Clinic Rev Allerg Immunol (2015) 49:288–297 DOI 10.1007/s12016-014-8438-7

Current Approach to Dry Eye Disease Valéria Valim & Virginia Fernandes Moça Trevisani & Jacqueline Martins de Sousa & Verônica Silva Vilela & Rubens Belfort Jr

Published online: 1 August 2014 # Springer Science+Business Media New York 2014

Abstract Dry eye disease (DED) is a multifactorial disease of the tears and ocular surface that causes tear film instability with potential damage to the ocular surface. The prevalence of dry eye in the world population ranges from 6 to 34 %. It is more common in those aged over 50, and affects mainly women. Since the introduction of the Schirmer’s test in 1903, other tests have been developed to evaluate dry eye, such as biomicroscopy, the tear film breakup time (BUT), vital dyes (lissamine green and rose bengal), fluorescein, leaf fern test, corneal sensitivity test, conjunctiva impression cytology,

V. Valim Centro de Referência de Doenças Reumáticas, Serviço de Reumatologia, Universidade Federal do Espírito Santo, Hospital Universitário Cassiano Antonio de Moraes, Rua Marechal Campos, 1468, Maruípe, Vitória, ES, Brazil 29040-091 V. F. M. Trevisani Disciplina de Medicina de Urgência e Medicina Baseada em Evidências, Universidade Federal de São Paulo, Rua Botucatu 740 Vila Clementino, São Paulo, SP, Brazil 04023-062 V. F. M. Trevisani Universidade de Santo Amaro, Rua Enéas Siqueira Neto, Jardim das Embuias, São Paulo, SP, Brazil J. M. de Sousa : R. Belfort Jr Escola Paulista de Medicina (EPM), Departamento de Oftalmologia e Ciências Visuais, Rua Botucatu 820, Vila Clementino, São Paulo, SP, Brazil 04023-062 V. S. Vilela Disciplina de Reumatologia, Universidade do Estado do Rio de Janeiro, Avenida 28 de Setembro 77, Vila Isabel, Rio de Janeiro, RJ, Brazil 20551-900 V. Valim (*) : V. F. M. Trevisani : V. S. Vilela Scientific Committee on Sjögren’s Syndrome, Brazilian Society of Rheumatology, Av. Brigadeiro Luís Antônio, 2466, Bela Vista, São Paulo, SP, Brazil 01402-000 e-mail: [email protected]

optical coherence tomography (OCT), and tear osmolarity measurement. Although there is no gold standard, it is advisable to combine at least two tests. Strategies for treating DED have recently been modified and include patient education, tear substitute, corticosteroids, secretagogues, fatty acids, immunomodulators, occlusion of lacrimal puncta surgery and, tarsorrhaphy. Biological therapy and new topical immunomodulators such as tacrolimus, tofacitinib and IL-1 receptor inhibitor are being tested. In this review, the evaluation tests for dry eye are compared and the main studies on treatment are presented, with emphasis on studies in patients with Sjögren’s syndrome. The authors propose an approach for the management of dry eye. Keywords Dry eye disease . Sjögren’s syndrome . Cornea . Ocular surface

Introduction Dry eye disease (DED) or lacrimal dysfunction syndrome (LDS) is a concept established in 2007 by the International Workshop on Dry Eye (DEWS). It is a multifactorial disease of the tears and ocular surface that causes symptoms of discomfort, change in visual acuity, and tear film instability with potential damage to the ocular surface. Dry eye also causes increase in tear osmolarity and ocular surface inflammation [1]. The tear film is dynamic and synergistic with the cornea and conjunctiva. It is composed of three layers: the mucin, aqueous and lipid layer. The main functions of the tear film are: optical, metabolic (provides corneal nutrition), antimicrobian (due to the presence of enzymes and IgA), and as a mechanical barrier (eliminates cellular debris and environmental substances). The lipid layer is external and produced by Meibomian glands. Its function is to delay the

