Navigating the challenges of diagnosing and managing Demodex blepharitis

Introduction

Dermatologic inflammation of the eyes known as Demodex blepharitis is a prevalent and underrecognized condition affecting the skin, eyelashes, lash follicles and sebaceous glands.^1,2 In the past, available approaches to managing this condition were constrained, often involving the use of tea tree oil or its primary component, terpinen-4-ol, which may be integrated into eyelid cleansers.³ Demodex blepharitis is frequently overlooked and not fully recognized despite a high global prevalence.^4-6

This article gives an overview of Demodex blepharitis; highlights the clinical and economic impact associated with this disease; reviews diagnostic challenges, best practices and treatment options; and underscores the need for education, training and evidence-based treatment to improve patient outcomes in the management of this disease.

Overview

Demodex mites can be found on the eye margin in healthy individuals and cause blepharitis only in certain cases.^4,7 The manifestations associated with Demodex blepharitis are not exclusive; they can encompass symptoms such as eyelid swelling and irritation, burning sensation, itching, foreign body perception, crusting, matting and eyelash loss.^2,5,8-10 The disease can give rise to secondary manifestations such as dry eye disease (DED), meibomian gland dysfunction, inflammatory conjunctivitis, rosacea, keratitis, chalazion and trichiasis.^2,8-13

Minimal research on the occurrence of Demodex blepharitis within the US population has been conducted. In a retrospective analysis involving 1,032 patients across six US eye clinics, 57.7% were identified with Demodex blepharitis based on the presence of Demodex-induced collarettes.⁵ Alternative assessments of the global prevalence of Demodex blepharitis are available, although their results exhibit considerable variation.⁶ Research conducted in specific countries reported Demodex mites in 30% to 90% of individuals with blepharitis.^14-22 Multiple studies have indicated an elevated occurrence of Demodex blepharitis among the older population.^4,14,23-27

Risk Factors

Conditions related to the immune system are linked to a higher occurrence of Demodex blepharitis. Facial rosacea is commonly associated with Demodex infestation, and a correlation of seborrheic dermatitis with increased Demodex proliferation is also reported.^28,29 An elevated occurrence of Demodex blepharitis has been linked with use of immunosuppressive agents like steroids and with individuals having diseases such as HIV or leukemia that compromise immunity.^29-32 A connection between alterations in immunity and the potential for Demodex infestation is unclear; further, whether Demodex mites contribute to inflammatory disease remains unknown.³³ Factors that are considered modifiable and believed to promote the proliferation of Demodex include inadequate hygiene, alcohol abuse and specific skin characteristics (e.g., oily or dry skin).^34,35

More research is needed on whether sex, age and race are independent risk factors for Demodex blepharitis. Sex appears to impact frequency of Demodex minimally, if at all. In the aforementioned US study, a slightly higher incidence of collarettes was seen in males (62.9%) than in females (54.5%).⁵ Globally, certain studies indicate a slightly elevated occurrence of Demodex infestation in males than in females, although the majority of studies report no significant difference.^{4,14,24,25,36-38} Various studies also indicate a higher prevalence of Demodex in older adults.^4,14,23-27 Importantly, a study published in 2021 revealed that, overall, there was no distinction in Demodex infection based on patient age. However, the D brevis mite was more prevalent among younger adults than older adults.³⁹ In the US study of patients with collarettes, Demodex blepharitis exhibited equal prevalence across individuals of all races.⁵ However, further research to explore potential racial, ethnic and geographical variations in Demodex infestation is needed.¹⁴

Pathophysiology

Healthy and asymptomatic individuals may host Demodex mites, yet an excessive population of these ectoparasites can induce inflammation by causing damage to the infested tissue.^4,7 Two separate species of Demodex mites — D folliculorum and D brevis — are present in both symptomatic and asymptomatic individuals (FIGURE 1).⁷ Both species feed on cellular components and oils.^1,36,40,41 During this process, it is believed that the mites release lipases to facilitate the digestion of sebum, potentially causing irritation to the tissue through the subsequent release of fatty acids.⁴² Additionally, minor abrasions caused by the mites’ claws are believed to lead to epithelial hyperplasia and keratinization around the base of the eyelashes. This process results in the formation of cylindrical dandruff (CD), or collarettes, on the upper lid margin (FIGURE 2⁷).¹ These waxy cylindrical plugs are found in 100% of cases of Demodex blepharitis.^5,43 Demodex mites have also been observed to block the orifices of the meibomian glands, which could contribute to the observed meibomian gland dysfunction and disruptions in tear film associated with Demodex blepharitis.^10,29,40 Lastly, Demodex mites may induce blepharitis by serving as vectors for harmful bacteria.^29,40

