Review Review

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Modern approach to the treatment of dry eye,
a complex multifactorial disease: a P.I.C.A.S.S.O.
board review
Pasquale Aragona ,1 Giuseppe Giannaccare ,2 Rita Mencucci,3 Pierangela Rubino,4
Emilia Cantera,5 Maurizio Rolando 6

1 ABSTRACT In a recent publication, a dry eye Experts Board

Department of Biomedical
Sciences, Ophthalmology Clinic, Dry eye disease (DED) is a growing public health concern presented a simple, time-saving flow chart, including
University of Messina, Messina, affecting quality of life and visual function, with a point-by-point explanatory guide, to better define
Italy a significant socio-economic impact. It is characterised by
2
Ophthalmology, Magna the diagnosis of DED, in what was defined as a three-
Graecia University of Catanzaro, the loss of homoeostasis, resulting in tear film instability, step method. To summarise, the three-step method
Catanzaro, Italy hyperosmolarity and inflammation of the ocular surface. If was described as follows: the first step consisted in
3
Institute of Ophthalmology, the innate immune response is unable to cope with asking about symptoms with a questionnaire;
Florence, Italy internal bodily or environmental adverse conditions, the
4 the second step in observing the ocular surface at the
Ophthalmology, University of persistent, self-maintaining vicious circle of inflammation
Parma, Parma, Italy slit lamp in order to study the tear film, the staining of
5 leads to the chronic form of the disease. Treatment of DED the ocular surface for epithelial damage and lid con-
Ophthalmology, Israelitic
Hospital, Rome, Italy should be aimed at the restoration of the homoeostasis of ditions; the third step in addressing tear clearance and
6
Ocular Surface Unit, ISPRE, the ocular surface system. A proper diagnostic approach is
corneal sensitivity.9 In this article, we address the
Genoa, Italy fundamental to define the relevance and importance of
management of the patients once the dry eye diagnosis
each of the DED main pathogenic factors, namely tear film
instability, epithelial damage and inflammation. has been made. Based on the existing literature and on
Correspondence to
Maurizio Rolando, Ocular Consideration also needs to be given concerning two a consensus among the members of our study group,
Surface Unit, ISPRE Genova, other pathogenic elements: lid margin changes and nerve the opportunity of a dynamic therapeutic strategy
Genoa, Italy; damage. All the factors that maintain the vicious circle of according to the clinical results obtained during the
m
​ aurizio.​rolando@​gmail.​com course of the disease, is suggested. In this article, we
DED in the patient’s clinical presentation have to be
Received 18 December 2019 considered and possibly treated simultaneously. The wish to focus on the treatment necessary to obtain an
Revised 18 March 2020 treatment should be long-lasting and personalised since it improvement of the ocular surface conditions and
Accepted 1 June 2020 has to be adapted to the different clinical conditions a long-term control of the disease.
Published Online First observed along the course of the disease. Since DED Taking into account the medical history and pre-
23 July 2020 treatment is frequently unable to provide fast and sence of possible risk factors, the authors proposed
complete relief from symptoms, empathy with patients a more personalised, clinical assessment that could
and willingness to explain to them the natural history of be achieved by considering the three pathogenic
the disease are mandatory to improve patients’ factors, which are always present at different levels
compliance. Furthermore, patients should be instructed of expression. These pathogenic factors are (1) tear
about the possible need to increase the frequency and/or film instability, (2) epithelial malfunction and
change the type of treatment according to the fluctuation damage and (3) more or less clinically evident
of symptoms, following a preplanned rescue regimen. inflammation. These factors can be exacerbated by
other two pathogenic findings: lid margin changes
and nerve damage (figure 1).26
INTRODUCTION In general, the treatment of DED should be aimed
at re-establishing and maintaining the ocular surface
Dry eye disease (DED) is a common ocular condi-
system homoeostasis that was disrupted as
tion with a prevalence ranging between 5% and
a consequence of the vicious circle of the disease.10
50% in the adult population.1 It is a disabling dis-
order affecting both visual function and quality of
life, and has a significant socioeconomic impact. The PATHOGENIC FACTORS OF DED
disease is characterised by the loss of homoeostasis Tear film instability is a hallmark of DED and is
of the ocular surface, which results in tear film caused by changes in lipid layer function and in
instability, hyperosmolarity and inflammation of quantity, quality, and availability of tear fluid. It is
the ocular surface.2–5 A report by van Setten et al an important source of symptoms and, possibly, one
© Author(s) (or their
has suggested a link between seasonal environmen- of the main sources of anatomical and functional
employer(s)) 2021. Re-use
permitted under CC BY-NC. tal conditions and DED. In that study, almost half of changes of epithelia and, hence, a starting point for
No commercial re-use. See responders stated that seasonal weather conditions inflammation.11 Another important factor is the
rights and permissions. had a significant impact on their symptoms, most function of transmembrane and secretory mucins,
Published by BMJ. notably wind and sunshine, whereas the summer which facilitate the contact between tear fluid and
To cite: Aragona P, and the winter were most commonly associated epithelial cells, adversely affected by tear film
Giannaccare G, Mencucci R, with dry eye complaints.6 Other factors that may instability.12–14
et al. Br J Ophthalmol contribute to the development or worsening of DED Epithelial malfunction caused by friction, adverse
2021;105:446–453 include contact lens wear.7 8 environmental factors, ocular surface irritation and/