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evaporation of the lacrimal film. The aqueous layer is the major one. It is produced by the lacrimal glands and has high aqueous content. The mucin layer is produced by conjunctival goblet cells and composed mainly of glycocalyx (tightly bound to the corneal and conjunctival epithelia), water soluble to mucin and proteins. Antimicrobian enzymes are found within the mucin layer [1]. There are two categories of dry eye according to the DEWS classification: aqueous deficiency and increased evaporation. The main cause of dry eye of the aqueous deficiency type is Sjögren’s Syndrome (SS). Besides SS, other systemic diseases that cause decreased tear film production are systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), sarcoidosis, graft-versus-host disease, episcleritis, lymphoma, diabetes, human immunodeficiency (HIV) or hepatitis C viruses infections, and hyper IgG4 syndrome. Other causes include deficiency of the lacrimal gland, lacrimal duct obstruction, reflex hyposecretion, and the use of systemic medications [1–6]. Evaporative dry eye can be caused by several other diseases, such as blepharitis, psoriasis, rosacea, seborrheic dermatitis, allergic conjunctivitis, and eyelid disorders (paralysis of the facial nerve, Graves’ disease), prolonged contact lens use, and use of systemic and topical medications. However, studies show that both mechanisms usually coexist, and the evaporative isolated form is more common than the aqueous isolated deficiency [1–3]. Tear deficiency causes dryness, red eyes, eye irritation, burning or foreign body sensation, excessive or lack of tearing, light sensitivity, blurred vision, and eyestrain. Severe cases can result in abrasion or corneal ulceration [7]. Symptoms often worsen in dry environments (air conditioning, dust, winds) when reading or using the computer for a long time [8, 9]. The discomfort can affect labor productivity and reading [10]. Besides affecting visual function, DED is also related to impairment in the health-related quality of life, with negative correlation with anxiety and depression [11].

Epidemiology The prevalence of DED in the world population ranges from 6 to 34 %. It is more common in those aged over 50, and affects mainly women (70 %) [12]. A population study in the USA in 2009 showed that its prevalence in men aged over 50 is 4.3 %, and it is expected to affect 2.79 million men in the USA by 2030 [13]. The Beaver Dam Offspring Study (BOSS) showed a 14.5 % prevalence of dry eye symptoms (14.1 % in aged 21–49 years and 15.2 % in 50 and older) with a significantly higher prevalence in women than in men. In women, the prevalence increased with age, but this was not observed in men in this study. The most important risk factors were: use of

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contact lenses, arthritis, osteoporosis, allergies, thyroid disease, severe headaches or migraine in the previous three months, history of head injury and use of some medications (including antihistamines, acetaminophen, benzodiazepines, antidepressants, and steroids). There is no association between a history of smoking or alcohol consumption and DED [11]. Environmental risk factors have been studied in the last years, and the increased air pollution and atmospheric pressure were the most important related factors. The risk of DED was 13 % higher in regions with higher atmospheric pressure. In metropolitan areas with high air pollution, people are three to four times more likely to have dry eye as compared to rural areas [14]. Computer use causes a decreased rate of blinking, thinning of mucin and lipid layers, instability of the tear film and increased tear evaporation, leading to DED. Lower environmental humidity increases tear evaporation in 5 and 40 % relative humidity, but not at 70 %, when the tear evaporation rate is close to zero. About 43 % of soft contact lens wearers refer dry eye symptoms [15]. Sjögren’s Syndrome is the main disease that causes dry eye and affects the lacrimal glands, leading to decreased secretion and, thus, aqueous tear film production in more than 80 % of patients. Dry eye is the main ocular manifestation in RA (30 %) and SLE (20 %) and occurs in 15 % of SSc cases [4, 5].