Clinical impact

In patients with Demodex blepharitis, these pathogenic processes are associated with itching and redness.⁴ Moreover, individuals affected by Demodex blepharitis often experience ocular dryness, pain, burning and irritation along with matted or crusty lashes, loss of lashes, a foreign body sensation, blurry vision, increased tearing and purulence.^2,4,8-10 Infection-induced inflammation can impact the health of the lid margin, potentially leading to ocular surface manifestations such as corneal damage, conjunctivitis, blepharoconjunctivitis, keratitis, chalazion and trichiasis.^2,9,10,12,29

The emotional well-being of patients also can be impacted by the symptoms and signs of Demodex blepharitis. In the Atlas study, a survey of 311 patients with Demodex blepharitis was conducted to investigate the psychosocial burden associated with the disease. A substantial percentage of patients (80%) expressed that the condition had a negative impact on their daily lives. Among them, 47% reported being consciously aware of their eyes throughout the day, 23% experienced constant worry about their eyes and an additional 23% believed that it gave their eyes or eyelids a negative appearance to others. Patients also noted the impact on their daily activities, with 47% reporting difficulty driving at night, 30% stating that it added time to their daily hygiene routine, 8% indicating a reduction in their ability to wear contact lenses and 34% expressing difficulty wearing makeup.^44,45

Economic impact

No specific economic studies on Demodex blepharitis have been published, but economic data on DED do exist. Demodex blepharitis has been documented in a majority of patients with DED and may serve as a precursor to the development of DED.^5,13 A 2011 study examining the US economic burden revealed that DED was linked to a direct overall cost of approximately $3.84 billion and an indirect overall cost of approximately $55.4 billion per year in the United States.⁴⁶ Adjusted for inflation, this represents $80.5 billion in direct and indirect costs in 2023.⁴⁷ These adjusted numbers are based only on the dollar amount without consideration of other factors, such as new therapies. Even if Demodex blepharitis is only a contributing factor to a portion of DED cases indicated in the US collarettes study, the associated costs of Demodex blepharitis could still be substantial.⁵

Diagnosis and related challenges

The definitive diagnosis of Demodex blepharitis is typically achieved through visual analysis. A prevalent method for confirming the presence of mites involves extracting several eyelashes, mounting them in oil on a microscope slide and examining the samples. A positive diagnosis for Demodex mites is established by identifying adult mites, larvae or eggs.^4,37 While it is commonly used to assess mite presence, this method has its limitations. Notably, it tends to underestimate the actual number of mites, as they may float away in the added oil or be retained in the collarettes that persist in the eyelid after lash removal. Sodium fluorescein can improve the microscopic visualization of mites by dissolving and expanding the collarettes. This enhancement aids in better visualization of embedded mites, resulting in a more accurate representation of the population sample.⁴⁸

Demodex blepharitis also can be identified through slit-lamp examination, which reveals the presence of collarettes localized at the base of the lashes at the lid margin. Slit-lamp examination is a common eye care procedure used to check overall eye health and a simple method to identify Demodex mites.^5,49

Underdiagnosis and Misdiagnosis

The diagnosis and research of Demodex blepharitis pose challenges, as the mite is present on both healthy and affected individuals.⁷ There is currently no established standard to determine the threshold of mite infestation leading to blepharitis symptoms. However, even a change in one mite per lash is associated with clinical improvement in patients already diagnosed.^4,50 The symptoms of this disease overlap with those of other ocular disorders, leading to its frequent oversight as a potential diagnosis. This is compounded by the fact that clinicians do not routinely screen presenting patients for Demodex mite infestation.^5,8

Findings from the Atlas study revealed that 51% of patients exhibited signs of blepharitis for at least four years. Additionally, 52% reported experiencing symptoms frequently or constantly over the preceding month. However, 58% of respondents reported never receiving the diagnosis even though their symptoms prompted a visit to a doctor between two to six times.⁴⁴ Moreover, in the US-based collarettes study mentioned earlier, 44% of patients with collarettes did not receive a diagnosis of Demodex blepharitis. This indicates a notable rate of underdiagnosis and misdiagnosis.⁵

Addressing the challenge of misdiagnosis and underdiagnosis in Demodex blepharitis is crucial; if left untreated, the disease may lead to punctate keratitis and corneal melting.^5,51 Moreover, the absence of an accurate Demodex diagnosis can lead to ineffective management options, disease progression and potential escalation of the overall cost of care.^5,8 As an illustration, the management of severe Demodex blepharitis may involve the use of microblepharoexfoliation, a procedure that necessitates four repetitions per year; each session may cost more than $175 (2023 US$).^8,52

