Introduction
Blepharitis—a common, typically chronic condition affecting the eyelid margins—represents a localized inflammation characterized by redness, discomfort, irritation, and accumulation of debris along and within the eyelashes.1,2 Although the condition is rarely considered sight-threatening, notable collateral damage may ensue in severe instances, including conjunctival inflammation, superficial corneal epitheliopathy, corneal infiltrates, and even microbial keratitis in the extreme.2
The most common etiology of blepharitis involves an overgrowth of resident bacterial flora; however, another significant cause of this condition may be found in an infestation of human facial mites of the species Demodex.3 While the issue of Demodex has entered the mainstream spotlight only within the past 20 years or so, its association with blepharitis has been definitively documented since 1967.4,5 It’s now estimated that as many as two-thirds of all blepharitis cases are associated with Demodex mites.5
Demodex mites are members of the phylum Arthropoda, class Arachnida, and family Demodicidae.6 They are obligate human ectoparasites, and are resident in or near the pilosebaceous units of hair follicles within sebum-rich skin, particularly that of the face.7 The species Demodex folliculorum and Demodex brevis are indigenous to human hosts, just as Demodex canis and Demodex injal are native to domestic canines.
The pathophysiology of Demodex blepharitis (DB) is believed to involve several mechanisms, including: (1) direct damage in the form of microabrasions from the mites’ claws and gnathosoma; (2) granulomatous foreign body reaction secondary to the mites’ chitinous exoskeleton; (3) heightened bacterial load from surface residency by microorganisms, including Streptococcus and Staphylococcus species, as well as Bacillus oleronius; and (4) delayed hypersensitivity and innate immune responses initiated by Demodex-specific proteins in debris or waste left behind after the organism’s death.8
Overview of Demodex Blepharitis
Prevalence
DB affects ~58% of eyecare patients in the US—that's approximately 25 million patients.9,10 In a retrospective study of 1,032 subjects (mean age: 60.2 ± 17.8 years), case records of consecutive patients who underwent biomicroscopy— regardless of chief complaint—were reviewed.9 Ultimately, more than half of subjects (57.7%) were found to have DB based solely on the presence of collarettes, the pathognomonic clinical sign - moreover, among those definitively identified, nearly half (44.0%) had never been diagnosed previously with any form of blepharitis.9 A subanalysis of this population is displayed in Table 1. It should also be noted that, while DB can be encountered in patients of any age or racial predilection, it is most often seen in individuals 60 years of age or older, with the majority described as being Caucasian.11
Impact
As previously mentioned, the impact of DB can be identified at numerous levels. Demodex mites have the potential to affect the eyelashes and their respective oil glands (D. folliculorum) as well as the meibomian glands within the eyelid (D. brevis). Important clinical manifestations may include follicular hypertrophy and accumulation of debris at the base of the lashes, a finding which is referred to by numerous monikers, including collarettes and cylindrical dandruff.12
As they feed on surface oils and epithelial cells within the glands, Demodex mites cause direct mechanical damage as well as epithelial hyperplasia and reactive hyperkeratinization.8 Mite eggs, deposited at the base of the lashes, may cause further follicular distention and a misdirection of lashes.13
Perhaps most significantly, accumulated waste deposits from both live and dead mites contain proteases and lipases which cause irritation, and often elicit an inflammatory response. Mites may also activate inflammatory cascades through additional internal and surface pathogens and toxins (e.g. Bacillus oleronius).14-16
Clinical Signs & Symptoms
In recent years, we have come to recognize that certain signs may be specific to DB, while others represent more generalized responses to ocular surface inflammation; this inflammation from DB can be a complicating factor in the management of overall eye health. The most pathognomonic sign associated with DB according to current research is the presence of collarettes at the base of the lashes; these have also been described as “cylindrical dandruff” by some researchers (Figure 1).9,11,17-19
In DB, collarettes appear as gelatinous accumulations, creating a cuff around the base of the individual lashes. These should not be confused with collarettes secondary to staphylococcal bacteria, which are golden-yellow and scaly in appearance, and located more distally on the lashes.18 Additional eyelid signs that have a significantly greater prevalence in subjects with DB include eyelid erythema, eyelid telangiectasia, scaly debris, and waxy debris.20
Conjunctival injection/hyperemia is another non-specific sign that is commonly encountered in DB, as is diminished tear stability and break-up time (TBUT).11,21 In severe and symptomatic cases, lid margin edema, misdirection of lashes, and madarosis are quite possible as well.11 It bears mentioning that a portion of patients with DB may present without complaints, even despite the presence of overt signs. In such instances, it may be possible that patients have become desensitized to the irritation, accepting it as their “new normal.”
