ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Treatment of moderate to severe dry eye in Sjögren’s disease

Treatment of moderate to severe dry eye in Sjögren’s disease
Literature review current through: Jan 2024.
This topic last updated: Mar 07, 2022.

INTRODUCTION — Sjögren’s disease (SjD) is a chronic multisystem inflammatory disorder characterized by diminished lacrimal and salivary gland secretion, resulting in dry eye and dry mouth. A variety of other disease manifestations may also be present, including ocular or systemic extraglandular features.

The term "keratoconjunctivitis sicca" was coined by Henrik Sjögren in 1933 to describe the ocular surface disease resulting from severe aqueous tear deficiency in a series of 19 patients [1]. This term has been largely supplanted in the medical literature by "dry eye."

SjD may occur alone or in association with other autoimmune rheumatic conditions, including rheumatoid arthritis and systemic lupus erythematosus.

The treatment of moderate to severe dry eye in patients with SjD will be reviewed here. General principles of therapy, initial treatment, and the approach to mild dry eye in patients with SjD are discussed separately, as are other issues in SjD including the clinical manifestations and diagnosis of SjD, the treatment of dry mouth and other non-ocular sicca symptoms in patients with SjD, and the treatment of extraglandular manifestations of SjD. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Diagnosis and classification of Sjögren’s disease" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease" and "Overview of the management and prognosis of Sjögren's disease".)

Dry eye unrelated to SjD and an overview of dry eye, including the clinical manifestations, diagnosis, and management of dry eye unrelated to SjD, are also presented separately. (See "Dry eye disease" and "Diagnosis and classification of Sjögren’s disease", section on 'Dry eye and mouth in older adults' and "Diagnosis and classification of Sjögren’s disease".)

GENERAL PRINCIPLES — General principles important in the treatment of all patients with Sjögren’s disease (SjD) are described in detail separately. Among these is multidisciplinary care, including collaboration with an eye care clinician. The aims of therapy for dry eye are twofold: to provide relief of symptoms, including dryness, burning, a sandy-gritty sensation, ocular irritation, pain, ocular fatigue, fluctuating or blurred vision, and pressure behind the eye; and to prevent damage to the eye due to ongoing inflammation of the ocular surface, such as corneal epithelial erosions, sterile keratitis with or without ulceration, and, eventually, neovascularization and scarring of the cornea. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'General principles'.)

There are only a few large, well-designed, randomized trials that have evaluated the ability of specific treatments to improve dry eye signs and/or symptoms ("xerophthalmia") in patients with SjD. No studies have assessed the ability of any form of treatment to prevent ocular complications such as corneal melt or sterile ulcers. In 2016, a consensus panel provided recommendations for the evaluation and management of dry eye specifically associated with SjD [2]. Similarly, an evidence-based review of therapies and management options for all forms of dry eye was published in 2017 by the Tear Film & Ocular Surface Society [3].

Our general approach is based upon the available data from published studies, as well as our clinical experience, and is generally consistent with previous consensus recommendations [2-5]. The choice of therapies depends upon the severity of the disease. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Initial therapy and mild disease' and 'Moderate disease' below and 'Severe disease' below.)

The management of dry eye disease is typically staged, beginning with treatments that are low risk, readily accessible, and inexpensive; then proceeding to those that are more advanced if the patient's symptoms and/or ocular signs do not improve with the simpler measures. Treatment decisions for dry eye are predicated not only on severity of symptoms and signs but also on whether or not there is an underlying ocular or systemic inflammatory/autoimmune disease (eg, SjD, graft-versus-host disease, sarcoidosis, atopy, rosacea) that is likely to be progressive. Successful management requires serial detailed slit lamp examinations to assess ocular surface integrity and tear film stability.

INITIAL THERAPY AND MILD DISEASE — Initial management in all patients should focus on symptomatic relief and prevention of ocular surface damage. Such treatment may be sufficient in patients with mild or only episodic discomfort and in those with only mild signs of local disease, such as mild corneal and or conjunctival staining or mildly increased tear osmolarity. These strategies, which are generally applicable to patients with moderate and more severe disease as well, are described in detail separately. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Initial therapy and mild disease'.)

Briefly, these include:

Patient education regarding the disease and its complications, including counseling regarding home, workplace, and other environmental factors that may worsen symptoms; self-management techniques for tear conservation; and instruction regarding the signs and symptoms of blepharitis, which are distinct from those of aqueous tear deficiency and require daily eyelid hygiene measures using warm compresses and lid scrubs for relief.

Avoidance of prescription and nonprescription systemic medications that may cause or exacerbate symptoms [6]. Many of these agents have anticholinergic effects (table 1).

Use of preservative free artificial tears as needed for relief of symptoms of ocular discomfort.

Attention to ocular exposure and care in patients undergoing surgical procedures and avoidance of selected ophthalmologic surgical procedures in patients with untreated Sjögren’s disease (SjD).

Patients with mild symptoms without significant ocular surface or tear film findings should be evaluated annually to monitor disease stability.

MODERATE DISEASE

Definition and general approach — In patients with episodic or chronic symptoms that regularly interfere with visual function (even in the absence of environmental stress), additional measures and some changes in topical therapies are usually required while continuing initial preventive measures. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Initial therapy and mild disease'.)

Signs of disease in these patients are not always present. When present, they may include variable corneal or conjunctival staining, mild debris in the tear film or decreased breakup time, increased tear osmolarity, or an abnormal Schirmer test, which is a test done to measure tear production. (See "Diagnosis and classification of Sjögren’s disease", section on 'Tests for dry eye'.)

The management of such patients includes:

Regular (every two to four hours) use of preservative free artificial tears. We suggest use of a lubricating ointment at night for these patients; a daytime gel formulation may be tried if relief is inadequate with artificial tears and an ointment at night. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Artificial tears' and 'Lubricant ointments' below.)

Patients should not instill artificial tears "as often as possible" due to the ability of each drop application to disturb the homeostasis of the existing tear film.

Use of topical cyclosporine or lifitegrast with or without an initial topical steroid. The latter should be prescribed in collaboration with an ophthalmologist, as frequent measurement of intraocular pressure must be performed during this treatment. Topical steroids should only be used for short periods to avoid well-known complications such as cataracts and glaucoma. (See 'Topical cyclosporine' below and 'Topical lifitegrast' below and 'Topical steroids' below.)

Use of punctal plugs for patients with moderate to moderately severe disease who do not respond adequately to artificial tears, topical lubricants, and topical cyclosporine and lifitegrast. (See 'Punctal occlusion' below.)

Vigorous treatment of meibomian gland dysfunction, which frequently coexists with the aqueous tear deficiency of Sjögren’s disease (SjD) and results in evaporative tear loss [7]. Patients benefit from eyelid scrubs using commercially available pads or simply baby shampoo and warm compresses; in addition, some patients may benefit from in-office treatments, including microblepharoexfoliation and forceful expression of meibum after heating the glands. Heating techniques may include intense pulsed light treatment and thermal pulsation. Intraductal probing of the glands should be reserved for patients with severe gland inspissation. Adding oral macrolide or tetracycline antibiotics can also be helpful in patients with significant meibomian gland disease.

We generally do not prescribe an orally administered secretagogue such as pilocarpine or cevimeline for dry eye alone in the absence of dry mouth since patients experience hypersalivation. However, among SjD patients with moderately severe dry eye, this discordance in ocular and oral disease is uncommon, and orally administered secretagogues can provide symptomatic relief and decrease ocular dryness [8-10]. (See "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease".)