Management options

Conventional treatments for Demodex blepharitis, including the use of tea tree oil, are frequently ineffective and poorly tolerated.^3,5,10,53-56 Very few randomized clinical trials have been conducted or are currently underway to assess the efficacy of therapies other than traditional tea tree oil for Demodex blepharitis.^57-61 In July 2023, the FDA approved lotilaner ophthalmic solution as the first and only treatment for Demodex blepharitis based upon results of the Saturn-1 and Saturn-2 (NCT04475432, NCT04784091) clinical trials.^62,63

Limitations of Traditional Management Options

No conventional approach has demonstrated long-term effectiveness in eradicating Demodex.^8,64 The absence of specific guidelines and a standard of care stems from a historical lack of effective treatments for the disease.⁸

Moreover, Demodex blepharitis remains an undertreated disease.⁵ In the Atlas study, 81% of patients reported actively seeking treatment. However, a substantial number discontinued use of management options provided because of issues related to efficacy, tolerability or other reasons.⁴⁴ In the US collarettes study, Demodex blepharitis persisted in 75% and 57% of individuals using tea tree oil and lid wipes, respectively, suggesting the limited effectiveness of existing management approaches for this condition.⁵

Tea tree oil has shown limited effectiveness in other studies; moreover, it is poorly tolerated and linked to ocular irritation, dermatitis and allergies.^{5,8,10,53,54,65} The outcomes of clinical studies on the use of commercial cleansers containing tea tree oil or linalool revealed that blepharitis symptoms were not completely resolved, and Demodex mites were not entirely eradicated.^3,55,56 Workarounds to mitigate irritation from tea tree oil include advising patients to be gentler when scrubbing their eyelids, dilute tea tree oil in another oil or opt for in-office treatments with higher-concentration tea tree oil scrubs and saline rinses.^8,64,66

Despite the availability of potential workarounds, adherence to treatment remains low, which leads to unfavorable outcomes for patients.^53,64,66 The challenge of nonadherence is further complicated by the requirement for long-term lid hygiene measures to alleviate symptoms.^8,64

Lotilaner Ophthalmic Solution

In July 2023, lotilaner ophthalmic solution, 0.25%, became the first therapeutic approved by the FDA for the treatment of Demodex blepharitis.^62,67 In mites, lotilaner inhibits gamma-aminobutyric acid (GABA) chloride channels in a manner causing paralysis and death. Tested in vitro at approximately 1,100 times the recommended human ophthalmic dose of 30 micrometers, lotilaner does not inhibit GABA-mediated chloride channels in mammals.⁶³ In patients, one drop of lotilaner ophthalmic solution, 0.25%, should be administered in each eye twice daily for six weeks; to avoid contamination, caution should be taken to avoid touching the tip of the dispensing container to fingers, eyes or other surfaces.63 FDA approval was based upon results of the 6-week, multicenter, randomized, double-masked and vehicle-controlled Saturn-1 and Saturn-2 studies.^63,68,69

Saturn-1

In the phase 2b/3 Saturn-1 trial, treatment with lotilaner ophthalmic solution, 0.25%, demonstrated complete collarette cure, mite eradication and composite cure of collarettes and erythema in higher proportions of patients than did treatment with vehicle in adults with Demodex blepharitis infestation. Patients at least 18 years of age with an 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 were recruited from 15 clinical sites within the United States. Among patients excluded were those who used any lid hygiene product within the previous two weeks, used or changed use of a prostaglandin analog (PGA) to promote eyelash growth within the previous 30 days or planned to change PGA use during the treatment phase or were unwilling to forego use of contact lenses, artificial eyelashes or eyelash extensions during the study.⁶⁸

A total of 421 patients were randomly assigned 1:1 to receive either lotilaner solution or vehicle. Patients self-administered one drop of study medication or vehicle in each eye in the morning and the evening for 43 days. In each patient, an analysis eye was chosen based upon mite density. The primary end point was complete collarette cure, which was defined as two or fewer collarettes on the upper eyelid of the analysis eye at day 43. The secondary end points were, at day 43, mite eradication and composite cure of collarettes and erythema (grade 0 erythema in the upper eyelid of the analysis eye). Before day 43, five patients in the control group and three patients in the study group discontinued from the study on account of COVID-19 (n = 5), adverse events related to treatment vehicle (n = 1), adverse events unrelated to treatment (n = 1), and other causes (n = 1).⁶⁸