446 Aragona P, et al. Br J Ophthalmol 2021;105:446–453. doi:10.1136/bjophthalmol-2019-315747

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Figure 1 Key pathogenic factors contributing to the vicious circle of dry
eye disease. Modified from Aragona and Rolando.26

or nerve impairment can lead to a further injury. This plays a key

role in the continued tear film instability, the increasing inflam-
matory reaction and the reduced protection of nerve endings.15
The initial inflammatory reaction on the ocular surface results
from innate immunological processes, involving the epithelial
response to external stimuli, mediated by the activation of toll- Figure 2 Dry eye disease management algorithm.
like receptors and the related cascade of events.16–25 A strong
and/or prolonged exposure to an inflammation-provoking stimu-
lus may lead to an immunologic adaptive reaction, responsible
for the chronic form of the disease. be used. Furthermore, the most active factor can be selected
The thickening and rounding of the lid margins, causing and addressed first and/or more aggressively (figure 2).
a reduced congruity with the eye bulb as well as the presence of For example, if significant inflammation of the meibomian
eyelid notches, can affect the shape and function of the menisci. glands (MGs) is present, stabilising the tear film without cor-
So the tear film distribution and the lipid layers spreading will be recting the lid inflammation will be ineffective. In fact, MG
adversely affected. Impairment or malfunction of the lid- changes will cause a disruption of the lipid layer stability,
associated glands greatly influence the qualitative and/or quanti- resulting in a reduced tear film break-up time and an inflam-
tative composition of tear lipids, and are a possible source of matory response in the conjunctival epithelium. Therefore, the
inflammation and infection. Nerve function impairment and main goal should be to reduce lid margin inflammation. This
anatomical changes will affect both epithelial viability and turn- will include lid margin hygiene, corticosteroids/antibiotic oint-
over, in addition to tear film production. However, the role of ment and eye drops, together with the use of tear substitutes in
nerve function in maintaining ocular surface homoeostasis and order to allow a more efficient control of the tear film stability.
inducing the inflammatory response has yet to be elucidated. The choice of the tear substitute is also an important factor to
consider: in this example, a low-viscosity formulation with
DIAGNOSIS AND ASSESSMENT OF DED limited retention time, thus able to dilute the pro-
At present, the cause of dysfunction can be difficult to be inflammatory agents present on the ocular surface and to
determined due to the number of potential factors already increase tear clearance would be recommended.27–29 The use
discussed, which makes an aetiological approach to treatment of punctal plugs, even in the presence of poor tear volumes,
difficult to pursue. It is therefore of critical importance that should be avoided, as good clearance of the pro-inflammatory
a proper diagnostic approach determines the relevance of each tear fluid is mandatory, together with efficient lid hygiene.
of these factors in the patient’s clinical presentation, so that However, a recent paper has demonstrated that the increase
an effective, long-lasting and personalised treatment can be of tear inflammatory cytokine levels in patients with DED,
administered and modified if necessary.26 All the factors, treated with punctal plugs was temporary and returned to base-
which contribute to and maintain the vicious circle of the line after 3 weeks.30 Once lid margin inflammation is under
disease, have to be considered and potentially treated simul- control, the therapeutic strategy can be changed to address tear
taneously. Therefore, establishing the role played by each of film instability and volume as well as epithelial protection, in
them in the clinical picture represents the basis of the ther- order to further decrease inflammation. The addition of more
apeutic strategy. This allows the identification of the key viscous tear substitutes with osmo-protective activity can be
factor(s) of DED in the single patient, which can be subse- used in conjunction with milder steroid eye drops. Punctal
quently targeted while also taking into account other altera- plugs, if still needed, could be taken into consideration, at this
tions. If there are two or more factors, a multiple strategy can point, as a further tool.