With regard to symptoms of DB, itching is decidedly the most prominent, and can often be further localized to the eyelid margin rather than to the eye itself.11 Other common complaints include ocular redness and tearing, although these are admittedly non-specific in nature.21 Patients also tend to experience the greatest amount of discomfort in the mornings rather than at other times during the day.11
Figure 1. Collarettes along the lid margin in Demodex blepharitis.
Figure 1: Courtesy of Alan G. Kabat, OD, FAAO.
Diagnosis
The differential diagnosis of DB includes a variety of eyelid and ocular surface disorders. In addition to blepharitis, which we’ve already discussed, conditions which may present with similar symptomatology include dry eye disease, allergic or infectious blepharoconjunctivitis, atopic keratoconjunctivitis, and ocular rosacea.
Eyelid specific disorders that can mimic or mask DB may include chalazion, trichiasis, meibomian gland dysfunction, and eyelid malpositioning conditions such as ectropion and entropion. In most instances, positive identification of DB is made simply by virtue of the clinical presentation. A review of symptoms can provide clues to suggest DB, however it is the physical examination that allows us to definitively identify the pathogen.
As already mentioned, the presence of collarettes along the base of the lash follicles is considered a pathognomonic finding for Demodex infestation.9,11,19 This sign is generally best observed during a routine slit lamp examination, with the patient looking down while gently retracting the upper eyelid to expose the lid margin (Figure 2).
Figure 2. Slit lamp viewing technique for CD associated with Demodex.
Figure 2: Courtesy of Alan G. Kabat, OD, FAAO.
Additional methods can be employed to confirm the presence of Demodex mites, should the clinician desire. Epilation of lashes with collarettes and their subsequent evaluation under light microscopy often yields “living proof” of Demodex infestation (Figure 3). This technique has been well-delineated in numerous publications.8,17,22
However, such an approach is quite involved and time consuming, and hence impractical outside of academic practice or research facilities.2 Several less complex methods of visualizing Demodex mites in situ have been described in the literature. In the first technique, blunt-tipped forceps are used to gently grasp and rotate the eyelash around the inner perimeter of the lash follicle, causing the mites to emerge tail-first where they can be observed with high-magnification biomicroscopy.23
In the second, the eyelash is similarly grasped with forceps, but slowly drawn in alternating nasal and temporal directions, under gentle constant tension; this also causes mites to emerge from the follicle for observation.24 Still, the evidence suggests that simply having patients look down at the slit lamp while observing for cylindrical dandruff is diagnostically effective in more than 92% of cases.25
Figure 3. Microscopic view of an epilated lash follicle infested by Demodex mites (40x).
Figure 3: Courtesy of Alan G. Kabat, OD, FAAO.
Treatment & Management
Conventional lid hygiene therapies
Despite our awareness of Demodex mites and their potential role in eyelid and ocular surface disease, they have proven quite challenging to manage effectively. Traditional methods of lid hygiene involving dilute baby shampoo or commercial detergent-based cleansers appear to be relatively ineffective against Demodex, based upon clinical research.17,27
Similarly, commercial hypochlorous acid solutions, which have demonstrated excellent antimicrobial capabilities against various bacterial and viral organisms, do not appear to have any significant efficacy toward eradicating the larger and more developmentally complex Demodex mites.28-30
Mechanical debridement
Blepharoexfoliation and similar mechanical cleaning of the lid margin has been advocated as a therapy for DB as well. Both in-office and at-home treatment platforms are currently available for this purpose. In a recent comparative study, a single session of blepharoexfoliation followed by manual eyelid scrubs was found to be more effective than eyelid scrubs alone in reducing patients’ symptoms and overall Demodex counts.31
However, this study utilized 2% tea-tree oil (TTO) shampoo in both the active and control groups, an agent with known acaricidal properties, which we will discuss shortly. The efficacy of blepharoexfoliation alone for DB has not been demonstrated to date; moreover, a recent meta-analysis of current treatments suggests that pharmacological interventions, including those which are TTO-derived, are more effective than non-pharmacological treatments.32
A recent, high-level consensus paper on DB management agreed with this sentiment, stating that “Another aspect of current treatment modalities was the inclusion of mechanical intervention in the form of lid scrubs or microblepharoexfoliation…experts agreed that…when an FDA-approved therapy becomes available, lid scrubs may no longer be a necessary part of management of DB.”33
Demodicidal therapies
Although not specifically approved for the management of DB, several products have been advocated for their ability to kill Demodex mites and reduce the overall bioburden in blepharitis management. The most well-known of these treatments involves the aforementioned TTO and derivatives thereof, particularly terpinen-4-ol (T4O).