Lubricant ointments — At night, a longer-acting petroleum-based lubricant ointment is useful for patients with moderate to severe disease because it reduces the rate of tear evaporation; it may also cause blurring, which limits daytime use. Only a small amount (such as 1/8 inch [2 to 3 mm]) should be used. Patients using lubricant ointments at night can clean their eyes using warm water and diluted baby shampoo (about 1 part in 300) in the morning to prevent blurred vision. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Potential harms' and "Blepharitis", section on 'Lid washing'.)

Topical antiinflammatory/immunomodulatory agents — We use a topical antiinflammatory/immunomodulatory agent, such as cyclosporine or lifitegrast, in patients with persistent symptoms or signs of dry eye disease despite the regular use of artificial tears and lubricants alone (see 'General principles' above and 'Definition and general approach' above). We recommend topical cyclosporine as the initial choice, given its long track record of safety and efficacy, and use it at the starting dose of twice daily for a period of three months before considering a dose increase in patients with persistent symptoms or signs (eg, persistent ocular surface staining). (See 'Topical cyclosporine' below.)

In patients with moderate to severe dry eye (significant corneal and/or conjunctival staining), we often use a starting dose of four times daily and may supplement with a topical steroid drop (in collaboration with the patient's ophthalmologist) for several weeks to suppress the inflammation quickly and alleviate the ocular discomfort sometimes associated with the initial use of topical cyclosporine. We typically treat patients with persistent symptoms or signs with topical cyclosporine in doses up to four times daily for a year before considering it a treatment failure. (See 'Topical cyclosporine' below.)

We switch to topical lifitegrast in patients on topical cyclosporine who have persistence of symptoms or moderately severe corneal staining or who experience undue discomfort with its instillation. (See 'Topical lifitegrast' below.)

Although there have been no head-to-head comparisons, topical lifitegrast may provide more rapid relief of symptoms and less ocular irritation than topical cyclosporine [11]. However, long-term efficacy and safety have only been established for topical cyclosporine. Lifitegrast is not approved by the US Food and Drug Administration (FDA) for individuals under the age of 18. The combined use of these two drugs has not been studied and thus cannot be advised.

Topical cyclosporine — Topical cyclosporine (0.05% ophthalmic emulsion or 0.09% nanomicellar formulation in single-use vials) is administered as one drop twice daily and can be used together with artificial tears. However, the efficacy increases substantially with more frequent daily dosing [12,13]. Use is contraindicated in patients with active ocular infections. Plasma cyclosporine levels are generally undetectable with the use of the 0.05% ophthalmic emulsion, even with eight times a day dosing [12,13]. A preservative free multidose preparation of cyclosporine 0.05% is also available for patients who have difficulty using the vials. Responses may take two to three months and sometimes up to a year in some patients [13]. Accordingly, we typically treat patients with persistent symptoms or signs with topical cyclosporine in doses up to four times daily for a year before considering it a treatment failure.

Cyclosporine drops can be prescribed by nonophthalmic health care professionals because of the minimal risk of adverse effects. Ocular stinging or burning and blurred vision are the most frequently reported treatment‐related adverse events [14]. Serious adverse events were not reported in 30 clinical trials [14]. In patients with "burning" symptoms as a side effect of topical cyclosporine, topical steroids (prescribed by an ophthalmologist) may be used to alleviate symptoms during the initial phase of treatment; the steroid drops can generally be tapered and discontinued over several weeks [15-17]. (See 'Topical steroids' below.)

We generally try cyclosporine drops prior to tear duct occlusion, as this procedure is invariably associated with a transient decrease in aqueous tear secretion [18]. Initial use of cyclosporine prior to tear duct occlusion might have an additional benefit of decreasing the local level of inflammatory mediators while avoiding risk of high local concentrations of such mediators and metalloproteinases that may result from occlusion without adequate antiinflammatory therapy. Although the initial phase III trials of topical cyclosporine did not show benefit in the subgroup of patients with punctal occlusion, the combination of both cyclosporine and punctal occlusion may be of greater benefit than either treatment alone [13,19]. (See 'Punctal occlusion' below.)

The benefits of topical cyclosporine for patients with SjD were shown in a series of randomized trials, which compared it with placebo and with artificial tears, and also in observational studies [12,20,21]. Clinical benefits in both subjective and objective measures of dry eye and in changes in the corneal surface occur in approximately 60 to 75 percent of patients with twice-daily dosing, and treated patients show a decrease in infiltrating T cells in conjunctival biopsies and increase in goblet cell numbers in histology [12,13,22-24].

In a systematic review of 30 randomized trials assessing efficacy of topical cyclosporine in all forms of dry eye (regardless of age, sex, severity, etiology, or classification of the dry eye), the benefits of the drug on dry eye symptoms and signs were inconsistent and did not always exceed that of the vehicle or artificial tear control for the time period of the clinical trial [14]. These and other observations have prompted several authors to challenge the widespread use and attendant cost of topical cyclosporine in the United States [25,26]. On the other hand, use of cyclosporine has been supported by evidence-based reviews of dry eye treatments conducted by the Tear Film & Ocular Surface Society and the Sjögren's Foundation [2,3,27].

Examples of evidence supporting the effectiveness and limited adverse effects of topical cyclosporine include the following:

Among 877 patients randomly assigned to receive twice-daily instillation of cyclosporine (0.05 or 0.1%) or vehicle alone, there was improvement in objective measures (corneal staining and Schirmer testing) and subjective measures (blurred vision, need for concomitant artificial tears, and clinicians' global evaluation of response to treatment) at time points between three and six months [13]. As examples, the mean improvements in blurred vision and in artificial tear use after six months were greater for the patients using cyclosporine 0.05% compared with those using the vehicle alone (reductions of approximately 0.5 versus 0.1 to 0.2 on a four-point scale, and reductions of nearly one-half versus one-tenth to one-fifth of a drop/day, respectively). The clinician's subjective assessment of global response was improved in all groups at six months (slight response or better in 63 to 69 percent, and moderate response or better in 32 to 39 percent). There was no additional benefit of a higher dose.

The most common adverse effect was a mild to moderate, usually transient, burning sensation or stinging in the eyes after administration (18 percent of patients receiving cyclosporine [0.05% solution] versus 8 percent of controls); only 2 percent of patients in the cyclosporine or control groups discontinued treatment because of burning or stinging. Less frequent side effects were red eye, epiphora (excessive watering of the eyes), foreign body sensation, itching, and blurred vision.

Sustained benefit with continued use was shown in a study of 412 patients with moderate to severe dry eye disease in a one- to three-year extension of 6- to 12-month randomized trials in which patients had received 0.05 or 0.1% cyclosporine [28]. The response to cyclosporine 0.1% ophthalmic emulsion was examined during the extension (mean duration of treatment of 19.8 months). Most survey respondents reported that their symptoms had begun to resolve in the first three months of cyclosporine treatment. During the extension, further improvements in objective and subjective measures of dry eye disease were modest, presumably because of the prior treatment. No serious treatment-related adverse events occurred.