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Once a clinical improvement is achieved, a continued lid Management of inflammation
hygiene programme, including appropriate tear substitutes to Control of inflammation is considered mandatory in order to
prevent recurrence of the acute disease, would be mandatory. improve symptomatology. Direct inflammatory damage or lack
Timing of controls would be based on the presumed efficacy of of epithelial protection can make free nerve endings of the cor-
the treatment used (table 1). neal epithelium more sensitive to normal and environmental
At the same time, the patient should be informed about the aim stimuli, inducing neuropathic pain, a typical symptom of
of the prescribed therapy that it could be changed based on the DED.54 However, the ability to immediately treat these symp-
clinical results and that the treatment effect may take some time toms is poor, which frequently leads to non-compliance due to
to manifest. lack of prompt effectiveness. Contact lenses (both scleral and
silicone-hydrogel) as well as blood-derived eye drops have been
TREATING SYMPTOMS AND SIGNS suggested as possible treatments for this condition.51 55–59
Diagnosis and subsequent treatment of DED can be extremely Another systemic approach addressing the central nervous sys-
challenging due to a lack of a single clinical assessment and the tem with gamma-aminobutyric acid (GABA)-mimetic substances,
wide variation in symptoms. In addition, patient-reported symp- used for peripheral pain, has also been suggested.60
toms frequently do not correspond to observed changes in clinical The control and reduction of ocular surface inflammation,
signs.52 53 Tear substitutes have been traditionally used for the which may derive from epithelial damage and environmental
treatment of DED to improve symptoms. However, it is important stressors, is another key component of any treatment regimen.
to note that tear substitutes are not specifically designed to Corticosteroids are typically used in the treatment of ocular sur-
improve symptoms, but to prevent their build-up. Consequently, face inflammation,31–33 particularly milder corticosteroids such as
they should be instilled regularly throughout the day to avoid those naturally produced by the ocular surface epithelium.
symptom aggravation and not used on an as-needed basis. It is Cortisol (called hydrocortisone, when used as a drug), which can
also important to consider that some eye drop formulations may be produced at the ocular surface by epithelial cells under certain
contain preservatives, which have the potential to adversely affect physiological conditions, contributes to the regulation of inflam-
the ocular surface and induce noxious symptoms. In these situa- matory processes ordinarily occurring and acts as a protective
tions, it is important to limit their long-term use. mechanism against environmental antigens.61 62 Inflammation is
To increase tear film stability, polymers such as hyaluronic acid an important contributor to the vicious circle of DED and is
have been suggested for use. These polymers allow the correction frequently the factor that causes the disease to become chronic.
of the tear film volume and improve its functional characteristics Therefore, controlling inflammation is fundamental to prevent
by increasing the tear film volume, ocular surface wettability and and treat chronic DED.63–66 Evidence suggests that long-term
fluid spreading. Recently, a new generation of multiple-action inflammation in DED elicits morphological and functional
tear substitutes, made of a combination of polymers with differ- changes, which can lead to a change in the expression profile of
ent characteristics, was put on the market.29 inflammatory cytokines (interleukin (IL)-1ɑ, IL-1β, IL-6, IL-17,