Diagnosis All patients with symptoms of dry eye must be clinically evaluated to exclude or confirm a systemic disease or use of a medication that may eventually lead to dryness [3–9]. Questionnaires can be used to detect patients with dry eye and evaluate its impact in the quality of life and follow-up treatment. The questionnaires named Dry Eye Screening Questionnaire [16] and Sicca Symptoms Inventory [17] evaluate ocular and oral symptoms and can be used in the active search for suspected SS patients. These questionnaires are composed of simple and direct questions, such as: – – –

Have you had dry eyes, foreign body sensation, or burning sand that was persistent over the last 3 months? Are your eyes sensitive to light? Do you usually need to use eye drops as tear substitute more than three times a day?

The Ocular Surface Disease Index (OSDI) questionnaire assesses ocular symptoms in patients with dry eyes. That questionnaire focuses on three issues: ocular symptoms within 7 days, possible environmental stimuli causing ocular discomfort, and limitations in daily activities caused by an eye disease. After, it creates an index based on the answers

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provided in each response question and on the total number of questions answered [18]. Some authors observed a weak correlation between patient complaints and findings on ophthalmologic examination [19]. Patients with very severe complaints do not always have important ocular changes. Several studies have shown that chronic inflammation in the cornea decreases its sensitivity in patients with SS compared to patients with other causes of keratoconjunctivitis sicca. Contrary to what one would expect when it causes most damage to the ocular surface, such patients show lower sensitivity of the central cornea. The corneal hypoesthesia makes the patient less symptomatic, which is one of the main factors for the dissociation between signs and symptoms [20, 21]. According to Fox, this discrepancy may delay the diagnosis of SS by up to ten years [22]. After performing a comprehensive interview, tear deficiency can be investigated by several different tests: & & & & & & & & & &

Biomicroscopy Schirmer’s test Breakup time of the tear film (BUT) Vital dyes (lissamine green 2 %, rose bengal 1 %) Fluorescein 1 % Test of the leaf fern Test of the corneal sensitivity Conjunctival impression cytology Optical coherence tomography (OCT) Tear osmolarity measurement

Ocular hyperemia, inflammation of Meibomian gland, symblepharon, absence of glare in the cornea are findings that suggest dry eye and can be observed by biomicroscopy [19]. Described in 1903, the Schirmer’s test is still one of the most used methods in assessing dry eye nowadays. Schirmer I (without the use of anesthetic eye drops before examination) uses a filter paper, Whatman No. 41, 5 mm in width and 35 mm in length, to quantify basal and reflex tear productions in a unit of time. The paper is carefully placed on the junction of the middle third and the lateral margin of the lower eyelid towards the temporal angle [23]. For the SS criterion, it is considered positive if ribbon wetting reaches ≤5 mm in 5 min. The possibility of modifying the cut-off Schirmer’s I test has been studied to see how good the tape with ≤10 mm in 5 min would perform. This modification resulted in increases of 78 % in sensitivity and 82 % in specificity for the diagnosis of SS. To evaluate basal tear secretion, it should be instilling a drop of anesthetic drops before the test was considered having a normal value ≤5 mm in 5 min [23]. It showed a sensitivity of 60 % and a specificity of 88 % [24–26]. The breakup time of the tear film (BUT) is measured 2 min after the application of the fluorescein dye, using the slit lamp. The patient is instructed to blink three times to evenly spread

