**3. Results**

#### *3.1. Patient Characteristics*

The characteristics of the 43 study subjects with refractory ADDE and mild MGD, including 23 individuals in the IPL-MGX group and 20 in the MGX group, are presented in Table 1. Approximately 40% of patients had Sjögren syndrome or rheumatoid arthritis.

**Table 1.** Characteristics of the study subjects with aqueous-deficient dry eye (ADDE) and mild meibomian gland dysfunction in the intense pulsed light (IPL)-meibomian gland expression (MGX) and MGX (control) groups.


*p* values were determined with Mann–Whitney U test (displayed in gray) or Fisher's exact test. SD, standard deviations.

The frequency of other ADDE therapies previously administered is shown in Table 2, with most patients having been treated with diquafosol eyedrops, topical steroids, hyaluronic acid eyedrops, or punctal plugs.

**Table 2.** Previous therapies for the study patients in the intense pulsed light (IPL)-meibomian gland expression (MGX) and MGX (control) groups.


#### *3.2. <sup>E</sup>*ffi*cacy of IPL-MGX*

The SPEED score was significantly reduced at 4 weeks after the final treatment session compared with baseline in both IPL-MGX group and MGX groups, and this di fference was maintained for up to 3 months (Table 3). LLT was significantly increased at both 1 and 3 months after the final treatment session in the IPL-MGX group but not in the control group (Table 3).

Both NIBUT and FBUT were significantly prolonged at both 1 and 3 months after the final treatment session in the IPL-MGX group, whereas they were significantly improved only at 1 month in the control group (Table 3). Changes in interferometric fringe pattern (lipid layer grade) from one typical of aqueous deficiency (Jupiter like) to the normal condition (pearl like) were apparent in 61% and 35% of eyes in the IPL-MGX group as well as in 30% and 5% of those in the control group at 1 and 3 months, respectively, after the final treatment session compared with baseline (Table 4). Lipid layer grade was thus significantly better in the IPL-MGX group compared to the control group at both 1 and 3 months after the final treatment session. The Fluo score had decreased significantly at both 1 and 3 months after the final treatment session in both groups, with the value being significantly lower in the IPL-MGX group than in the control group at both posttreatment assessment points (Table 3).

The logMAR VA of eyes in the IPL-MGX group was significantly improved at both 1 and 3 months after treatment completion compared with baseline, although the values that did not differ between the two groups either before or 1 or 3 months after treatment (Table 5). Eleven of 40 (27.5%) and 12 of 46 (26.1%) eyes in the control and IPL-MGX groups, respectively, manifested central corneal epitheliopathy central corneal epitheliopathy (CCE) with these frequencies not differing significantly between the two groups (*p* = 1, Fisher's exact test). A significantly improvement in log MAR VA was apparent for the eyes with CCE in the IPL-MGX group compared with those in the control group, both after amerilration of the CCE at 1 month and at 3 months after treatment completion (Table 5, Figure 1).

Meibum grade was significantly decreased in both groups at both 1 and 3 months after treatment completion compared with baseline, whereas vascularity score was significantly decreased at both time points only in the IPL-MGX group (Table 3). Plugging score was significantly decreased in both groups at 1 month after treatment completion compared with baseline, whereas only in the IPL-MGX at 3 months (Table 3). The IPL-MGX group showed a significant di fference in meibum grade and lid margin abnormality (plugging and vascularity) scores compared with the control group at both 1 and 3 months after the treatment (Table 3). The meiboscore was not significantly changed at either 1 or 3 months in the IPL-MGX or control group (Table 3). Schirmer's test value also remained unchanged at 1 and 3 months after the final treatment session in both the IPL-MGX and control groups (Table 3). Finally, TMH was low at baseline and remained so after treatment in both groups (Table 4).

**Table 3.** Characteristics of the study subjects with aqueous-deficient dry eye and mild meibomian gland dysfunction in intense pulsed light (IPL)-meibomian gland expression (MGX) and MGX (control) groups before as well as 1 and 3 months after the final treatment session.


eye dryness; LLT, lipid layer thickness; NIBUT, noninvasive breakup time; FUBT, fluorescein breakup time; Fluo, fluorescein staining; SE, standard errors; SD, standard deviations.


*J. Clin. Med.* **2020**, *9*, 3467

**Table 4.** Lipid layer grade and tear meniscus height (TMH) of the study subjects with aqueous-deficient dry eye and mild meibomian gland dysfunction in the intense pulsed light (IPL)—meibomian gland expression (MGX) group (*n* = 46 eyes) and MGX (control) group (*n* = 40 eyes) at baseline as well as 1 and 3 months after


**Table 5.** Logarithm of the minimum angle of resolution (logMAR) visual acuity of the study subjects with or without central corneal epitheliopathy (CCE) in the intense pulsed light (IPL)—meibomian gland expression (MGX) group (*n* = 12 and 32, respectively) and MGX (control) group (*n* = 11 and 29, respectively) at baseline as well as 1 and 3 months after the final treatment session. *p* values were determined with the Wilcoxon signed-rank test vs. baseline or Mann–Whitney U test vs. control with Bonferroni's correction (\* adjusted *p* < 0.05, \*\* adjusted *p* < 0.001). SE; standard errors, SD; standard deviations.