Among 744 patients randomly assigned to receive twice-daily instillation of the 0.09% nanomicellar formulation of cyclosporine or vehicle alone, the primary endpoint of the clinical trial was achieved (significantly greater percentage of eyes with an increase of 10 mm or more in the Schirmer test score) in the cyclosporine-treated group at day 84 [29]. Corneal and conjunctival staining also improved significantly, relative to vehicle. Patient-reported symptom scores were reduced after treatment in both groups, but mean changes from baseline were not statistically different between the two groups. Most adverse effects were rated as mild and related to instillation site pain (24 percent cyclosporine versus 4 percent vehicle).

The superiority of topical cyclosporine compared with artificial tears was shown in a trial involving a total of 150 patients, in which patients were randomly assigned to use preservative free artificial tears (containing 0.5% carboxymethylcellulose sodium) four times daily, together with either cyclosporine (0.05%) ophthalmic solution twice daily or vitamin A (retinyl palmitate, 0.05%) ophthalmic solution four times daily, or to receive the artificial tears alone [30]. Patients who received topical cyclosporine had improvement from baseline in blurred vision (from 1.21 ± 0.25 to 0.95 ± 0.19 [on a 0 to 4 scale] at month 3); in tear film breakup time (from 3.4 ± 1.3 to 5.9 ± 2 seconds at month 2); and in Schirmer testing (from 3.9 ± 1.2 to 7.3 ± 1.8 mm at month 3). The effects of cyclosporine and vitamin A were comparable, while the artificial tears alone did not result in statistically significant improvement compared with baseline.

In patients who have inadequate relief of symptoms and/or signs after three to four months of twice-daily treatment with topical cyclosporine, the frequency of administration may be increased to three or four times per day. In one case series, six of nine patients with SjD, without an adequate response after four months of twice-daily therapy, experienced improvement in objective measures of dry eye after two months of treatment with three or four times daily dosing [23]. We start patients with significant ocular surface staining on four times daily dosing. Patients will usually know if the medication (together with the topical steroid drops) will be tolerated within two weeks.

The indications for tapering or discontinuing cyclosporine drops have not been clearly defined. We generally continue this treatment until ocular surface staining has improved significantly and then only discontinue it if the risk of recurrence is low. These include SjD patients who have experienced no worsening of their ocular surface staining with the tapering of the cyclosporine and do not anticipate worsening of their environmental conditions, such as moving to a dry climate. In most SjD patients, the treatment is long term, although in other dry eye patients, long-term drug-free remission has been reported after topical cyclosporine treatment [31,32].

SjD patients with moderate dry eye should be seen twice yearly to monitor the ocular surface and tear film parameters, even in the absence of symptoms.

In addition to cyclosporine, other calcineurin inhibitors, including topical preparations of voclosporin, are under investigation in clinical trials [33]. Efficacy of voclosporin has been demonstrated for experimental dry eye in a mouse model [34].

Topical lifitegrast — Topical lifitegrast (5% ophthalmic solution) is administered as one drop twice daily and can be used together with artificial tears. We consider a trial of six to eight weeks long enough to assess the clinical response, as improvement was observed in the phase III clinical trials more rapidly than what has been reported for topical cyclosporine. The optimal duration of lifitegrast therapy has not been studied. As for topical cyclosporine, we generally continue topical lifitegrast until ocular surface staining has improved significantly and then only discontinue it if the risk of recurrence is low, as described above for cyclosporine drops. (See 'Topical cyclosporine' above.)

There are no available data regarding whether an increased dose is safe or effective in those with an inadequate response to the twice-daily dose. (See 'Topical cyclosporine' above.)

A 5% ophthalmic solution of lifitegrast was approved by the FDA in 2016 for treatment of the signs and symptoms of dry eye disease, based upon improvement in patients' symptoms and corneal staining score. Lifitegrast binds to lymphocyte function-associated antigen (LFA)-1, a protein on the cell surface of leucocytes, and blocks its interaction with its ligand, intercellular adhesion molecule (ICAM)-1. This molecular interaction of lifitegrast is thought to prevent T-cell activation and migration, thereby reducing ocular surface inflammation.

The benefits of topical lifitegrast for dry dye disease were demonstrated in four separate 12-week, randomized, vehicle-controlled trials comprising over 1000 adult subjects [35,36]. The principal outcome measures were reduction in dry eye symptoms, rated by patients using a visual analog scale, and improvement in inferior corneal fluorescein staining (ICSS) score. In three of the four trials, subjects randomized to lifitegrast showed significantly greater reduction in the eye dryness score at days 42 and 84 relative to vehicle alone. Lifitegrast-treated subjects also showed improvement in mean change of ICSS from baseline to day 84 versus placebo in three of the studies, but not the same three that showed improvement in symptoms. Tear flow, assessed with the Schirmer test, did not improve with lifitegrast treatment in the one phase 3 study in which it was assessed [37]. In a post-hoc analysis of two of these randomized trials, the subset of patients with moderate to severe dry eye disease had higher odds of achieving simultaneous improvement in clinical signs and symptoms when treated with lifitegrast versus placebo [38].

In all of the trials, lifitegrast was generally well tolerated. In a multicenter one-year safety study involving 331 subjects who received either lifitegrast or placebo, there were no serious ocular treatment-related adverse effects [39]. The proportion of subjects who experienced ≥1 ocular adverse effects was greater with lifitegrast (54 versus 34 percent); rates of lifitegrast and placebo discontinuation because of adverse effects were similar (12 and 9 percent). The most common adverse effects (ie, those seen in >5 percent of subjects) in either treatment group were instillation site irritation (burning), instillation site reaction, reduced visual acuity, dry eye, and dysgeusia. Ocular safety parameters for lifitegrast were similar to placebo. The mean plasma lifitegrast concentration at 360 days was below the limit of detection. There was no evidence of systemic toxicity or localized infectious complications secondary to chronic immunosuppression.

Topical steroids — In patients with moderate to severe disease and with signs of ocular inflammation who have not responded to artificial tears, lubricants, and topical cyclosporine or lifitegrast, topical steroids may be used in collaboration with an ophthalmologist for several weeks as pulse therapy. Topical steroids may also be helpful as temporary adjunctive therapy early in the course of topical cyclosporine or lifitegrast for faster symptom relief and alleviation of the burning or stinging that may occur with their initial use [15,17,40] (see 'Topical cyclosporine' above and 'Topical lifitegrast' above). As topical steroids have potential risks, they should be administered under the direction and continued supervision of an eye care professional. Treatment is usually of limited duration because of concern regarding adverse effects such as glaucoma and cataract formation [15,41]. An increase in intraocular pressure is a symptomless complication of topical steroid use and requires frequent pressure checks for detection.

Loteprednol etabonate ophthalmic suspension 0.25% is the only topical steroid approved by the FDA for dry eye disease, specifically for short-term treatment (≤2 weeks) [42]. Other therapeutic options include 0.5% loteprednol suspension and 0.1% fluorometholone suspension. Both are prescribed as one drop applied topically (in the conjunctival sac) four times daily for two to four weeks, followed by a gradual taper over several weeks to months. The risk of intraocular pressure elevation with topical steroid drops increases with prolonged use, more frequent administration, younger age, greater intraocular penetrance, and higher antiinflammatory potency. A maximum accepted duration of their use has not been established, due in part to these variables and inability to complete meta-analyses of existing data [41]. Although treatment of up to two years has been reported in retrospective studies of 133 Chinese [43] and 199 Korean patients with SjD [44], we do not use topical steroids for dry eye indication for any more than three months.