The results indicated that at day 43, 44% of patients treated with lotilaner and 7.4% of patients treated with vehicle had complete collarette cure. At that time, 67.9% of eyes treated with lotilaner and 17.6% of eyes treated with vehicle demonstrated mite eradication. In all, 13.9% of patients treated with lotilaner and 1.0% of patients treated with vehicle demonstrated composite cure. Ocular treatment-emergent adverse events (TEAEs) occurred in 19.8% of patients in the study group and 21.5% of patients in the control group. All TEAEs were mild for patients treated with lotilaner. Instillation site pain, the most common TEAE in the study group, occurred in 11.8% of lotilaner-treated patients and 7.7% of vehicle-treated patients. Treatment with lotilaner solution did not have clinically significant adverse effects (AEs) on corrected distance visual acuity, corneal staining, intraocular pressure or other established safety measures. The difference in comfort reported by patients between lotilaner and vehicle was not significant. At day 43, 91.9% of lotilaner-treated patients found the drops to be neutral to very comfortable.⁶⁸

Saturn-2

Designed similarly to the Saturn-1 trial, Saturn-2 was a phase 3 trial in which treatment with lotilaner ophthalmic solution, 0.25%, again demonstrated complete collarette cure, mite eradication and composite cure of collarettes and erythema in higher proportions of patients than did treatment with vehicle in adults with Demodex blepharitis infestation. Patients meeting the selection criteria articulated for Saturn-1 were recruited from 21 clinical sites within the United States, although patients who participated in Saturn-1 were excluded from Saturn-2.⁶⁹

In all, 412 patients were randomly assigned 1:1 to receive either lotilaner solution or vehicle. Dosing and administration protocol, study duration, selection of analysis eye, primary end point and secondary end points matched criteria articulated for Saturn-1.⁶⁹ Before day 43, nine patients in the control group and nine patients in the study group discontinued from the study on account of AEs unrelated to treatment (n = 3) and for other causes (n = 15).^69,70

The results indicated that at day 43, 56.0% of patients treated with lotilaner and 12.5% of patients treated with vehicle had complete collarette cure. At that time, 51.8% of patients treated with lotilaner and 14.6% of patients treated with vehicle demonstrated mite eradication. In all, 19.2% of patients treated with lotilaner and 4.0% of patients treated with vehicle demonstrated composite cure.⁶⁹

Ocular TEAEs occurred in 19.2% of patients in the study group and 12.4% of those in the control group. None of the TEAEs for patients treated with lotilaner were serious. Instillation site pain was the most common TEAE in the study group; it occurred in 7.9% of lotilaner-treated patients and 6.7% of vehicle-treated patients. Treatment with lotilaner solution did not have clinically significant AEs on corneal staining, intraocular pressure or other established safety measures. At day 43, 90.7% of lotilaner-treated patients and 88.5% of vehicle-treated patients found the drops to be neutral to very comfortable.⁶⁹

Improving outcomes: Disease awareness, provider training, and patient education

A Demodex blepharitis checklist can provide important information for managed healthcare executives (BOX). Healthcare providers must be made aware of Demodex blepharitis as distinctive from DED and other conditions with overlapping symptoms.^5,8 Providers should be informed that underdiagnosis and misdiagnosis are prevalent with this disease; they should be encouraged to make early and accurate diagnoses, which can prevent clinical exacerbations and increased economic cost.^5,8,51 Providers also should be encouraged to use standardized diagnostic protocols that include slit-lamp examination.⁵ Provider knowledge of the safety and efficacy of available treatments is critical to the successful management of this disease. For promoting treatment adherence, enhancing patient and caregiver education of Demodex blepharitis and its chronic nature is essential.⁷¹

Conclusions and unmet needs

Demodex mites play a substantial role in the development of blepharitis and other ocular diseases.^4,5 The conclusive diagnosis of Demodex blepharitis is typically achieved through visual analysis, which may involve the identification of mites under a slit lamp.^5,48 Nevertheless, underdiagnosis and misdiagnosis of the disease persist due to the absence of routine screening for Demodex mites and a lack of awareness among patients, caregivers and healthcare providers.^4,5,8

Historically, management options have involved products containing tea tree oil, terpinen-4-ol, and/or linalool. However, the use of these products may not completely eliminate mites, may only provide partial relief of symptoms and may lead to irritation.^5,53 In July 2023, lotilaner ophthalmic solution became the first and only treatment for Demodex blepharitis to be approved by the FDA.^62,63

In all, Demodex infestation is a common cause of blepharitis, yet a lack of disease awareness prevails. Enhancing education among patients and providers and encouraging the use of standard screening and diagnostic procedures will improve treatment outcomes.

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