**Figure 1.**Representative case of a 72-year-old woman treated with intense pulsed light-meibomian gland expression. Slitlamp images of fluorescein staining of the left eye obtained before (**a**) and 3 months after completion of (**b**) treatment showed amelioration of central corneal epitheliopathy. The logMAR visual acuity also improved from 0.15 to 0.09 in association with improvement in the lipid layer of the tear film, whereas tear meniscus height was unchanged.

## **4. Discussion**

This is the first multicenter study to show an improvement in subjective symptoms and objective signs in patients with refractory ADDE (including those with Sjögren syndrome or rheumatoid arthritis) with mild MGD by treatment with a series of IPL sessions combined with MGX compared to MGX alone. Clinical parameters including ocular symptoms, tear film stability, fluorescein staining, and meibomian gland function were significantly improved by IPL-MGX treatment compared with MGX alone, although tear fluid parameters remained unchanged. Moreover, eyes with CCE showed an improvement in VA associated with IPL-MGX after amelioration of the epitheliopathy. Our results thus sugges<sup>t</sup> that IPL-MGX might be an effective treatment not only for EDE but also for ADDE and mixed EDE-ADDE, although the present study examined only patients with refractory ADDE accompanied by mild MGD. Given that homeostasis of the lipid and tear fluid components of the tear film appears to be important for tear film health, IPL-MGX may have a role as a supportive treatment for ADDE.

We found that IPL-MGX therapy was more effective for the managemen<sup>t</sup> of refractory ADDE accompanied by mild MGD than was MGX alone, and it was associated with an improvement in meibomian gland-related parameters but not with a change in tear fluid-related parameters. Although >30 studies have indicated that IPL is safe and effective for the treatment of MGD, as far as we are aware only one previous study included patients with Sjögren syndrome [20]. However, this previous study did not evaluate tear fluid-related parameters such as TMH or Schirmer's test value, but instead assessed only ocular symptoms and meibomian gland expressibility [20]. Five previous studies determined the Schirmer's test value [30,42–44], but all of these studies with the exception of one [43] found no significant change in this parameter in response to IPL therapy. The one exception among these five studies showed that the median Schirmer's test value increased from 13 to 15 mm (*p* = 0.046) after IPL therapy [43]. The one previous study that measured TMH found no significant difference in this parameter between before and after IPL treatment [21]. Our present results are thus largely consistent with those of previous studies and sugges<sup>t</sup> that IPL does not affect lacrimal glands, but rather influences meibomian glands alone.

With regard to the mechanism of action of IPL in MGD, the treatment likely warms meibomian glands by increasing the temperature of the thin periocular skin and thereby promotes the melting of meibum [16,23]. In addition, the IPL device emits energy that is absorbed by chromophores in hemoglobin and likely thereby promotes closing of abnormal vessels in the lid margin and adjacent conjunctiva as well as attenuates the local release of inflammatory factors from the abnormal vessels [45,46]. A recent study found that the concentrations of various inflammatory factors—including interleukin-17A, interleukin-6, and prostaglandin E2—in tear fluid were reduced after IPL therapy [25]. IPL treatment is also likely able to reduce bacterial load of the eyelid margin and the number of *Demodex* mites surrounding adnexa [44] as well as to ameliorate the associated inflammation [47].

Our present results show that MGX alone was also e ffective for the treatment of refractory ADDE accompanied by mild MGD with regard not only to subjective symptoms but also objective parameters with the exception of LLT, vascularity of lid margins, the meiboscore, TMH and Schirmer value. MGX alone likely does not have anti-inflammatory and meibum-melting e ffects or improve the condition of the aqueous layer of the tear film. In contrast, IPL-MGX showed significant e ffects on all of the parameters measured with the exception of the meiboscore, TMH and Schirmer's test value compared with MGX alone. Our findings sugges<sup>t</sup> that IPL alone might be e ffective for the treatment of refractory ADDE, although the present study did not examine the e ffects of IPL without MGX.