Table 1 Treatment schema proposed from P.I.C.A.S.S.O. board for different clinical conditions
~Month 1 ~Month 2 ~Month 3
Tx for dry eye and inflammation
Lid hygiene (at home) Warm/hot compresses + medicated wipes (two times per day)
Anti-inflammatory Mild corticosteroids for 2 weeks
Tear substitutes Use fluid tear substitutes two to four times a day in order to restore tear film stability (ie, semifluorinated alkane eye drops) and break DE vicious
circle (ie, sodium hyaluronate/trehalose, other MATS)
Tx for MGD with blepharitis
Lid hygiene (at home) Warm/hot compresses + medicated wipes (two times per day)
Anti-inflammatory Potent corticosteroids at decreasing doses + other anti- Milder corticosteroids at decreasing Stop corticosteroids; continue other
inflammatory molecules (ie, omega3 supplementation) doses; continue other anti-inflammatory anti-inflammatory molecules (ie,
molecules (ie, omega3 supplementation) omega3 supplementation)
Antibiotics Treat with courses of ointments based on drugs with anti- Reduce ointment application: once daily Continue ointment application: once
inflammatory activity once daily or two times per day (ie, for 10 days daily for 10 days
20 days with tetracyclines, macrolides, fluoroquinolones)
Tear substitutes Use fluid tear substitutes five to six times a day in order to favour tear film dilution and clearance (based on low viscosity formulations of sodium
hyaluronate)
Tx for dry eye with severe
epithelial damage
Lid hygiene (at home) Warm/hot compresses + medicated wipes (two times per day)
Anti-inflammatory Potent corticosteroids at decreasing doses + cyclosporine Milder corticosteroids at decreasing doses Stop corticosteroids; cyclosporine
once daily + cyclosporine once daily once daily
Antibiotics Systemic doxycycline 100 mg two times per day Systemic doxycycline 100 mg once daily Stop doxycycline (consider to continue
its use, at lower concentrations that is,
40 mg/day if necessary)
Tear substitutes High-mean viscosity (sodium hyaluronate, linear or cross-linked; other polymers) + molecules helping epithelial healing (vitamins, antioxidants
and bioprotectors) one drop five to six times a day
The treatment should be given for a 3-month course followed by a further evaluation of patients’ conditions.
DE, dry eye; MATS, multiple action tear substitute; MGD, meibomian gland dysfunction; Tx, therapy.

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tumour necrosis factor-ɑ, matrix metalloproteinases). The expres- ocular surface: they improve tear fluid clearance and reduce the
sion of these and other molecules, such as intercellular adhesion concentration of pro-inflammatory agents. This is in contrast to
molecule 1, may trigger, in case of prolonged stimuli, the activa- punctal plugs, which are used to prolong the permanence of tears
tion of adaptive immune pathways with lymphocytes migrating to on the ocular surface by inhibiting their clearance. Consequently,
the conjunctiva and eliciting a chronic immune-mediated inflam- the use of punctal plugs should be reserved for conditions in
matory response. Corticosteroid treatment with high-medium which inflammation of the ocular surface is not present or upon
potency molecules has been demonstrated to be effective but patient request in specific social occasions like celebrations or
with significant, serious side effects; therefore, their long-term extensive video terminal use. In these situations, punctal plugs
use is not recommended. The use of mild steroids, such as hydro- use should be limited to short time periods.
cortisone, is highly indicated for patients with DED, where a long-
lasting anti-inflammatory treatment is advisable.34 This treatment
can be considered safer than other types of corticosteroid mole- Epithelial protection
cules; however, it is always mandatory to check intraocular pres- Another pillar of DED therapy is epithelium protection, necessary
sure and the lens status during the treatment. to interrupt the vicious circle that is sustained by pro-
Other molecules can be used to treat inflammation alone or in inflammatory cytokines produced during epithelial damage. The
combination with corticosteroids.41–43 Omega-3 fatty acids, protective physical and biological characteristics of some tears
cyclosporine A, tacrolimus and lifitegrast have all been indicated have been identified as a potential treatment to protect epithelial
as possible treatments acting on specific aspects of inflammation. damage (table 2).46–48 70–88 Trehalose has been indicated as
Omega-3 is a useful supplement able to address some aspects of a possible therapeutic tool, able to interfere with the cellular
inflammation through the formation of potent anti- metabolic dysfunction associated with DED and control inflam-
inflammatory and pro-resolving lipid mediators.39 40 67 68 mation. This naturally occurring sugar is a non-reducing disac-
A recent study has demonstrated that the use of eye drops con- charide, found in high concentrations in many organisms, and is
taining n-3 eicosapentaenoic (EPA) and docosahexaenoic acids a key element involved in anhydrobiosis (ability to survive almost
(DHA) has a positive effect on the entire ocular surface system complete dehydration). Its presence also confers resistance
and could be a complementary therapeutic strategy for the treat- to desiccation and high osmolarity in bacterial and human
ment of DED and photorefractive keratectomy.67 cells.79 80 Owing to these characteristics, trehalose was used to
However, in a recent multicenter, double-masked clinical trial protect the amniotic membrane for ocular surface reconstruction
where moderate-to-severe DED patients were randomised to during the process of preservation.80 In addition, it has been
receive for 1 year, either a daily oral dose of EPA and DHA hypothesised that the ability of trehalose to effectively control
(treatment group) or olive oil (placebo group), there were no inflammation is due to the activation of the transcription factor
significant differences between the two groups for both the signs E-boxB/autophagy cellular degradation pathway, which seems to
and symptoms of DED.69 be involved in the maintenance of corneal homoeostasis and sup-
Other molecules, including cyclosporine A, tacrolimus and pression of cell death during an apoptosis-inducing inflammatory
lifitegrast act by inhibiting lymphocyte migration to the ocular insult.47 48 88 It has been demonstrated that trehalose preserves the
surface but require a longer period compared to corticosteroids integrity of the cells and their intracellular organelles through
before they become effective in controlling inflammation.35–38 65 multiple mechanisms, which are not yet fully understood.49 89
The correct use of tear substitutes can play an important role in Hyaluronic acid is a strongly hydrophilic, non-sulfated, disac-
helping to achieve the control of the inflammatory process on the charide, glycosaminoglycan, with a molecular weight ranging