The use of topical steroids is based upon relatively limited data, including several small randomized trials of varying duration, a small number of uncontrolled case series, and clinical experience. The randomized trials used several different agents and included patients with both SjD and other inflammatory eye disorders. The degree of benefit varies. The range of evidence is illustrated by the following:

Two small randomized trials, in which benefit for moderate to severe dry eye patients was suggested by improvement within two weeks both in symptoms and in objective findings in patients given topical loteprednol etabonate or fluorometholone drops [17,45]. In one trial, loteprednol reduced symptoms, but both loteprednol and vehicle use resulted in a similar degree of improvement in the worst symptoms compared with baseline values (26 to 28 mm on a 100 mm visual analogue scale) [17]. Topical fluorometholone plus artificial tears reduced symptom severity compared with baseline and with artificial tears alone after both 15 and 30 days of treatment (approximately 50 percent reduction compared with baseline or placebo) [45]. Adverse events did not differ between treated and control patients in each of these studies.

A randomized trial compared the efficacy of fluorometholone drops with cyclosporine drops in 40 patients with SjD [46]. Both treatments were associated with improvements in corneal fluorescein staining and ocular symptom severity at eight weeks, although the topical fluorometholone provided faster improvement in both measures.

Four randomized trials compared the efficacy of loteprednol etabonate 0.25% drops with vehicle alone in a total of 2871 patients with dry eye disease. Use of artificial tears was not permitted during the trials. At day 15 of treatment, there were significantly greater reductions in ocular discomfort and conjunctival hyperemia severity with loteprednol than with its vehicle alone [42].

Two case series in which substantial relief of symptoms and improvement in objective measures were also seen within two weeks from use of nonpreserved methylprednisolone drops, with moderate or complete relief of symptoms of irritation [15,47]. In one study, adverse effects were noted in 3 of the 13 patients who had continued lower-dose treatment beyond two weeks after symptoms worsened with efforts at weaning; these included increased intraocular pressure (n = 1) and worsening or development of cataracts (n = 2) after three and six months of therapy, respectively [15].

Topical diquafosol is a P2Y2 agonist (a purinergic stimulator) and secretagogue for chloride ions that increases aqueous tear volume in animal models by directly transporting fluid across the serosal membranes of the ocular surface. It may also stimulate mucin secretion [48,49]. It is approved for the treatment of dry eye in Japan and South Korea [50].

Intranasal secretagogue — Varenicline is a cholinergic agonist in a nasal spray formulation that has been approved by the FDA for the treatment of dry eye disease [51]. In two 28-day, double-masked trials, a 10 mm or greater increase in tear production was more frequent in patients with dry eye disease treated with varenicline than with vehicle alone [51,52]. Sneezing, cough, throat irritation, and instillation-site irritation were the most common adverse effects. This intranasal drug treatment has not yet been compared with ophthalmic treatments for dry eye disease.

Punctal occlusion — We suggest punctal occlusion using punctal plugs or cauterization of the punctum in patients with moderate to severe ocular dryness and with abnormal ocular findings, in whom frequent instillation of artificial tears or lubricants is inadequate or impractical and appropriate use of topical cyclosporine and lifitegrast has not provided adequate relief.

We use punctual plugs in SjD patients with moderate dry eye in whom there is an expectation that the signs and symptoms of dry eye will improve with continued medical treatment. In these patients, the plugs can be removed or not replaced as the dry eye improves.

Cauterization of the punctum is reserved for those SjD patients, often older, with moderate to severe dry eye in whom there is no expectation of an improvement in tear volume. Alternatively, we may consider cauterization in patients who have failed topical therapies over the course of at least one year and in whom punctal plugs have provided benefit.

There is disagreement among experts regarding the type of punctal plug and the best timing for these procedures. Inflammation and local infection, such as blepharitis, should be controlled prior to performing these procedures to help avoid retention of proinflammatory tear components that could cause further injury [4,12]. The placement of punctal plugs should be done by eye care professionals. The topical immunomodulatory medications (cyclosporine or lifitegrast) should be continued following punctal occlusion.

Several different types of punctal plugs are available. We prefer silicone plugs, since they are hypoallergenic, durable, and easily removed if necessary. Temporary collagen punctal plugs are primarily used after corneal surgery to retain tears on the ocular surface for a limited period, such as refractive laser procedures. They often do not block the tear duct adequately and thus should not be used to judge whether occlusion of the tear ducts with permanent (eg, silicone) punctal plugs would be beneficial. Intracanalicular plugs are made of various different materials, including a bovine collagen and hydrogel.

The effectiveness of punctal occlusion has been shown in small randomized trials, including a trial in which occlusion was performed unilaterally in a randomly chosen eye and compared with the contralateral eye [53], and in uncontrolled studies in which comparisons were made with baseline assessments [54-56]. In these reports and in our experience, a majority of patients describe improvement in symptoms and a decreased need for artificial tears, although less than 25 percent of patients have improvement in an objective measure of dryness or corneal surface injury. About 25 to 35 percent of plugs are extruded during follow-up requiring reinsertion. In a study of 19 SjD patients who underwent partial lacrimal punctal occlusion of both eyes, there was improvement from baseline at 24 weeks and 24 months in Schirmer test values and ocular surface staining scores [57].

Complications of "permanent" (silicone) punctal plugs include local infections and pyogenic granuloma formation around the plugs; and plug extrusion or migration into the canaliculi [58,59]. The potential risk for lacrimal sac infection (eg, dacryocystitis) is a concern but is low. Discomfort may occur with plug insertion. Another complication in some patients is epiphora due to inadequate drainage.

When indicated, laser or handheld thermal cautery can be used for a permanent closure [60]. Closing the punctum with a surgical suture is also an alternative. Permanent closure of the tear duct should only be done if one is confident that it will not result in epiphora. Punctal occlusion is a tear preservation strategy; as a result, it is of little benefit unless supplemented with artificial lubricants in those with minimal to no tear production.

SEVERE DISEASE — Patients with frequent or constant symptoms should be managed initially using the measures described for mild and moderate disease, but they may not respond adequately to these approaches alone. Patients with severe disease may require intensification of therapies already being employed or additional interventions. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and 'Moderate disease' above.)

Signs of severe disease may include marked or severe punctate corneal erosions, filamentary keratitis, and significant conjunctival vital dye staining, low Schirmer levels, and significantly increased tear osmolarity.

For these patients, additional measures that may be employed, depending in part upon patient preference, include:

Use of topical cyclosporine, which may be increased to four times daily [23]. (See 'Topical cyclosporine' above.)

Topical steroids, under the direction of an ophthalmologist, followed by a gradual taper. (See 'Topical steroids' above.)

Hydroxypropyl cellulose ophthalmic inserts are a proprietary device for relief of moderate to severe dry eye. These rice-shaped inserts are placed in the inferior cul-de-sac of the eye where they release the demulcent over the course of the day and lubricate the ocular surface. Blurred vision is a potential side effect of their use.

Use of moisture goggles or other physical barriers for tear conservation. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Physical barriers'.)

Permanent punctal occlusion of all four ducts [61]. (See 'Punctal occlusion' above.)

Systemic antiinflammatory and immunomodulatory therapies. (See 'Systemic antiinflammatory and immunosuppressive therapy' below and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)

Other therapies, including certain types of therapeutic contact lenses (eg, monthly bandage soft contact lenses, Prosthetic Replacement of the Ocular Surface Ecosystem [PROSE]) and autologous serum tear preparations, which may be of benefit in selected patients. (See 'Therapeutic contact lenses' below and 'Autologous serum tears' below.)