The improvement of ADDE by IPL-MGX is consistent with the notion that tear film homeostasis is required for maintenance of tear film health. Self-reported ocular symptoms covered by the SPEED questionnaire were significantly ameliorated after IPL-MGX treatment in the present study, similar to the results of previous studies [20,23,25,29,42,48]. Twenty-two of the 23 study patients (96%) thus showed a decrease in the SPEED score of ≥8 points at both one and three months after the final IPL-MGX treatment session. The Fluo score was also significantly reduced after IPL-MGX therapy, again consistent with previous data [21,23,28–30,42–44,49]. Of note, eyes with CCE showed a significant improvement in VA after IPL-MGX compared with those receiving MGX alone. The targeting of MGD by IPL-MGX may thus improve the quality and quantity of lipids in the tear film and thereby result in a decline in the concentrations of inflammatory cytokines in tear fluid. Such an action might break the vicious cycle of corneal-conjunctival epitheliopathy and ocular surface inflammation.

The patients treated with IPL-MGX therapy in the present study had experienced ADDE for 8.1 ± 6.7 years (range of 2–24 years), and conventional therapies had proven insu fficient of amelioration of ocular symptoms and improvement of tear film–related parameters. A recent study found that most patients with ADDE due to Sjögren syndrome and a disease duration of >3 years also developed MGD, likely because the early destruction of lacrimal glands eventually begins to a ffect meibomian glands [50]. Indeed, ~40% of patients in the present study also had systemic diseases such as Sjögren syndrome or rheumatoid arthritis. The conditions of such patients may be too severe to manage even with a combination of several conventional therapies. Our study has now demonstrated an improvement in clinical parameters of patients with refractory ADDE and mild MGD by treatment with IPL-MGX or MGX alone, suggesting that therapy targeted to the lipid layer of the tear film may be necessary for such patients who do not respond to conventional therapies. The e fficacy of MGX alone in the present study was essentially apparent only one month after treatment completion, whereas that of IPL-MGX remained manifest at three months. The combination of therapies that target both aqueous and lipid layers may thus improve homeostasis of the tear film, resulting in amelioration of corneal-conjunctival epitheliopathy and subjective symptoms as well as an increase in VA.

Previous studies have found that ADDE and EDE occur frequently together, given that not only lacrimal glands but also meibomian glands can be a ffected in ADDE. A reduced production of tear fluid can increase friction between the eyelid and the ocular surface and thereby promote eyelid inflammation [4,5]. We propose that IPL therapy can increase the quality and quantity of lipid in the tear film, dampen the inflammatory reaction due to abnormal vessels, and thereby block the vicious circle underlying the pathophysiology of dry eye. It ameliorates ocular surface epitheliopathy and increases tear film stability, leading to an improvement in ocular symptoms (Figure 2). Together, our results sugges<sup>t</sup> that it is important to treat not only the aqueous layer but also the lipid layer of the tear film in order to restore ocular surface health in patients with ADDE including those with refractory ADDE associated with mild MGD.

**Figure 2.** Proposed mechanism of action of IPL therapy on the vicious cycle of dry eye. IPL increases the quality and quantity of the lipid layer of the tear film as well as reduces inflammation of the ocular surface and lid margin. These e ffects result in amelioration of ocular surface epitheliopathy (ocular surface staining) and an increase in tear film stability, followed by improvement of ocular symptoms without any change in tear fluid secretion. IPL can block the vicious cycle (yellow x) underlying the pathophysiology of dry eye. IPL, Intense pulsed light.

Limitations of the present study include its retrospective nature and the relatively small sample size. In addition, both eyes of the study subjects were included, although the two eyes of each patient are not independent. Moreover, the study was not randomized or performed in a masked manner. Finally, osmolarity of tear fluid was not measured as an indicator of the e fficacy of IPL-MGX treatment. Our data nevertheless sugges<sup>t</sup> that prospective case-control studies with long-term follow-up are warranted for IPL-MGX treatment of patients with refractory ADDE associated with mild MGD. Further studies should also investigate the e ffectiveness of such treatment for patients with ADDE alone. Guidelines for IPL therapy based on disease severity are also needed for dry eye patients.

In conclusion, our results sugges<sup>t</sup> that IPL-MGX therapy is e ffective for patients with refractory ADDE accompanied by mild MGD, with the severe disease of such patients being di fficult to manage with conventional therapies. IPL-MGX thus has the potential to improve the condition of not only patients with MGD but also those with refractory ADDE and mild MGD.

**Author Contributions:** Conceptualization, R.A. and S.F.; formal analysis, S.F.; investigation, R.A., T.M. and N.M.; writing—original draft preparation, R.A.; writing—review and editing, N.M., S.F. and T.M.; supervision, N.M.; project administration, R.A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** R.A. has the patent of the non-invasive meibography system (JP Patent Registration No. 5281846, US Patent Publication No.2011-0273550A1, EP Patent Publication No. 2189108A1). R.A. is a consultant for Lumenis Japan, KOWA company and TOPCON Japan. No conflicting relationship exists for the other authors.