the dye over the ocular surface. It is defined as the time in seconds between the last blink and the appearance of the patient’s dry spot on the surface of the cornea. It needs to be measured three times using a stopwatch, and the average of the three measurement values is used. It is considered abnormal if it is less than 10 s. This test shows a good correlation with the Schirmer’s test [27]. The rose bengal test evaluates the corneal-conjunctiva involvement using a slit lamp and white light reddish-pink blush identifies cells of the corneal epithelium and conjunctival that are suffering or devitalized. It is considered abnormal if more than four points are observed according to the Bjsterveld scale. The rose bengal stain is able to differentiate SS from keratoconjunctivitis sicca [28, 29], however, it presents toxic effects to surface epithelial cells of the cornea and conjunctiva [30]. The lissamine green test is equivalent to rose bengal assay, but it is less irritating to the cornea and is more comfortable for the patient (Fig. 1). One drop of dye should be applied in the bottom of the lower conjunctival sac of both eyes, and immediately after installation, examination is done using slit lamp with white light or red filter [31, 32]. The fluorescein test assesses the cornea of the patient as well as flushing epithelial defects. Assessment with the slit lamp should be performed 4–8 min after the dye installation with a blue cobalt light to identify punctate epithelial erosions. The maximum possible score is 6, and the test shows good clinical correlation [33, 34]. For aqueous tear film deficiency, changes in upper and lower parts of the cornea were more predictive than in the overall cornea [35] (Fig. 2). The Sjögren’s International Collaborative Clinical Alliance (SICCA) recommends the combination the lissamine green test to evaluate the severity of the commitment of the conjunctiva with the fluorescein test for corneal involvement. Using both assays, the SICCA group created a score for SS diagnosis called ocular staining scores (ocular staining score or OSS). The abnormal OSS≥3 out of 12 for each eye presented sensitivity of 89.7 % and specificity of 37.8 % for SS [36]. The test of fern leaf (ferning test) assesses the pattern of crystallization of tear when placed on a glass slide. It is considered normal when it forms a fernlike pattern. The absence of this pattern indicates primary deficiency of mucin in the tear film [37]. Dry eye patients rarely exhibit patterns I and II that are considered normal in a comparative study of patients with Sjögren’s syndrome and normal controls. The presence of patterns III, IV, and V demonstrated a sensitivity of 90 % and specificity of 88 % for DED [38]. The test of corneal sensitivity is performed with the Cochet-Bonnet esthesiometer consisting of nylon filaments of different lengths; pressures higher than 0.57 g/mm2 at five different points in the cornea are regarded as abnormal values [38]. Hypoesthesia after mechanical, thermal, and chemical

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Fig. 1 a Rose bengal staining in severe dry eye. b Lissamine green in moderate dry eye

stimuli is observed in patients with dry eye, and this observation correlates with the results of other assessment tests [39]. Cytology of the ocular surface shows changes in the conjunctival surface, especially the number, size, and shape of goblet cells through a cellulose acetate paper smear [40]. Other ways of assessing tear are through osmolarity measure, protein profile, and the presence of extracellular DNA, which are found to be helpful in diagnosing systemic diseases such as SS [41–43]. A recent study showed that corneal epithelial thickness measured by optical coherence tomography (OCT) increases in patients with dry eye compared with the control group. The OCT can also be used to measure the height of the tear film, which is impaired in patients with aqueous tear deficiency film; such examination has good clinical correlation with other parameters such as the tear film BUT and fluorescein test [44]. The tear osmolarity test may be carried out by various methods, with a high osmolality value usually found in all types of dry eye. There are devices that can measure

osmolarity of the tear in 20 s, with a cut-off of 308 mOsm/ ml but with variations of 8 mOsm/ml between two measurements being suggestive of the DED diagnosis [45]. Decreased levels of proteins, such as lysozyme and lactoferrin are also related to tear deficiency. Elevated levels of metalloproteinase-9 in tear are found in patients with aqueous and lipid tear deficiency. Many researchers are studying over 1,540 different proteins existing in tears, with the hope of finding possible diagnostic and therapeutic options in the future [41–43]. There is no gold standard for the evaluation of dry eye. In 2006, a Delphi panel of experts agreed that DED severity is an important parameter for the therapeutic decision [46]. Recently, the European multinational ODISSEY Consensus Group, formed by ocular surface experienced ophthalmologists, established a practical guide for dry eye diagnostic algorithm. This guide suggests that a combination of two criteria, including the presence of symptoms (OSDI≥33) and the corneal fluorescein staining (≥3), is sufficient to diagnose SS. If no or only mild symptoms are observed, they recommended the combination of at least two objective tests [47]. In studies of therapies for dry eye symptoms, 75.5 % used symptom questionnaires, 69.4 % used ocular surface staining, 55.1 % utilized the Schirmer’s test, and 51 % BUT [48]. Therefore, OSS and Schirmer’s test parameters are the most widely used, but the BUT has a better accuracy (Table 1).