Systemic antiinflammatory and immunosuppressive therapy — We generally do not use systemic antiinflammatory or immunosuppressive therapies for the treatment of sicca symptoms alone as first-line treatment. Several of these agents, alone or in combination, were efficacious in one small case series of four patients with severe keratitis in the context of active systemic rheumatic disease, including Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus [62]. (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Efficacy of specific therapeutic agents'.)

The following agents, which are sometimes used in patients with systemic or extraglandular disease, are sometimes beneficial as well for dry eye symptoms in patients with Sjögren’s disease (SjD):

Hydroxychloroquine (HCQ), which has shown mixed results. These include a study showing improvement in symptoms and objective measures of dryness and corneal surface findings in 50 to 60 percent of 40 patients who received HCQ (6 to 7 mg/kg/day) for 24 to 48 months [63]; a study of 32 patients treated for at least 48 months with HCQ, who were found to have worsening in dry eye symptoms and objective measures of dryness and corneal epithelial findings three months following discontinuation of therapy [64]; a small series of 21 patients showing statistically nonsignificant benefit in dry eye findings but significant benefit for dry mouth [65]; and a randomized two-year crossover trial involving only 19 patients that failed to demonstrate benefit in ocular symptoms or findings, despite some improvement in signs of inflammation including acute phase reactants and hyperglobulinemia [66]. In a randomized trial of HCQ in 120 patients, patient-reported dryness symptoms (assessed by a visual analog scale) and Schirmer test results did not show improvement from baseline when compared with placebo after only 24 weeks of treatment [67].

Rituximab, which has shown limited evidence of benefit for dry eye (or dry mouth), despite evidence of benefit for systemic and extraglandular manifestations of SjD. Some benefit was suggested in a randomized trial involving 30 patients in only one of three measures of lacrimal gland function (corneal staining with lissamine green, but not Schirmer testing or tear breakup time) and improvement in subjective scoring of ocular dryness compared with baseline values [68]. In another randomized trial involving 17 patients, there was no significant change in glandular function six months after administration of rituximab, and there was no improvement in Schirmer test scores or in the unstimulated salivary flow rate at that time point [69].

In the 24-week TEARS randomized trial of rituximab, involving 120 patients, there were no significant improvements in Schirmer test score and dryness symptoms in the patients who received rituximab compared with those who received placebo [70]. The TRACTISS randomized trial, involving 143 patients, was conducted for 48 weeks but also failed to show improvement in tear flow among the rituximab-treated patients compared with the placebo-treated patients [71]. In a prospective, two-center follow-up study of 41 patients with early active SjD, Schirmer test results were improved at 120 weeks in the 19 who received rituximab treatments every 24 weeks, relative to the 22 who received conventional disease-modifying antirheumatic drug (DMARD) therapy [72]. These findings need to be reproduced in a randomized trial, but they suggest that prolonged therapy with rituximab in early active disease is needed to realize meaningful clinical benefit.

Other medications that have been evaluated in patients with SjD without objective evidence of benefit include systemic glucocorticoids [73], methotrexate [74], leflunomide [75], azathioprine [76], infliximab [77], etanercept [78,79], abatacept [80], mycophenolate [81], and belimumab [82].

Other therapies — Several interventions may be of benefit in selected patients with severe disease. However, these approaches should only be prescribed under the direction and ongoing care of an ophthalmologist with particular interest and expertise in treating patients with dry eyes due to SjD. (See 'Therapeutic contact lenses' below and 'Autologous serum tears' below and 'Avoidance of topical NSAID drops' below.)

Autologous serum tears — Several randomized trials and other studies have shown that a dilution of patient's serum (termed "autologous tears") may be useful in patients with refractory dry eye [2,83-86]. Artificial tears prepared from umbilical cord serum have also been used in severely dry patients [87].

Therapeutic contact lenses — Large-diameter gas-permeable scleral contact lenses (PROSE) may be used in selected patients with severe dry eye [88]. These lenses are completely supported by the sclera and have a fluid reservoir in the space between the posterior surface of the lens and the anterior surface of the cornea [89,90]. They protect the ocular surface and provide continuous hydration of the ocular surface. The main indications for their use are improvement in visual acuity and protection of the ocular surface from the shearing forces of the eyelid on blink; they require a complex fitting process, and they are costly, which limit their availability.

Bandage contact lens use may result in symptomatic improvement; however, the risk of corneal infection is considerable.

Tarsorrhaphy — Tarsorrhaphy is a surgical procedure in which a part or all of the upper and lower eyelids are sutured together to protect the cornea [91]. This procedure is mostly applicable to dry eye patients with nonhealing corneal epithelial defects.

Avoidance of topical NSAID drops — Topical nonsteroidal antiinflammatory drug (NSAID) drops should never be used in patients with SjD-related dry eye due to potential risks such as corneal-scleral melts, perforation, and severe keratopathy [92].

INVESTIGATIONAL AGENTS — In addition to established immunosuppressive or immunomodulatory agents, there are other therapies requiring further study for which there is some evidence suggesting potential benefit. These include dietary fatty acid supplements, such as fish oil and evening primrose oil, and other investigational therapies.

Dietary fatty acid supplements — Omega-3 fatty acids may be beneficial in patients with dry eye, including those with Sjögren’s disease (SjD), but the evidence is mixed, and the degree of benefit from such supplements remains uncertain. We include omega-3 fatty acid supplementation as a self-management option for dry eye patients, including those with SjD, but caution patients that these are still investigational and without established benefit. A reasonable daily dose is from 1000 to up to 3000 mg daily, depending upon patient preference and tolerance. (See "Fish oil: Physiologic effects and administration".)

The optimal amount of dietary omega-3 supplementation needed for systemic antiinflammatory effects is not known. The American Heart Association recommends 1 g of omega-3 fatty acids per day from dietary sources, primarily oily fish [93]. Commercially available dietary supplements for dry eye contain 1000 to 1200 mg of omega-3 fatty acids in a daily dose, in compliance with US Food and Drug Administration (FDA) regulations that the labels of dietary supplements should not recommend a daily intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) higher than 2 g [94]. Intake of more than 3 g of omega-3 fatty acids from capsules may increase bleeding time by reducing platelet aggregation [95] or prolong clotting times when taken with warfarin [96].

Rationales for the use of omega-3-acid ethyl esters in dry eye relate to their possible antiinflammatory properties and contribution to the lipid layer of the eye, which retards evaporation and thus preserves the integrity of the tear film. In a randomized trial involving 535 patients with moderate to severe dry eye despite other therapies, omega-3 fatty acid supplements (fish-derived n-3 eicosapentaenoic and docosahexaenoic acid, 3000 mg daily) and placebo, used in addition to their background therapy, were both associated at one year with very similar and modest, yet clinically significant, improvements in symptom scores, ocular surface staining scores, and tear break-up times [97]. There was no improvement in Schirmer test results in either group. One-third of the trial participants had a systemic immune disease, including 56 patients with SjD, as well as patients with rheumatoid arthritis and thyroid disease; results for these patients did not differ from the group as a whole. Treatment was well tolerated, although diarrhea was more prevalent in the active treatment group.

Other evidence, including one large cohort study and other, mostly small, trials, has suggested that a diet enriched in omega-3 fatty acid consumption or omega-3 supplements is associated with a decreased incidence of dry eye [98-102]. The largest of these trials was in contact lens wearers [102].