Nearly 20 years ago, Gao and associates identified the demodicidal capabilities of TTO in both in vitro and in vivo models.34 Numerous subsequent studies with both TTO and T4O have only served to reinforce these findings.29,35-39 By all accounts, however, the limiting factors regarding tea-tree oil-based products seem to be tolerability and the need for chronic therapy to maintain the clinical results.40-43
XDEMVY (lotilaner ophthalmic solution 0.25%)
The first and currently the only commercially available, US Food and Drug Administration (FDA)-approved therapy for DB was launched approximately 1 year ago in August 2023.44,45 XDEMVY® (lotilaner ophthalmic solution 0.25%; Tarsus Pharmaceuticals, Inc.) represents a unique class of drug, targeting and killing the Demodex mites that are responsible for the eyelid redness and collarettes specifically associated with DB.44
Lotilaner is by design an isoxazoline class ectoparasiticide, initially developed for flea and tick infestations in dogs, and still commonly used in veterinary medicine. In this context, lotilaner is known to provide immediate and persistent killing activity for approximately one month against multiple pathogenic organisms (e.g., Ctenocephalides felis, C. canis, Dermacentor reticulatus, Ixodes ricinus, holocyclus, and Rhipicephalus sanguineus).46,47
The reformulation of this agent for human use resulted in a viable therapy for DB. Lotilaner’s mechanism of action seems to involve the selective blocking of γ-aminobutyric acid (GABA)-gated chloride channels, resulting in spastic paralysis and leading to starvation and eventual death of target arthropod organisms, including those of the Demodex species.44,45,47,48
Extensive clinical trials on lotilaner 0.25% (dosed twice daily, approximately 12 hours apart for a duration of 6 weeks) have been conducted to date, leading to its FDA-approval in July of 2023. The pharmaceutical agent was evaluated in 833 subjects with DB in two randomized, double-masked, vehicle-controlled studies (SATURN-1 and SATURN-2).44 SATURN-1 (NCT04475432) and SATURN-2 (NCT04784091) had identical clinical design and outcome measures, with comparable populations, and hence we can discuss the results concurrently.
For both studies, the primary outcome was met and defined as "improvement in lids (reduction of collarettes to no more than 2 collarettes per upper lid) at day 43" vs. control. In SATURN-1, the proportion of patients with collarette grade 0 (0 to 2 collarettes) was significantly higher in the study group (n=209) than in the control group (n=204). Values at day 43 were 44% vs. 7.4% (p < 0.0001). Similarly, in SATURN-2 the proportion of patients with collarette grade 0 (0 to 2 collarettes) was significantly higher in the study group (n=193) than in the control group (n=200). Values at day 43 were 56% vs. 12.5% (p < 0.0001). The secondary endpoints of mite eradication (mite density of 0 mites/lash) and erythema cure (Grade 0) of XDEMVY vs. vehicle also demonstrated statistically significant improvement at day 43 across both the SATURN-1 and SATURN-2 studies; the specific values are shown in Table 2.49,50
A longer term, observational extension study was also conducted on lotilaner for DB in patients who completed the SATURN-1 study and returned for the day 180 visit (n=239).51 In the SATURN-1 study, eligible subjects were randomized to receive either XDEMVY (n=212) or vehicle (n=209) applied twice daily for 43 days.49
In the extension study, subjects were evaluated at days 180 and 365 after completion of a 6-week treatment with the study drug or vehicle control. Subsequent analysis demonstrated that the proportion of patients with collarette grade 0 (0 to 2 collarettes) was significantly higher in the study group (n=128) than in the control group (n=111). Values at day 180 were 39.8% vs. 2.7% (p < 0.0001), and 23.5% vs. 2.9% at day 365 (p < 0.0001). Likewise, the proportion of patients with ≤10 collarettes (collarette grade 0–1) in the study group was significantly higher than in the control group; values at day 180 were 70.3% vs. 18.0% (p < 0.0001) and 62.6% vs. 21.9% at day 365 (p < 0.0001).