Treatment

Fig. 2 Examination with fluorescein 1 % at the slip lamp with cobalt blue light. a Mild dry eye. b Moderate dry eye. c Severe dry eye

Strategies for treating DED have recently been modified and include patient education, lacrimal substitute, antiinflammatories, secretagogues, fatty acids, and antioxidants.

292 Table 1 Comparison of diagnostic tests for keratoconjunctivitis

LR likelihood ratio, CI confidence interval

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TEST

Sensitivity (%)

Accuracy

LR (95 % CI)

Schirmer I Test [86]

76.9

72.4

74.5

2.75 (95 % CI 1.97–3.83)

Tear breakup time [36]

82

86

84

5.86 (95 % CI 3.57–9.60)

Rose bengal [86, 87] Lissamine green [26]

64.3 63

81.7 89

73 76

3.56 (95 % CI 2.28–5.54) 5.73 (95 % CI 3.22–10.20)

Fluorescein [26]

63

84

73.5

3.93 (95 % CI 2.45–6.32)

All these strategies are focused on symptomatic relief. The use of immune modulators, such as cyclosporine eye drops, is well established, and new biological therapies that consider the importance of the inflammatory process in the pathogenesis of dry eye have been tested. For untreated patients, the risk of ocular infection increases at considerable level, and the clinical course of the disease may proceed to infection, corneal ulceration, or blindness. The vast majority of studies were conducted in the last decade, including more than 5,000 individuals [48] but there is still great difficulty in managing moderate to severe DED. Figure 3 presents a flowchart with the evidence-based treatment of mild to severe dry eye. There are few studies about systemic treatments, most of those in SS patients (Table 2). The main approach to dry eye is symptom relief, using lacrimal substitute, which are able to improve dry eye and the functional testing. The ideal lacrimal substitute should be similar to the composition of the tear and preservatives-free. Eye drops containing glucans, such as sodium hyaluronate (0.1–0.4 %) and carboxymethylcellulose (0.5 %) were tested in several clinical trials and found effective, acting better than saline solutions [68–71]. Frequency of use should be at least four times a day. Gel formulations are long lasting and more effective. Nighttime use is recommended, but

Fig. 3 Flow-chart for the treatment of dry eye

Specificity (%)

Mild

more frequent use can be done daily, in cases of moderate to severe dry eye that are very symptomatic. Topical cyclosporine was tested in 14 clinical trials involving 2,241 patients with dry eye, including 1,451 patients with Sjögren’s syndrome, with moderate to severe symptoms, during 1–12 months of follow-up. Marked improvements were observed in the scores of corneal staining, and the Schirmer’s test score as well as the symptom of blurred vision [72–77]. Burning eye sensation was the main adverse effect reported. Comparing the results of 0.1 and 0.05 % concentrations, the lowest concentration is found to be as effective and better tolerated. It is recommended for twice a day use, for a period of 6 to 12 months. With the local administration of cyclosporin A (CsA), the expectation is to obtain an effective drug concentration at the target area and avoid various side effects associated with systemic immunosuppression. Microspheres, implants, and liposomes have been developed for the administration of CsA subconjunctivally to enhance its efficiency [77]. Topical corticosteroids (fluorometholone, clobetasone, loteprednolol, and methylprednisolone) are useful for the symptomatic relief of dry eye or as the initial treatment. However, its use should be limited to only a few weeks because there is an increased risk of developing subcapsular cataracts [78, 79].