In addition, oral preparations of omega-6 essential fatty acids, linoleic acid, gamma-linolenic acid [103]; and of evening primrose oil [104] each modestly improved ocular symptoms and/or signs in small randomized trials.

Other investigational therapies — Other investigational therapies include [33]:

Lacritin, which is a tear protein secreted by the acinar cells of the lacrimal glands. A formulation of this protein is being tested in patients with dry eye due to SjD [33,105].

Thymosin beta-4, a naturally occurring peptide in human tissues with wound-healing and antiinflammatory properties, which was evaluated as a topical treatment for severe dry eye disease in a randomized phase II trial of nine subjects [106]. Improvement of both signs and symptoms was observed.

TOP1630 is an investigational narrow-spectrum kinase inhibitor that simultaneously targets several kinases involved in innate and adaptive immune responses [107]. In a randomized phase II trial of 61 subjects, TOP1630 was associated with significant improvements in ocular symptoms and ocular surface lissamine green staining, relative to vehicle [108]. There were no serious adverse events.

RISKS OF OPHTHALMOLOGIC PROCEDURES — Patients with Sjögren’s disease (SjD) may be at increased risk compared with the general population if they undergo certain ophthalmologic procedures, including laser vision correction and blepharoplasty. These issues are described in more detail separately. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Risks of ophthalmologic procedures'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sjögren's disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Sjögren's disease (The Basics)")

Beyond the Basics topics (see "Patient education: Sjögren's disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Patients with dry eye related to Sjögren’s disease (SjD) benefit from multiple measures, including multidisciplinary care, attention to environmental factors, avoidance of medications that may exacerbate dryness, and attention to ocular exposure and care when undergoing surgical procedures. Certain ophthalmologic surgical interventions should be avoided in patients with SjD. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Tear conservation' and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Risks of ophthalmologic procedures'.)

For most patients with SjD, we recommend the regular use of artificial tears as needed rather than the use of interventions for tear conservation alone (Grade 1B). Identifying the agent that provides the most comfort for an individual patient is best determined by trying different agents. At night, a longer-acting lubricant ointment may be useful. Use of artificial tears more than four times daily requires switching to a preservative free preparation. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Artificial tears'.)

Meibomian gland dysfunction, which may complicate SjD and may be misinterpreted as an inadequate response to therapies, is important to differentiate from aqueous tear deficiency because it requires separate treatment rather than intensification of ocular lubricant therapy. Frequent instillation of topical lubricants can make meibomian gland dysfunction worse by depleting the oil layer of the tear film. (See 'Definition and general approach' above and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Potential harms' and "Blepharitis".)

For patients with moderate disease without sufficient symptom relief or with persistent ocular surface staining with the use of artificial tears and lubricants three or four times a day, we recommend the addition of a topical antiinflammatory/immunomodulatory agent (eg, cyclosporine or lifitegrast) rather than continued use with increased frequency of artificial tears and lubricants alone (Grade 1B). We typically use topical cyclosporine as the initial choice, given its long track record of safety and proven ability to improve tear flow. Topical lifitegrast is a reasonable alternative, particularly in patients with undue discomfort with instillation of cyclosporine. Topical cyclosporine (0.05% ophthalmic emulsion or 0.09% nanomicellar formulation) is administered as one drop (0.4 mL) twice daily. Topical lifitegrast (5% ophthalmic solution) is administered as one drop (0.4 mL) twice daily. Either agent can be used together with artificial tears. (See 'Topical antiinflammatory/immunomodulatory agents' above and 'Topical cyclosporine' above and 'Topical lifitegrast' above.)

In patients with moderate to severe disease who have not responded to combination of artificial tears and topical antiinflammatory/immunomodulatory treatment (cyclosporine and/or lifitegrast), topical steroids may be used judiciously for several weeks as pulse therapy. Topical steroids may also be helpful as temporary adjunctive therapy early in the course of topical cyclosporine or lifitegrast to ease the side effects of burning or stinging. Topical steroids have potential risks and they should be administered under the direction and continued supervision of an ophthalmologist or an optometrist with monitoring of intraocular pressures. Treatment is usually of limited duration because of concern regarding adverse effects such as glaucoma and cataract formation. (See 'Topical steroids' above.)

In patients with moderate to severe ocular dryness in whom frequent installation of artificial tears and the use of topical cyclosporine and lifitegrast is inadequate or impractical, we suggest punctal occlusion rather than using topical agents alone (Grade 2C). Punctal occlusion may help to maximize tear preservation and relief of symptoms in such patients. Inflammation should be controlled prior to punctal occlusion. (See 'Punctal occlusion' above.)

Patients with frequent or constant symptoms should be managed initially using the measures described for mild and moderate disease, but they may not respond adequately to these approaches alone. Patients with severe disease may require intensification of therapies already being employed or additional interventions. (See 'Severe disease' above and 'Investigational agents' above.)

Patients with SjD-related dry eye do not always report ocular discomfort, particularly if their ocular disease is advanced. Regular ocular examination with corneal and conjunctival dye staining is useful.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to an earlier version of this topic review.