Table 2 Topical treatment options for the control of ocular surface inflammation
Drug Characteristics Author, year (Ref.)
Corticosteroids Fast action, highly effective, possible side effects, usually not for chronic use. Marsh, 199931
Pfulgfelder, 200432
Aragona, 201333
Rolando, 201734
Cyclosporine A Acts on T lymphocyte recruitment, delayed achievement of full therapeutic effect. Sall, 200035
Leonardi, 201636
Tacrolimus Acts on T lymphocyte recruitment, delayed achievement of full therapeutic effect. Moscovici, 201237
Lifitegrast Inhibits lymphocyte activation by blocking ICAM-1 and LFA-1 receptors. Perez, 201638
Omega-3 Reduces the activation of pro-inflammatory cytokines, increases anti-inflammatory prostagliandins, promotes the resolution Li, 201039
of inflammation (resolvins), improves nerve neuroprotection (neuroprotectins) Cortina, 201040
Non-steroidal anti- Mediate the breakdown of arachidonic acid cascade; side effects are decreased corneal sensitivity and sporadic corneal Rolando, 200241
inflammatory drugs melting; currently not strongly suggested. Aragona, 200042
Aragona, 200543
Doxycycline Reduces MMP-9 expression, macrophage, interleukin 1β, interleukin 6 and TNF-alfa. Zhang, 201444
Azithromycin Restores the levels of carotenoids in meibum and decreases signs and symptoms of DED. Foulks, 201345
Tear substitutes Increase tear fluid clearance, reduce concentration of pro-inflammatory factors. Osmoprotection and increase autophagy Baudouin, 201346
(ie, trehalose) Uchida, 201447
Sarkar, 200748
Fariselli, 201749
Nerve growth factor Regenerates corneal nerve, improves tear secretion and epithelial cell turnover. Coassin, 200550
Autologous serum Improve tear stability, fluorescein and rose bengal staining scores as well as subjective symptom scores Kojima, 200551
DED, dry eye disease; ICAM-1, intercellular adhesion molecule 1; LFA-1, lymphocyte function-associated antigen 1; MMP-9, matrix metalloproteinase 9; TNF, tumour necrosis factor.

