 1:1 ratio to receive either lotilaner ophthalmic solution, 0.25%, or vehicle. Participants were instructed to self-administer 1 drop of the assigned medication or vehicle in each eye both in the morning and evening for a period of 43 days.61 The mite density was used to determine an analysis eye for each patient.61 The primary end point was achievement of complete collarette cure in the analysis eye, which was defined as having no more than 2 collarettes on the upper eyelid at day 43.61 Secondary end points included mite eradication and composite cure of collarettes and erythema (grade 0 erythema in the upper eyelid of the analysis eye) on day 43.61 During the trial period, 5 and 3 patients in the control and study groups, respectively, discontinued the study because of COVID-19 (n = 5), adverse events (AEs) related to treatment vehicle (n = 1), AEs unrelated to treatment (n = 1), and other causes (n = 1).61
The results showed that a larger proportion of patients with Demodex blepharitis who were treated with lotilaner ophthalmic solution than treated with vehicle achieved composite cure of collarettes and erythema.61 Complete collarette cure was observed in 44% of patients treated with lotilaner ophthalmic solution and 7.4% of patients treated with vehicle at day 43 (P < .0001).61 Mites were eradicated in 67.9% of eyes treated with lotilaner ophthalmic solution and 17.6% of eyes treated with vehicle (P < .0001).61 Composite cure occurred in 13.9% of patients treated with lotilaner ophthalmic solution and 1.0% of patients treated with vehicle (P < .0001).61
In the treatment group, 19.8% of patients experienced ocular treatment-emergent AEs (TEAEs); this rate was 21.5% in control group patients. All TEAEs occurring in patients treated with lotilaner ophthalmic solution showed mild severity. The most common TEAE was instillation site pain, which occurred in 11.8% of patients in the lotilaner ophthalmic solution group and 7.7% of patients in the vehicle group.61 Administration of lotilaner ophthalmic solution did not result in clinically significant AEs on corrected distance visual acuity, corneal staining, intraocular pressure, or other established safety measures.61
Comfort did not significantly differ between patients treated with lotilaner ophthalmic solution and those given vehicle. The drops were reported to be neutral to very comfortable by 91.9% of patients in the treatment group on day 43.61
Saturn-2
Saturn-2, which was similar in design to Saturn-1, was a phase 3 trial in which the safety and efficacy of treatment with lotilaner ophthalmic solution, 0.25%, were evaluated in adults with Demodex infestation.62 Selection criteria were the same as those in the Saturn-1 trial. Eligible patients were recruited from 21 clinical sites within the US. Those who participated in Saturn-1 were excluded from participating in Saturn-2.62
Patients (N = 412) were randomly assigned in a 1:1 ratio to either the lotilaner ophthalmic solution group or vehicle group.62 The study used the same dosing and administration protocol, study duration, and selection of analysis eye, and primary and secondary end points matched the criteria used in the Saturn-1 trial.62 Nine patients each in the control and treatment groups discontinued the study because of AEs unrelated to treatment (n = 3) and other causes (n = 15) before 43 days.62,63
Overall, the results again demonstrated complete collarette cure, mite eradication, and composite cure of collarettes and erythema in higher proportions of patients treated with lotilaner ophthalmic solution than of those treated with vehicle.62 Among all patients, 56.0% of those treated with lotilaner ophthalmic solution and 12.5% of those treated with vehicle had complete collarette cure by day 43.62 Additionally, mites were eradicated in 51.8% of patients treated with lotilaner ophthalmic solution and 14.6% of patients treated with vehicle.62 Furthermore, composite cure occurred in 19.2% and 4.0% of patients treated with lotilaner ophthalmic solution and vehicle, respectively.62
In the study group, ocular TEAEs were observed in 19.2% of patients compared with 12.4% in the control group. None of the TEAEs experienced by patients treated with lotilaner ophthalmic solution were serious. The most common TEAE in the treatment group was instillation site pain, which occurred in 7.9% of patients in the treatment group and 6.7% of patients in the vehicle group.62 Clinically significant AEs involving corneal staining, intraocular pressure, or other established safety measures were not observed in patients treated with lotilaner ophthalmic solution.62 The drops were reported to be neutral to very comfortable by 90.7% of patients treated with lotilaner ophthalmic solution and 88.5% of those treated with vehicle at day 43.62
INSIGHTS FROM RECENTLY PUBLISHED LITERATURE
