Unmet Needs in the Management of Demodex Blepharitis

Supplements and Featured Publications, The Evolving Landscape of Demodex Blepharitis Management,

Demodex blepharitis is a common inflammatory eye condition involving the skin, eyelashes, lash follicles, and sebaceous glands that is often overlooked.1-3 The disease is associated with infestation with Demodex mites, which are ectoparasites commonly found on human skin.4-6 Two distinct species of Demodex mites are found in both symptomatic and asymptomatic individuals: D folliculorum and D brevis.6 D folliculorum inhabits the margin of the lash follicle; it is associated with anterior blepharitis. D brevis burrows deep into the sebaceous glands at the base of the lash line; it is associated with posterior blepharitis.1,7

Symptoms are nonspecific to Demodex blepharitis and may include swollen and irritated eyelids, ocular burning, itching, foreign body sensation, crusting, matting, and loss of eyelashes.2,8,9 Secondary manifestations include rosacea, chalazion, meibomian gland dysfunction, trichiasis, dry eye disease, keratitis, and inflammatory conjunctivitis.2,8-12 Demodex mites can be identified using microscopic techniques (eg, slit lamp) and sampling and evaluation of individual lashes (Figure).4,6 Currently, there are no FDA-approved treatment options for Demodex blepharitis. Available management options are limited and commonly include tea tree oil or its active ingredient terpinen-4-ol, which may be included in eyelid cleansers.13 Treatment with this substance may take several weeks to be effective; however, it often is unsuccessful at fully eradicating Demodex mites.8 Further, use of tea tree oil can cause mild irritation and discomfort.8,14

Left untreated, Demodex blepharitis can lead to more serious corneal conditions that may lead to scarring and blindness.2,5 Despite its worldwide prevalence, Demodex blepharitis remains largely underdiagnosed and underappreciated.4,5,15 This article describes the clinical burden of Demodex blepharitis and the unmet needs for patients and practitioners, particularly with respect to the lack of effective treatments to improve ocular health and the impact on patient quality of life.

Incidence and Prevalence

Demodex mites may be present on the eye margin in healthy humans, but this presence causes blepharitis only in some cases.4,6 Studies of the incidence of Demodex blepharitis in the US population are limited. Results of a retrospective study of Demodex-induced collarettes showed that among 1032 patients who visited 1 of 6 US eye clinics, 57.7% had Demodex blepharitis; collarettes were observed in 69.1% of these cases.5

Additional estimates of worldwide prevalence of Demodex blepharitis exist, but vary widely.15 Studies from individual countries reported the presence of Demodex mites in 30% to 90% of patients with blepharitis.16-24

The difference in frequency of Demodex infestation between sexes appears to be small, if it even exists. In the US study described previously, men had a slightly higher incidence of collarettes (62.9%) than did women (54.5%).5 Worldwide, some studies also noted a slightly higher incidence of Demodex in men than in women, although no difference was found in most of the research.4,16,25-28

Several studies reported a higher prevalence of Demodex blepharitis in older adults.4,16,25,28-30 The results of 1 US study suggested that Demodex blepharitis was common in patients of all races, but more research is needed on racial, ethnic, and geographical differences in Demodex infestation.5,16 A search of MEDLINE, PubMed, EBSCO, Cochrane, PROQUEST, and Google Scholar in June 2022 revealed that there were no known studies measuring Demodex blepharitis in commercial insurance, Medicare, or Medicaid databases. More research is needed to effectively evaluate the frequency of Demodex blepharitis in various patient populations.

Economic Burden

No economic studies on Demodex blepharitis have been published. However, economic data on dry eye disease is available; Demodex blepharitis has been reported in a majority of patients with dry eye disease and may be a precursor to this condition.5 The results of a study of the US economic burden of dry eye disease performed in 2011 showed that the condition was associated with a direct overall annual cost of approximately $3.84 billion and an indirect overall annual cost of about $55.4 billion.31 Even if Demodex blepharitis only contributes to a portion of dry eye disease cases, as found in the US collarettes study, related costs still could be substantial.5

Pathophysiology

Healthy, asymptomatic people can harbor Demodex mites, but an overpopulation of these ectoparasites can lead to inflammation through damage to infested tissue.4,6 Proliferation of Demodex mites is more common in older patients due to several variables, including abnormal skin barrier (eg, reduced surface hydration), decreased immunity, and poor personal hygiene.6