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from <100 to >1000 kDa, occurring naturally in the human obtained, the anti-inflammatory treatment can be continued
body.90 It is currently considered an essential component in tear with milder corticosteroids in a lower dosage for long-term use
substitution formulations, where it increases viscosity, improves (table 3).
retention time, and optimises ocular surface hydration and The use of medium-viscosity formulation tear substitutes to
lubrication.91–93 There are several formulations present on the increase tear clearance and stabilise the tear film is an important
market, particularly in Europe, which differ in concentration, consideration in treating MGD/blepharitis. The frequency of
molecular weight and viscosity, whereas in some products, addi- instillation should be consistent (four to six times a day), with
tional components are added to sodium hyaluronate in order to the aim of controlling symptom presentation. The ancillary use of
address specific aspects of DED.29 Generally, viscous solutions eye drops containing resolvins that are molecules derived from
may be useful to treat conditions where epithelial recovery is omega-3 polyunsaturated fatty acids, EPA and DHA is advisable
necessary, whereas less viscous eye drops are used when an (two to three times a day). Self-administered lid hygiene is man-
increased tear clearance is required. datory and should be based on warm/hot compresses or heating
goggles (Blephasteam) and medicated wipes. Recently, a new in-
office treatment has been developed to safely administer thera-
Lid management peutic levels of heat and pressure (LipiFlow), which has demon-
For a complete ocular surface treatment, other aspects must be strated a higher and more sustained improvement in reducing
taken into account, most notably, the meibomian gland dysfunc- both the signs and symptoms of MGD compared to conventional
tion (MGD)/blepharitis and nerve impairment. warm/hot compresses.94 Subjects with lid margin problems
To control MGD/blepharitis, several measures are necessary, should be informed that their disease is chronic and caused by
including lid hygiene, by means of warm/hot compresses and structural alterations of MG, which can be treated to reduce
medicated wipes, topical or systemic antibiotic treatments, anti- episodic flare-ups but cannot be completely resolved. In case of
inflammatory agents and less viscous tear substitutes for increas- worsening, the administration of more potent drugs should be
ing tear clearance. MGD and blepharitis are the consequence of considered, followed by tapering and returning to baseline treat-
MG disease: this can be isolated but is more frequently associated ments once the relapsing episode is under control.
with skin alterations, indicating a general sebaceous dysfunction. Recently, the use of intense pulsed light has been suggested
Rosacea is a chronic skin disorder that affects the facial skin and is and documented by the literature as a possible treatment of
characterised by transitory vasodilation, persistent telangiectasia MGD.95–97 However, further appropriately controlled studies
with papules and pustules. It is frequently accompanied by severe are desirable to demonstrate that this method is more effec-
MGD and blepharitis, potentially leading to corneal neovascular- tive compared to correctly performed warm/hot compresses.
isation in more advanced stages. To treat this condition, both oral Tolerance with this procedure may be an issue, with some
tetracyclines (eg, minocycline and doxycycline) and topical anti- patients reporting an increase in long-lasting ocular pain after
inflammatory treatments can be useful.44 45 A tapering course of the procedure, suggesting a possible interference with the
potent corticosteroids can be used and, once the response is sensitive nervous system. Furthermore, this method is not

Table 3 Protective physical and biological characteristics of tear substitutes

Molecule Characteristics Author, year (Ref.)
Physical protection
Cellulose derivates Increase residence time and tear film volume. Good level of adhesion to epithelial cells, especially in Toda, 199670
high concentration. Garrett, 200771
Hydroxypropyl guar Lubricates the interface between lids and bulbar surface reducing epithelial stress. Rolando, 200972
Medium/high- molecular-weight and chain length Non-Newtonian viscoelastic activity. Allow for a good viscosity when the eye is open that suddenly Iester, 200073
biopolymers (ie, sodium hyaluronate) decreases during blinking, thus improving tear film thickness when the eyes are open and comfort Aragona, 200274
during eye closure. Aragona, 200275
High concentration polymers, complexed Retain water in their structure so reducing the effect of lid friction and maintaining the volume of the Garrett, 200771
biopolimers, carbomer gels tear film. Postorino, 201776
Cagini, 201777
Sullivan, 199778
Membrane stabilisers Ectoin and trehalose stabilise lipid layers cells by the interaction between hydrocomplexes and lipids, Graf, 200886
creating a protective and stabilising water shell.
Biological protection
Sodium hyalunorate Reduces squamous metaplasia improving goblet cells expression and epithelial cells morphology; Entwistle, 199681
improves cellular kinetics, binds to CD44, the specific receptor present in the cells. Lerner, 199882
Gomes, 200483
Aragona, 200784
Compatible solutes Osmoprotection by antagonising cell dehydration protecting from denaturation of cellular proteins, Baudouin, 201346
preventing cellular shape changes and apoptosis (carnitin, eritritol, trehalose, glycerin, betaine, etc). Aragona, 201485
Vitamins, antioxidants, and fundamental ions Influence metabolic activities of the cells improving cell viability Macrì, 201587
Uchida, 201447
Trehalose Cell hydration maintainer; its presence confers desiccation resistance to bacterial and human cells; its Guo, 200079
remarkable effectiveness is due to the ability to replace some of the water in the cell, thereby stabilising Nakamura, 200880
and protecting the cellular membrane and proteins during the freezing process. Ohsumi, 201488
Autophagy promotion: cleaning of immunostimulating DNA fragments lowering the risk of adaptive Sarkar, 200748
immune response.