In the American Academy of Ophthalmology (AAO) Blepharitis Preferred Practice Pattern, which was published electronically in February 2024, no explicit recommendations for the treatment of Demodex blepharitis are made. Studies of the safety, efficacy, and tolerability of TTO, oral and topical ivermectin, eyelid hygiene, hypochlorous acid, lotilaner ophthalmic solution, microblepharoexfoliation, medicated scrubs, and intense pulsed light therapy are discussed. Lotilaner ophthalmic solution is cited as the FDA-approved treatment option for this disease.64
Updated results of the Atlas study published in March 2024 add insight into traditional treatments not approved by the FDA. In the study, patients were currently using or had stopped using artificial tears (65.7% of respondents), warm compresses (60%), lid wipes (41.5%), antibiotic or steroid ointment (34.2%), TTO (16.2%), and/or an oral antibiotic (16.1%).40 Overall, 33 of 502 patients (6.6%) had undergone microblepharoexfoliation, thermal pulsation, or other in-office procedures.40 Authors of this study expressed concern regarding the efficacy of treatments not approved by the FDA for Demodex blepharitis.40 Indeed, among patients who discontinued a traditional therapy regimen, 45.9% did so due to a lack of tolerability or efficacy, highlighting an unmet need for an effective and well-tolerated treatment.40
According to results of a meta-analysis also published in March 2024, lotilaner ophthalmic solution enhanced mite eradication compared with control treatment among patients with Demodex blepharitis, with a summary risk ratio of 3.55 (95% CI, 2.87-4.40; P < .00001).65 Results of this analysis demonstrated significantly better outcomes for patients treated with lotilaner compared with patients who received placebo,65 indicating that this agent could address an unmet need and provide a therapy with proven efficacy.
MANAGED CARE CONSIDERATIONS
Managed care organizations can implement various strategies to improve the outcomes of patients with Demodex blepharitis (Figure 3).3,5,9,45,64,66 In particular, efforts can be made to increase awareness among health care providers about the unique nature of Demodex blepharitis relative to DED and other conditions with similar symptoms.3,9 Similarly, to prevent disease progression and reduce costs, educational programs can be created to train providers regarding the diagnosis of Demodex blepharitis.3,9 Promoting the use of standardized diagnostic protocols, including slit-lamp examination, by providers can enhance diagnostic accuracy.3
The AAO Blepharitis Preferred Practice Pattern states that the goals of blepharitis treatment should be to reduce signs and symptoms of the disease, minimize structural damage, and prevent visual function loss.64 To this end, providers should have knowledge of the safety and efficacy of available treatments and engage patients in disease management.64,66 Treatment adherence can be improved if health care providers educate patients and caregivers on the chronic nature of Demodex blepharitis and stress the necessity of continuous and consistent care.64,66
Before receiving coverage for lotilaner ophthalmic solution, patients may be required to fulfill prior authorization criteria and/or attempt other treatments such as TTO and/or an eyelid hygiene regimen (step therapy).67,68 However, given the limited efficacy and poor tolerability of these and other traditional therapies, delays in initiating effective treatment due to prior authorization and step therapy requirements may allow disease progression, increase burden on patients, and escalate rather than reduce costs.
CONCLUSIONS AND UNMET NEEDS
Infestation with Demodex mites strongly contributes to the development of blepharitis and other conditions affecting the eye.3,7 Definitive diagnosis of Demodex blepharitis typically involves visual analysis, which may include the detection of mites using a slit lamp.3,44 The condition is often underdiagnosed and misdiagnosed because of the lack of routine screening for Demodex mites and limited awareness among patients, caregivers, and health care providers.3,7,9
Traditional options for managing Demodex blepharitis include products containing TTO, terpinen-4-ol, and/or linalool. The effectiveness of these products is limited, as they may not eliminate mites, may provide only partial relief of symptoms, and can cause irritation.3,48 Lotilaner ophthalmic solution received FDA approval in July 2023 for treating Demodex blepharitis.5,60 Evidence published in March 2024 underscores the lack of lack of tolerability and efficacy of traditional therapies40 and the efficacy of lotilaner ophthalmic solution.65
Although Demodex infestation is a common cause of blepharitis, there remains a widespread lack of awareness about the condition. Improving patient and provider education, advocating for the adoption of standardized screening and diagnostic procedures, and promoting evidence-based therapeutic strategies can improve treatment outcomes.
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