D folliculorum is found in clusters along the lash line, whereas D brevis more commonly is detected in sebaceous glands; both types of these mites consume cell components and oils.1,26,32 During this process, the mites are believed to release lipases to aid digestion of sebum that may cause irritation to the tissue due to subsequent release of fatty acids.33 Further, small abrasions caused by the mite’s claws may result in epithelial hyperplasia and keratinization around the base of the eyelashes, forming collarettes (ie, cylindrical dandruff) on the upper lid margin.1 These waxy cylindrical plugs are present in 100% of Demodex blepharitis cases.5,34

Demodex mites also have been known to plug the meibomian gland orifices, which could lead to observed meibomian gland dysfunction and tear film disruptions in Demodex blepharitis.1,7,8 Clogging of the meibomian glands and sebaceous glands by Demodex mites may result in the formation of chalazia and granulomatous reactions; however, chalazia are not always present in Demodex infestation, and further studies are needed to assess this relationship.7,12

Finally, Demodex mites may trigger blepharitis by acting as vectors for harmful bacteria.7,35 Bacillus oleronius, a pathogen also often seen in chronic blepharitis, may initiate an immune response in individuals with rosacea.7,36

Presentation

These pathogenic processes of Demodex blepharitis commonly are associated with itching and redness.4 Further, patients with Demodex blepharitis report ocular pain and burning, foreign body sensation, dryness, lacrimation, purulence, irritation, loss of lashes, matted or crusty lashes, and blurry vision.2,4,8,9,37 Lid margin health can be affected by infection-induced inflammation, and ocular surface manifestations (eg, corneal damage, chalazion, trichiasis, keratitis, conjunctivitis, blepharoconjunctivitis) may occur due to the infection.2,7,8,9,12

The symptoms and signs of Demodex blepharitis also can affect patients emotionally. Recently, in the Atlas study (part of the phase 2b/3 Saturn-1 clinical trial described below), 311 patients with Demodex blepharitis were surveyed to understand the psychosocial burden of the disease.38 A large proportion of patients (80%) reported that the condition negatively affected their daily life, 47% indicated that they were conscious of their eyes all day, 23% constantly worried about their eyes, and 23% reported that Demodex blepharitis gave their eyes or eyelids a negative appearance to others.38 Patients also stated that this condition affected their daily activities; 47% reported that it made driving at night difficult, 30% said that it added time to their daily hygiene routine, and 34% said that it made it difficult to wear makeup.38,39

Diagnosis

The definitive diagnosis of Demodex blepharitis is generally accomplished by visual analysis. A common method of determining the presence of mites is to remove several eyelashes, mount them in oil on a microscope slide, and examine the samples. A positive result for Demodex mites includes the presence of an adult mites, larvae, or eggs.4,27

Although this method is commonly used to determine the number of mites, it has several limitations. For example, it underestimates the number of mites present, as they can float away in the added oil and be retained in the collarettes that remain in the eyelid after lash removal.34 Sodium fluorescein can enhance the microscopic visualization of mites by dissolving and expanding the collarettes, thereby improving visualization of embedded mites and resulting in a more accurate population sample.40 The presence of Demodex blepharitis can also be identified via slit-lamp identification of collarettes localized at the base of the lashes at the lid margin.5

Risk Factors

Immune-related skin conditions are associated with an increased incidence of Demodex blepharitis. Facial rosacea most frequently is postulated to be related to Demodex infestation, and seborrheic dermatitis also is reported to correlate with Demodex proliferation.41,42 Immunosuppressive agents (eg, steroids) and diseases such as HIV or leukemia that compromise immunity are associated with an increased incidence of Demodex blepharitis.7,43-45 However, it remains unclear whether changes in immunity allow for Demodex infestation or whether Demodex mites cause inflammatory disease.46 Modifiable factors believed to encourage proliferation of Demodex include poor hygiene, alcohol abuse, and specific skin characteristics (eg, oily, dry).47,48

Underdiagnosis and Misdiagnosis

Diagnosis of and research concerning Demodex blepharitis are complicated, because the mite resides on both healthy and affected individuals.6 There is no standard to determine the threshold of mite infestation that results in blepharitis symptoms, although recent reports suggest that a change in even 1 fewer mite per lash is associated with clinical improvement in patients who have been diagnosed with the condition.4,49 The disease shares symptoms with other ocular disorders; thus, it is frequently overlooked as a potential diagnosis, especially because clinicians do not routinely screen presenting patients for Demodex mite infestation.5,37