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indicated in subjects with skin prototype VI or very dark skin If the patient responds to one or more of these questions with
where the results are poor.95 yes, it is reasonable to assume that the patient would need to
increase the frequency of tear substitute instillation, enhancing/
starting anti-inflammatory treatment or possibly a new course of
Nerve treatment
antibiotics.
The last pillar of DED is neurological impairment, which is
It is also important to schedule follow-up visits to demonstrate
responsible for the frequent lack of correlation between signs
that the physician is managing the patients’ care and to discuss
and symptoms in patients. There is still a lack of treatments able
any issues with the treatment and adapt it if necessary. It is
to address nerve structures, although human recombinant nerve
advisable, if the clinical conditions allow it, to initially schedule
growth factor (NGF) is now on the market for neurotrophic
visits every 3 months, and then every 6 months. It is important to
keratitis and is under investigation in the USA and Europe for
assure the patient that the physician will be ready to support them
DED treatment.50 Several substances have been suggested and are
with any queries and schedule further visits if necessary.
currently used to improve ocular surface sensation. Among these,
In conclusion, dry eye is a multifactorial disease of the tears and
omega-3 derivatives seem to play a significant role in nerve
the ocular surface, a system formed by several structures working
protection and regeneration, when used either alone or in com-
together to protect the eye from excessive environmental and
bination with NGF or pigment epithelium-derived factor.98–101
biological stress. It is therefore critical to treat the main patho-
The use of vitamin B12 has been proven in an animal model to
genic mechanism(s) involved in DED and to address also the
improve both corneal epithelial healing and nerve
secondary mechanisms that, if not appropriately controlled,
regeneration,102 whereas sodium hyaluronate eyedrops contain-
might contribute to perpetuate the vicious circle of DED.
ing vitamin B12 are commonly used for epithelial
A proper and adaptable treatment will improve the ocular surface
improvement.103 Other vitamins involved in ocular surface
inducing a relief from symptoms and an effective improvement of
health are vitamins A and D used as oral supplements and vitamin
the quality of life.
A as a topical application, which have demonstrated an improve-
ment in DED signs and symptoms.104–107 Amino acid–enriched Contributors PA, RM, PR, EC, MR designed and directed the project; all authors
conceived the idea of the review; PA, GG, MR drafted the manuscript with input from
tear substitutes have been proven to be effective in improving all authors; RM, PR, EC provided critical feedback. All authors contributed to the final
corneal nerve structure in patients with DED.108 version of the manuscript.
Possible future developments will consider the use of biological Funding This paper was supported by an unrestricted grant from Théa Farma S.p.A.
drugs in the treatment of DED and associated conditions such as
Competing interests None declared.
psoriasis.109 110
The goal of treatment should be to improve patients’ signs and Provenance and peer review Not commissioned; externally peer reviewed.
symptoms, while adapting the treatment is necessary in order to Open access This is an open access article distributed in accordance with the
achieve good homoeostasis. Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially, and
The relationship with the patient is also a crucial aspect of the license their derivative works on different terms, provided the original work is properly
treatment plan. cited, appropriate credit is given, any changes made indicated, and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
DOCTOR AND PATIENT RELATIONSHIP ORCID iDs
Empathy and willingness to explain the disease with patients, Pasquale Aragona http://orcid.org/0000-0002-9582-9799
who often fell isolated without much understanding and com- Giuseppe Giannaccare http://orcid.org/0000-0003-2617-0289
Maurizio Rolando http://orcid.org/0000-0002-4982-1462
prehension from both medical professionals and relatives, is an
important part of the treatment process. Patients generally feel
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