Moderate

Severe

Patient Education/Non-pharmacological treatment (4D) Tear substitute (preservative free) (1A) Essential fatty acids supplementation (2B)

Topical cyclosporine A (1A) Topical corticosteroid (1A) Secretagogues (muscarinic agonists) (2B) Punctual occlusion (1A)

Autologous serum (4C) Contact Lens (4D) Consider Systemic treatment, in special if SS Immunossupressant (4C) Biological erapy (2B) Surgery (4C)

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Table 2 Clinical trials for systemic treatment of dry eye in Sjögren’s syndrome patients Author/Year

Medicine/intervention

N

Papas 2004 [49]

Pilocarpine 20 at 30 mg/day

256 RCT

12

Significant relief of symptoms of dry mouth ocular symptoms

Petrone 2002 [50]

Cevimeline 15–30 mg 3×/day

197 RCT

12

Improvement of ocular and oral symptoms

Fife 2002 [51] Ono 2004 [52]

Cevimeline 30–60 mg 3×/day Cevimeline 20–30 mg 3×/day

75 60

RCT RCT

6 4

Improvement of ocular and oral symptoms Improvement of ocular and oral symptoms

Leung 2008 [53] Aragona 2005 [54]

Cevimeline 30 mg 3×/day 50 Linoleic acid 40 Gamma linoleic acid Flaxseed oil (Linun Ussitatissum) 38 1 vs. 2 g/day

RCT RCT

10 4

No improvement symptoms and OSDI Improvement of PGE1, da xerophthalmia, Schirmer

RCT

24

Improvement of symptoms (OSDI), Schirmer’s test, BUT and conjunctival impression cytology

Pinheiro 2007 [55]

Design

Duration Outcome/result (weeks)

Manthorpe 1984 [56] Ac. Gamalinoleic (efamol)

36

RCT

3

Improvement of Schirmer. No improvement of BUT, rose bengal and impression cytology.

Oxholm 1986 [57]

Ac. Gamalinoleic (efamol)

28

RCT

28

No improvement in Schirmer, BUT and rose bengal

Theander 2002 [58]

Ac. Gamalinoleic×Corn oil

90

RCT

24

Fox 1993 [59] Fox 1988 [60] Kruize 1993 [61]

Corticosteroid Hydroxichloroquine Hydroxichloroquine

16 40 19

RCT 24 Retrospective 52 Cross over 52

No improvement in fatigue, xerostomia, xerophthalmia, salivary flow, rose bengal, Schirmer, use of lubricant eye drops, No improvement Improvement of rose bengal and oral dryness No improvement of dryness, rose bengal, BUT, tear lysozyme and salivary scintigraphy

Yavuz 2011 [62]

Hydroxichloroquine

34

Retrospective 12

Sankar 2004 [63]

Etanercept 25 mg 2×/week

28

RCT

12

Mariette 2004 [64]

Infliximab 5 mg/kg

103 RCT

22

Meijer 2010 [65]

Rituximab 1 g 2× 2 weeks

30

RCT

18

DevauchellePensec 2010 [66] Carubbi 2013 [67]

Rituximab 375 mg/m2

15

Retrospective 36

Rituximab 1 g 2× 2 weeks

41

Prospective, controlled

120

Improvement of dry eye (symptoms, BUT, fluorescein, BAFF in the tear) There was no significant difference in the symptoms of ocular and oral dryness There was no significant difference in the symptoms of ocular and oral dryness Improvement of salivary flow and ocular stating score (Lissamine Green) No improvement Schirmer’s test improvement

RCT randomized controlled trial; BUT breakup time of the tear film; OSDI Ocular Surface Disease Index questionnaire; BAFF B-Cell Activating Factor; PGE1 prostaglandin E1

Occlusion of lacrimal puncta is indicated for moderate to severe dry eye that failed to improve with the use of tear substitute and topical cyclosporine. It can be done through surgical occlusion with silicone plugs or collagen implants. Plug extrusion is a common adverse event, while other complications, such as migration, canaliculitis, and infection, may also occur. There is no clear advantage in occluding both the superior and inferior points and just the inferior [80, 81]. Forty-two eyes of patients with primary Sjögren’s syndrome were analyzed after random allocation to the use of artificial tears or occlusion of lacrimal puncta. The values of the Schirmer’s test and the time of tear film BUT had better results with the use of plugs. In the assessment of contrast sensitivity, no significant differences between the two different treatments were found [81].