  1. Sjögren H. Zur Kenntnis der Keratoconjunctivitis sicca. Keratitis filiformis bei Hypofunktion der Tränendrüsen. Acta Ophthalmol (Copenh) 1933; 1:151.
  2. Foulks GN, Forstot SL, Donshik PC, et al. Clinical guidelines for management of dry eye associated with Sjögren disease. Ocul Surf 2015; 13:118.
  3. Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. Ocul Surf 2017; 15:575.
  4. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006; 25:900.
  5. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Report Executive Summary. Ocul Surf 2017; 15:802.
  6. Fraunfelder FT, Sciubba JJ, Mathers WD. The role of medications in causing dry eye. J Ophthalmol 2012; 2012:285851.
  7. Sullivan DA, Dana R, Sullivan RM, et al. Meibomian Gland Dysfunction in Primary and Secondary Sjögren Syndrome. Ophthalmic Res 2018; 59:193.
  8. Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group. Arch Intern Med 1999; 159:174.
  9. Petrone D, Condemi JJ, Fife R, et al. A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren's syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum 2002; 46:748.
  10. Papas AS, Sherrer YS, Charney M, et al. Successful Treatment of Dry Mouth and Dry Eye Symptoms in Sjögren's Syndrome Patients With Oral Pilocarpine: A Randomized, Placebo-Controlled, Dose-Adjustment Study. J Clin Rheumatol 2004; 10:169.
  11. Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3). Ophthalmology 2017; 124:53.
  12. Foulks GN. Treatment of dry eye disease by the non-ophthalmologist. Rheum Dis Clin North Am 2008; 34:987.
  13. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology 2000; 107:631.
  14. de Paiva CS, Pflugfelder SC, Ng SM, Akpek EK. Topical cyclosporine A therapy for dry eye syndrome. Cochrane Database Syst Rev 2019; 9:CD010051.
  15. Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren syndrome. Ophthalmology 1999; 106:811.
  16. Pflugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye: a twenty-five-year review. Cornea 2000; 19:644.
  17. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol 2004; 138:444.
  18. Yen MT, Pflugfelder SC, Feuer WJ. The effect of punctal occlusion on tear production, tear clearance, and ocular surface sensation in normal subjects. Am J Ophthalmol 2001; 131:314.
  19. Roberts CW, Carniglia PE, Brazzo BG. Comparison of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. Cornea 2007; 26:805.
  20. Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, et al. Topical and systemic medications for the treatment of primary Sjögren's syndrome. Nat Rev Rheumatol 2012; 8:399.
  21. Ramos-Casals M, Tzioufas AG, Stone JH, et al. Treatment of primary Sjögren syndrome: a systematic review. JAMA 2010; 304:452.
  22. Tatlipinar S, Akpek EK. Topical ciclosporin in the treatment of ocular surface disorders. Br J Ophthalmol 2005; 89:1363.
  23. Dastjerdi MH, Hamrah P, Dana R. High-frequency topical cyclosporine 0.05% in the treatment of severe dry eye refractory to twice-daily regimen. Cornea 2009; 28:1091.
  24. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol 2000; 118:1489.
  25. Schwartz LM, Woloshin S. A Clear-eyed View of Restasis and Chronic Dry Eye Disease. JAMA Intern Med 2018; 178:181.
  26. Seitzman G, Lietman T. Dry Eye. N Engl J Med 2018; 379:e19.
  27. Akpek EK, Lindsley KB, Adyanthaya RS, et al. Treatment of Sjögren's syndrome-associated dry eye an evidence-based review. Ophthalmology 2011; 118:1242.
  28. Barber LD, Pflugfelder SC, Tauber J, Foulks GN. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 2005; 112:1790.
  29. Goldberg DF, Malhotra RP, Schechter BA, et al. A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease. Ophthalmology 2019; 126:1230.
  30. Kim EC, Choi JS, Joo CK. A comparison of vitamin a and cyclosporine a 0.05% eye drops for treatment of dry eye syndrome. Am J Ophthalmol 2009; 147:206.
  31. Wilson SE, Perry HD. Long-term resolution of chronic dry eye symptoms and signs after topical cyclosporine treatment. Ophthalmology 2007; 114:76.
  32. Straub M, Bron AM, Muselier-Mathieu A, Creuzot-Garcher C. Long-term outcome after topical ciclosporin in severe dry eye disease with a 10-year follow-up. Br J Ophthalmol 2016; 100:1547.
  33. Gupta PK, Asbell P, Sheppard J. Current and Future Pharmacological Therapies for the Management of Dry Eye. Eye Contact Lens 2020; 46 Suppl 2:S64.
  34. Alam J, de Souza RG, Yu Z, et al. Calcineurin Inhibitor Voclosporin Preserves Corneal Barrier and Conjunctival Goblet Cells in Experimental Dry Eye. J Ocul Pharmacol Ther 2020; 36:679.
  35. Lifitegrast (Xiidra) for dry eye disease. Med Lett Drugs Ther 2016; 58:110.
  36. Holland EJ, Whitley WO, Sall K, et al. Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials. Curr Med Res Opin 2016; :1.
  37. Sheppard JD, Torkildsen GL, Lonsdale JD, et al. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology 2014; 121:475.
  38. Holland EJ, Jackson MA, Donnenfeld E, et al. Efficacy of Lifitegrast Ophthalmic Solution, 5.0%, in Patients With Moderate to Severe Dry Eye Disease: A Post Hoc Analysis of 2 Randomized Clinical Trials. JAMA Ophthalmol 2021; 139:1200.
  39. Donnenfeld ED, Karpecki PM, Majmudar PA, et al. Safety of Lifitegrast Ophthalmic Solution 5.0% in Patients With Dry Eye Disease: A 1-Year, Multicenter, Randomized, Placebo-Controlled Study. Cornea 2016; 35:741.
  40. Byun YJ, Kim TI, Kwon SM, et al. Efficacy of combined 0.05% cyclosporine and 1% methylprednisolone treatment for chronic dry eye. Cornea 2012; 31:509.
  41. Musleh MG, Bokre D, Dahlmann-Noor AH. Risk of intraocular pressure elevation after topical steroids in children and adults: A systematic review. Eur J Ophthalmol 2020; 30:856.
  42. Loteprednol 0.25% (Eysuvis) for dry eye disease. Med Lett Drugs Ther 2021; 63:75.
  43. Jung HH, Ji YS, Sung MS, et al. Long-Term Outcome of Treatment with Topical Corticosteroids for Severe Dry Eye Associated with Sjögren's Syndrome. Chonnam Med J 2015; 51:26.
  44. Ahn H, Ji YW, Jun I, et al. Comparison of Treatment Modalities for Dry Eye in Primary Sjögren's Syndrome. J Clin Med 2022; 11.
  45. Avunduk AM, Avunduk MC, Varnell ED, Kaufman HE. The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study. Am J Ophthalmol 2003; 136:593.
  46. Lin T, Gong L. Topical fluorometholone treatment for ocular dryness in patients with Sjögren syndrome: a randomized clinical trial in China. Medicine (Baltimore) 2015; 94:e551.
  47. Hong S, Kim T, Chung SH, et al. Recurrence after topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren's syndrome. J Ocul Pharmacol Ther 2007; 23:78.
  48. Tauber J, Davitt WF, Bokosky JE, et al. Double-masked, placebo-controlled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye. Cornea 2004; 23:784.
  49. Ohashi Y, Munesue M, Shimazaki J, et al. Long-Term Safety and Effectiveness of Diquafosol for the Treatment of Dry Eye in a Real-World Setting: A Prospective Observational Study. Adv Ther 2020; 37:707.
  50. Keating GM. Diquafosol ophthalmic solution 3 %: a review of its use in dry eye. Drugs 2015; 75:911.
  51. Varenicline nasal spray (Tyrvaya) for dry eye disease. Med Lett Drugs Ther 2021; 63:198.
  52. Wirta D, Vollmer P, Paauw J, et al. Efficacy and Safety of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The ONSET-2 Phase 3 Randomized Trial. Ophthalmology 2022; 129:379.
  53. Mansour K, Leonhardt CJ, Kalk WW, et al. Lacrimal punctum occlusion in the treatment of severe keratoconjunctivitis Sicca caused by Sjögren syndrome: a uniocular evaluation. Cornea 2007; 26:147.
  54. Balaram M, Schaumberg DA, Dana MR. Efficacy and tolerability outcomes after punctal occlusion with silicone plugs in dry eye syndrome. Am J Ophthalmol 2001; 131:30.
  55. Gilbard JP, Rossi SR, Azar DT, Heyda KG. Effect of punctal occlusion by Freeman silicone plug insertion on tear osmolarity in dry eye disorders. CLAO J 1989; 15:216.