In the study group, erythema continued to improve even after completion of the 6-week lotilaner treatment, with 21.1% of patients in the study group achieving an erythema cure (grade 0) at day 180 vs. 6.3% in the control group (p = 0.0005); at day 365, the outcomes were 28.7% vs. 14.3%, respectively (p = 0.0049).51
With regard to safety, both the SATURN-1 and SATURN-2 clinical trials demonstrated excellent safety and tolerability for lotilaner 0.25% dosed twice daily for 6 weeks.49,50 The most common treatment-emergent adverse events (TEAE) experienced by patients and noted in the prescribing information are summarized in Table 3.
In both trials, all ocular TEAEs noted by study group participants were described as mild or moderate, and ~90% of patients rated drop comfort as neutral to very comfortable (all visits averaged).44,49,50 Similarly, the SATURN-1 extension study reported no serious long term, treatment-related safety concerns observed during the trial.51
Employing XDEMVY in clinical practice
XDEMVY (lotilaner ophthalmic solution 0.25%) is approved for twice daily dosing (approximately 12 hours apart) for a duration of 6 weeks, the identical study protocol employed in both SATURN-1 and SATURN-2.44,49,50 As with most topical ophthalmic medications, contact lenses should be removed prior to instillation of XDEMVY, and may be reinserted at least 15 minutes following its administration.44
For patients utilizing other topical ophthalmic medications (e.g., intraocular pressure [IOP]-lowering agents for glaucoma, anti-inflammatory agents for dry eye disease or ocular allergy), it is advised that a period of at least 5 minutes be maintained between drop applications.44
XDEMVY is approved for use in adults 18 years of age and older. The safety and effectiveness of XDEMVY in pediatric patients below the age of 18 years has not been established.45 Regarding the geriatric population, no overall differences in safety or effectiveness have been observed between elderly and other adult patients.44
Coding and Billing for Demodex Blepharitis
For your DB patients, practitioners are reminded to always utilize the most specific code possible, designating the specific eye(s) and lid(s) involved.
Most importantly however, to distinguish DB from the many other forms of anterior and posterior blepharitis, including B88.0 (other acariasis) will help to differentiate Demodex from other etiologies, and underscore the need for disease-specific treatment. A summary of common codes for DB is shown in Figure 4.
Figure 4. Common codes for Demodex blepharitis.
Tarsus is dedicated to making it easier for patients to get access to XDEMVY. Affordability programs such as the Tarsus Connect Program, have been implemented to better facilitate access for eligible patients who may have trouble getting XDEMVY due to insurance or cost-related issues.
This program establishes affordability options for patients with the following criteria:
- Eligible, commercially insured patients may pay as little as $0*
- Patients may be eligible for other assistance options and pay as little as $50 or less*
- XDEMVY is delivered directly to patient’s home free of charge
- Tarsus Field Reimbursement Managers offer support and solutions to eyecare practitioners and office staff
*With payer coverage and available assistance options, based on eligibility requirements.
Conclusions
Despite misconceptions, Demodex is a ubiquitous ectoparasite that impacts us all, with the potential to initiate a unique and symptomatic form of blepharitis when the population multiplies unhindered, causing an infestation.
Identifying this etiology is very much a straightforward process, as Demodex collarettes—also known as cylindrical dandruff—are now accepted by expert consensus to be the pathognomonic sign of DB, particularly in those patients with symptoms of chronic eyelid erythema and itching.
While numerous treatment options have been introduced to date, there was no FDA-approved treatment available for this condition until recently. Having a treatment modality like XDEMVY, with its demonstrated safety and efficacy, represents a paradigm shift in DB management, providing clinicians with a simple, well-tolerated therapeutic option.
With this approach, the availability of such a treatment changes the standard of care for clinicians, shifting the onus of controlling this disease state from the patient to the physician. Eyecare practitioners can no longer choose to ignore DB, and move beyond relying on outdated therapies.
Our obligation as healthcare providers requires us to identify and educate patients with this pervasive condition. Although there were several treatments previously available, XDEMVY® is the first FDA approved treatment to treat the root cause of Demodex blepharitis.