The fatty acids, in special omega-3, may have an antiinflammatory action and it seems to be useful for evaporative type of dry eye but its benefit is still controversial when the main pathogenic issue is production deficiency, like in SS. Flaxseed oil and omega-3 showed improvement in ocular tests, ocular discomfort, and increased PGE1 in preliminary studies [56–58]. Considering that they have low cost and have a good safety profile, fatty acids (1–2 g/day) could be prescribed for all cases. Pharmacological stimulation can be obtained by acetylcholine receptor agonists such as pilocarpine (M1 and M3 agonists) or cevimeline (M3 selective agonist). Although most studies in Sjögren’s syndrome have shown more benefit for dry mouth, there is also evidence that it can improve symptoms and measures of dry eye. Muscarinic agonists are

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contraindicated in closed-angle glaucoma and should be used carefully in asthma and heart disease patients [49–53]. In previous meta-analysis, acupuncture (one session= 30 min daily for 10 times) was more effective than artificial tears, applied six times a day for 30 days (response rates of 63 % vs 33 %; p=0.03) in improving tear BUT, Schirmer’s test results, and fluorescent spots on the cornea (p=0.02, p= 0.001, and p=0.03, respectively) [82]. In cases of very severe dry eye, there is an advantage in using autologous serum as the substitute for tears. No lubricant eye drops has active components in the formula, such as growth factors, vitamins, and immunoglobulins. Another disadvantage of using lubricants is that most have preservatives in their formula with are potentially toxic and may trigger allergic reactions. Although the majority of patients have good control of the disease using tear substitute only, in some cases, the symptoms and complaints persist despite the proper use of medication. Such patients have more severe disease and require optimized treatment. The benefits of autologous serum eye drops application were first described in SS patients by Fox in 1984 [83]. Currently, its use is recommended for cases of severe ocular surface changes, such as the SS, graft disease, neurotrophic keratitis, persistent epithelial defects, superior limbic keratoconjunctivitis, and ocular surface reconstruction. Besides improving ocular lubrication, autologous serum has similar pH and osmolarity of the tear, plus several components that allow maintenance of epithelial cell viability during the repairing process [83–88]. Autologous serum eye drops application produces a temporary benefit that lasts only during its use. Patients report improvement in symptoms within the first days of use, but the clinical improvement of the lesion tends to occur after the second week of use [89]. Studies with autologous serum 20 % in patients with severe dry eye showed improvement in signs and symptoms in relation to the use of lubricants with no preservatives for 2 weeks. Lacrimal substitute with autologous serum is safe for extended use [88, 89]. It

Fig. 4 Tarsorraphy in severe dry eye

Clinic Rev Allerg Immunol (2015) 49:288–297 Table 3 Patient education • Reassure the patient and explain that dry eyes usually does not progress to blindness • Explain that some medications could increase dryness, such as diuretics, beta blockers, antidepressants and anxiolytics; • Advise to use humidifiers environments; • Advise to avoid environments with air conditioning and dry climate; • Advise to suspension of consumption of caffeinated beverages, alcohol and tobacco; • Advise to avoid activities that reduce the act of blinking as long periods on the computer or prolonged readings; • Advise to wear goggles with side protection during exposure to wind or practice outdoor sports; • Explain how to remove makeup properly.

is generally well tolerated, and most patients experience improvement of the ocular discomfort [89, 90]. A major complication is immunoglobulin deposition in the cornea, which is the presence of peripheral corneal infiltrates, when used at a concentration of 100 % [91]. Some patients may present discomfort, mild epitheliopathy, bacterial conjunctivitis, and eyelid eczema.