  56. Willis RM, Folberg R, Krachmer JH, Holland EJ. The treatment of aqueous-deficient dry eye with removable punctal plugs. A clinical and impression-cytologic study. Ophthalmology 1987; 94:514.
  57. Holzchuh R, Villa Albers MB, Osaki TH, et al. Two-year outcome of partial lacrimal punctal occlusion in the management of dry eye related to Sjögren syndrome. Curr Eye Res 2011; 36:507.
  58. Musadiq M, Mukherji S, Sandramouli S. Pyogenic granuloma following silicone punctal plugs: report of two cases. Orbit 2005; 24:149.
  59. Kim BM, Osmanovic SS, Edward DP. Pyogenic granulomas after silicone punctal plugs: a clinical and histopathologic study. Am J Ophthalmol 2005; 139:678.
  60. Cohen EJ. Punctal occlusion. Arch Ophthalmol 1999; 117:389.
  61. Vrabec MP, Elsing SH, Aitken PA. A prospective, randomized comparison of thermal cautery and argon laser for permanent punctal occlusion. Am J Ophthalmol 1993; 116:469.
  62. Cordero-Coma M, Anzaar F, Sobrin L, Foster CS. Systemic immunomodulatory therapy in severe dry eye secondary to inflammation. Ocul Immunol Inflamm 2007; 15:99.
  63. Fox RI, Dixon R, Guarrasi V, Krubel S. Treatment of primary Sjögren's syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus 1996; 5 Suppl 1:S31.
  64. Yavuz S, Asfuroğlu E, Bicakcigil M, Toker E. Hydroxychloroquine improves dry eye symptoms of patients with primary Sjogren's syndrome. Rheumatol Int 2011; 31:1045.
  65. Rihl M, Ulbricht K, Schmidt RE, Witte T. Treatment of sicca symptoms with hydroxychloroquine in patients with Sjogren's syndrome. Rheumatology (Oxford) 2009; 48:796.
  66. Kruize AA, Hené RJ, Kallenberg CG, et al. Hydroxychloroquine treatment for primary Sjögren's syndrome: a two year double blind crossover trial. Ann Rheum Dis 1993; 52:360.
  67. Gottenberg JE, Ravaud P, Puéchal X, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA 2014; 312:249.
  68. Meijer JM, Meiners PM, Vissink A, et al. Effectiveness of rituximab treatment in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010; 62:960.
  69. Dass S, Bowman SJ, Vital EM, et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis 2008; 67:1541.
  70. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med 2014; 160:233.
  71. Bowman SJ, Everett CC, O'Dwyer JL, et al. Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjögren's Syndrome. Arthritis Rheumatol 2017; 69:1440.
  72. Carubbi F, Cipriani P, Marrelli A, et al. Efficacy and safety of rituximab treatment in early primary Sjögren's syndrome: a prospective, multi-center, follow-up study. Arthritis Res Ther 2013; 15:R172.
  73. Fox PC, Datiles M, Atkinson JC, et al. Prednisone and piroxicam for treatment of primary Sjögren's syndrome. Clin Exp Rheumatol 1993; 11:149.
  74. Skopouli FN, Jagiello P, Tsifetaki N, Moutsopoulos HM. Methotrexate in primary Sjögren's syndrome. Clin Exp Rheumatol 1996; 14:555.
  75. van Woerkom JM, Kruize AA, Geenen R, et al. Safety and efficacy of leflunomide in primary Sjögren's syndrome: a phase II pilot study. Ann Rheum Dis 2007; 66:1026.
  76. Price EJ, Rigby SP, Clancy U, Venables PJ. A double blind placebo controlled trial of azathioprine in the treatment of primary Sjögren's syndrome. J Rheumatol 1998; 25:896.
  77. Mariette X, Ravaud P, Steinfeld S, et al. Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS). Arthritis Rheum 2004; 50:1270.
  78. Zandbelt MM, de Wilde P, van Damme P, et al. Etanercept in the treatment of patients with primary Sjögren's syndrome: a pilot study. J Rheumatol 2004; 31:96.
  79. Sankar V, Brennan MT, Kok MR, et al. Etanercept in Sjögren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum 2004; 50:2240.
  80. Baer AN, Gottenberg JE, St Clair EW, et al. Efficacy and safety of abatacept in active primary Sjögren's syndrome: results of a phase III, randomised, placebo-controlled trial. Ann Rheum Dis 2021; 80:339.
  81. Willeke P, Schlüter B, Becker H, et al. Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial. Arthritis Res Ther 2007; 9:R115.
  82. Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis 2015; 74:526.
  83. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjögren's syndrome. Br J Ophthalmol 1999; 83:390.
  84. Kojima T, Ishida R, Dogru M, et al. The effect of autologous serum eyedrops in the treatment of severe dry eye disease: a prospective randomized case-control study. Am J Ophthalmol 2005; 139:242.
  85. Fox RI, Chan R, Michelson JB, et al. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum 1984; 27:459.
  86. Pan Q, Angelina A, Zambrano A, et al. Autologous serum eye drops for dry eye. Cochrane Database Syst Rev 2013; :CD009327.
  87. Yoon KC, Heo H, Im SK, et al. Comparison of autologous serum and umbilical cord serum eye drops for dry eye syndrome. Am J Ophthalmol 2007; 144:86.
  88. Romero-Rangel T, Stavrou P, Cotter J, et al. Gas-permeable scleral contact lens therapy in ocular surface disease. Am J Ophthalmol 2000; 130:25.
  89. van der Worp E, Bornman D, Ferreira DL, et al. Modern scleral contact lenses: A review. Cont Lens Anterior Eye 2014; 37:240.
  90. Schornack MM, Pyle J, Patel SV. Scleral lenses in the management of ocular surface disease. Ophthalmology 2014; 121:1398.
  91. Valim V, Trevisani VF, de Sousa JM, et al. Current Approach to Dry Eye Disease. Clin Rev Allergy Immunol 2015; 49:288.
  92. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology 2001; 108:936.
  93. http://www.heart.org/HEARTORG/HealthyLiving/HealthyEating/Fish-101_UCM_305986_Article.jsp#aha_recommendation (Accessed on June 20, 2018).
  94. https://www.fda.gov/Food/LabelingNutrition/ucm073992.htm#cardio (Accessed on June 20, 2018).
  95. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (macronutrients). National Academy Press; Institute of Medicine, Food and Nutrition Board, Washington, DC, 2005.
  96. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother 2004; 38:50.
  97. Dry Eye Assessment and Management Study Research Group, Asbell PA, Maguire MG, et al. n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease. N Engl J Med 2018; 378:1681.
  98. Miljanović B, Trivedi KA, Dana MR, et al. Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr 2005; 82:887.
  99. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea 2003; 22:97.
  100. Wojtowicz JC, Butovich I, Uchiyama E, et al. Pilot, prospective, randomized, double-masked, placebo-controlled clinical trial of an omega-3 supplement for dry eye. Cornea 2011; 30:308.
  101. Kangari H, Eftekhari MH, Sardari S, et al. Short-term consumption of oral omega-3 and dry eye syndrome. Ophthalmology 2013; 120:2191.
  102. Bhargava R, Kumar P. Oral omega-3 fatty acid treatment for dry eye in contact lens wearers. Cornea 2015; 34:413.
  103. Aragona P, Bucolo C, Spinella R, et al. Systemic omega-6 essential fatty acid treatment and pge1 tear content in Sjögren's syndrome patients. Invest Ophthalmol Vis Sci 2005; 46:4474.
  104. Oxholm P, Manthorpe R, Prause JU, Horrobin D. Patients with primary Sjögren's syndrome treated for two months with evening primrose oil. Scand J Rheumatol 1986; 15:103.
  105. Vijmasi T, Chen FY, Balasubbu S, et al. Topical administration of lacritin is a novel therapy for aqueous-deficient dry eye disease. Invest Ophthalmol Vis Sci 2014; 55:5401.
  106. Sosne G, Dunn SP, Kim C. Thymosin β4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial. Cornea 2015; 34:491.
  107. Hagan S, Fyfe MCT, Ofori-Frimpong B, et al. Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders. Invest Ophthalmol Vis Sci 2018; 59:1443.
  108. Taylor M, Ousler G, Torkildsen G, et al. A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease. Clin Ophthalmol 2019; 13:261.
Topic 112281 Version 15.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