Results of the Atlas study indicated that 51% of patients had signs of blepharitis for at least 4 years; 52% reported experiencing symptoms frequently or all the time over the previous month.38 However, 58% of respondents reported never receiving the diagnosis even though symptoms led them to visit their doctor 2 to 6 times.38 Further, results of the US-based collarettes study described above determined that 44% of patients with collarettes were not diagnosed with Demodex blepharitis, suggesting a high rate of underdiagnosis and misdiagnosis.5 Addressing the issue of misdiagnosis and underdiagnosis in Demodex blepharitis is important; left untreated, the disease can result in punctate keratitis and corneal melting.5,50 Further, lack of a proper Demodex diagnosis can result in ineffective management options and disease progression and a possible increase in the cost of care.5,37 For example, management of severe Demodex blepharitis may require use of microblepharoexfoliation, which costs approximately $150 per session and needs to be repeated 4 times per year.51,52

Current Management Options

Common management options are available for Demodex blepharitis, but no single strategy is always effective for long-term Demodex eradication.37,53 Recommendations for managing patients with Demodex blepharitis are briefly discussed in the blepharitis clinical management guidelines offered by the College of Optometrists.54 Lid hygiene measures are advised to reduce symptoms and prevent relapse. These include lid cleansing to wipe away debris and improve symptoms and use of warm wet compresses to loosen collarettes and crusts in anterior blepharitis.54 Patients are advised to avoid cosmetics, especially eye liner and mascara. Cleansing options include microblepharoexfoliation and OTC lid scrubs and wipes.13,37,55-59 Many of these products contain tea tree oil or its active ingredient terpinen-4-ol; these substances have acetylcholinesterase-inhibiting effects responsible for acaricidal activity to reduce the number of Demodex mites.13,14,37,54,60 Linalool (a fragrant, plant-derived monoterpene alcohol that also is an ingredient of many commercial blepharitis cleansers) has acaricidal effects.13,61 Of note, comorbid conditions may necessitate treatment.5

Limitations of Current Management Options

Demodex blepharitis continues to be an undertreated disease with no FDA-approved treatment options.5 Because no single management option currently fully eradicates Demodex mites, there are no specific guidelines or a standard of care.37 In the Atlas study, 81% of patients reported seeking treatment, but many discontinued the management options provided due to efficacy or tolerability issues or other reasons.38 In the US collarettes study, patients using tea tree oil and lid wipes continued to have Demodex blepharitis in 75% and 57% of cases, respectively, indicating that current management tools for this disease are largely ineffective.5

Tea tree oil has low efficacy; further, it is poorly tolerated and associated with allergies, dermatitis, and ocular irritation.5,8,14,62,63 Indeed, the results of clinical studies on the use of tea tree oil– or linalool-containing commercial cleansers showed that blepharitis symptoms were not fully resolved, and Demodex mites were not fully eradicated.13,52,64 Methods to prevent irritation caused by tea tree oil include instructing patients to be less vigorous when scrubbing their eyelids, diluting the tea tree oil with mineral oil, or applying scrubs and saline rinses that have a higher concentration of tea tree oil during an office visit.53,63 Despite these precautions, poor adherence to these therapeutic options due to discomfort is associated with low Demodex eradication rates.63 Lack of adherence is further complicated by the need for long-term lid hygiene measures to relieve symptoms.37,53

Treatments Under Investigation

Only a few randomized, clinical trials have been or are being performed to test the efficacy of therapies other than conventional tea tree oil (Table). Active ingredients in these products include the antiparasitic drug ivermectin used with the antioxidant and anti-inflammatory drug metronidazole and the acaricidal drug lotilaner.65-71

Conclusions and Unmet Needs

Demodex mites are a major contributor to blepharitis and other ocular diseases.4,5 Several studies have assessed the prevalence of Demodex blepharitis worldwide, but, as of August 2022, only 1 study did so in the United States, suggesting that this disease is overlooked in this country.4,5,16-24 Although the economic burden of Demodex blepharitis specifically is unknown, based on data for dry eye disease, the annual cost of Demodex blepharitis is likely substantial.5,31

The paucity of research on the epidemiology of Demodex blepharitis is reflected in a lack of routine screening for Demodex mites and a lack of standardized criteria for diagnosing the disease.4,37 Likewise, there are no standalone guidelines for managing Demodex blepharitis.54 Current management options include products containing tea tree oil, terpinen-4-ol, and/or linalool; however, use of these products may not fully eradicate mites, may only partially relieve symptoms, and may cause irritation.5,13,14,38 A few studies have examined the use of therapeutic alternatives (eg, ivermectin, metronidazole, lotilaner) and yielded mixed results.66,68,69 To date, these studies have been small, and larger controlled studies are needed to confirm the efficacy and safety of these agents. In all, though Demodex infestation is a common cause of blepharitis, a dearth of disease awareness, a lack of best diagnostic practices, and an absence of FDA-approved treatments remain as obstacles in the management of this ophthalmic condition.

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For other articles and videos in this AJMC® Perspectives publication, please visit “The Evolving Landscape of Demodex Blepharitis Management.