Table 4 Main pharmacological and surgical recommendations for dry eye treatment 1. Lacrimal substitute improve comfort and functional tests (A). It must be hypotonic, having a greater colloidal osmolarity, and preservatives-free (D). 2. Ocular corticosteroids improve comfort and functional tests and may be used in more symptomatic cases for a limited period due to the risk of subcapsular cataracts (A). 3. Ocular cyclosporine 0.05 % BID for 6–12 months is effective in the symptomatic and functional improvement of dry eye and must be prescribed (A). Eye irritation is frequent even in the concentration of 0.05 %. Therefore, greater concentrations are not recommended. 4. Punctual occlusion improves the symptoms and the ocular lacrimal test results and is superior to lacrimal substitute (A). Plug extrusion is common, and complications, such as migration, canaliculitis, and infection, may occur. 5. Pilocarpine (5 mg, 3 TID) or cevimeline (30 mg, 3 TID) could improve dry eye symptoms and lacrimal test results (A). Attention must be given to contraindications for the use of muscarinic agonist, such as closed angle glaucoma, asthma, and heart diseases. 6. Supplementation of fatty acids can be used. It is effective for evaporative DED, but results are controversial for production deficiency (B). 7. Autologous serum can be used in severe and refractory cases. It has the advantage of being preservatives-free, and it is enriched with growth factors, immunoglobulins, and vitamins, thus favoring epithelial healing (C). 8. Tarsorrhaphy is an extreme option that could be used in very severe and refractory cases (D). 9. New topical immunomodulators, such as tacrolimus, tofacitinib, and IL1 receptor inhibitor, are being tested, and the results are promising (C).

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Tarsorrhaphy is a simple and safe procedure that is used as an extreme option in cases of very severe dry eye (Fig. 4). It includes temporary or permanent closure of the eyelids and can be accomplished in four ways: (1) short tarsorrhaphy sutures: eyelid closure with tape or glue (lasting a few days) or paralysis of the elevator muscles through local injection of toxin botulinum (lasting about 16 days); (2) temporary tarsorrhaphy suture: with or without cushion (lasting 4– 6 weeks); (3) Permanent tarsorrhaphy, which can be opened in the future: excision of the opposite eyelid margins, which h ea l t o ge t h er f or m i n g a s t r on g ad he s i o n . F i n al blepharorraphy: making tarsal flaps. Tarsorrhaphy palpebral fissure decreases the rate of evaporation of the tear film, allows a better distribution of the tear film on the epithelial defect, and decreases the effect caused by the mechanical motion of the injured eyelid corneal epithelium. There are many advantages of tarsorrhaphy on total occlusion, including increased oxygen supply to the epithelium, and the possibility of administering eye drops, partial view, and examination the injured eye [92, 93]. Certain treatment approaches are designed to modulate the underlying disease process. Cyclosporin A (CsA) is now frequently used for the treatment of moderate to severe DED. It is the first immunomodulatory topical agent that has an evident anti-inflammatory effect. Tacrolimus is another calcineurin inhibitor that inhibits the production of IL-2, which is already used for vernal keratoconjunctivitis, and corneal transplants, where it has been recently tested in pilot studies at 0.1 % concentration in topical formulation for dry eye patients [94]. Topical ophthalmic JAK-3 inhibitor tofacitinib may act as an immunomodulator in patients with DED. In a pilot study, treatment for 8 weeks showed a promising reduction of conjunctival cell surface HLA-DR expression and tear levels of proinflammatory cytokines and inflammatory markers [95]. Topical treatment with IL-1Ra was effective in ameliorating the clinical signs of dry eye disease, as well as in reducing underlying inflammation. These effects were comparable with those resulting from treatment with topical methylprednisolone. Topical IL-1Ra may hold promise as a novel therapeutic strategy in the treatment of dry eye [96]. Systemic immunosuppressant or biological therapy has been tested for dry eye treatment of SS patients (Table 2) [59–67]. In spite of not having evidence for using it routinely, maybe in some more severe cases, if the diagnosis is early in the evolution score, systemic treatment could be useful. Biologic agents like rituximab, abatacept, and belimumab [97–99] are promising and should be tested in large and randomized controlled trials. Main topics for patient education are presented in Table 3. Evidence-based recommendations of pharmacological and surgical treatment are summarized in Table 4 of this review.

295 Conflict of interest The authors declare that they have no conflicts of interest concerning this article.

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