Version May 2024
INTRODUCTION — Sjögren’s disease (SjD) is a chronic multisystem inflammatory disorder characterized by impaired lacrimal and salivary gland function with resultant dryness of the eyes and 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 with concomitant dry mouth and frequent deforming arthritis [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 general principles and initial treatment of dry eye in patients with SjD will be reviewed here. The treatment of dry eye in patients with moderate to severe involvement and 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, are discussed separately. (See "Treatment of moderate to severe dry eye in Sjögren’s disease" 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 — Patients with Sjögren’s disease (SjD) benefit from multidisciplinary care. An eye care professional should evaluate and manage the dry eye of SjD patients for a number of reasons. Several tests for diagnosing and monitoring dry eye, including ocular surface staining and the tear break-up time, require a slit lamp and therefore an ophthalmological examination (see "Diagnosis and classification of Sjögren’s disease", section on 'Tests for dry eye'). In addition, hydroxychloroquine therapy, if prescribed for systemic manifestations of the disease, needs to be monitored at least annually for potential retinal toxicity.
Once-yearly ophthalmologic evaluations suffice for those with mild dry eye. Measuring the tear film osmolarity can be performed by non-ophthalmologists as point-of-care testing and has been reported as useful to assess presence of dry eye [2,3]. Nevertheless, some studies have questioned its diagnostic value, citing the high variability of the test in healthy subjects [4] and in patients with dry eye [5,6].
Symptoms of ocular irritation may arise from multiple causes, not only aqueous tear deficiency, and these can be differentiated by an eye care professional through slit-lamp evaluations and require specific management. Some experts thus prefer the use of the term “dysfunctional tear syndrome” [7] rather than “dry eye” to reflect the inclusion of symptomatic patients who have abnormalities in tear film stability/composition but no reduction in tear volume. Over 80 percent of patients with SjD have concomitant meibomian gland dysfunction, and this requires recognition and specific treatment [8-10]. Finally, patients with SjD and severe dry eye disease are at risk of vision-threatening ocular complications, sometimes with minimal antecedent symptoms, and regular monitoring by an eye care professional is therefore warranted [11].
The aims of therapy for dry eye are twofold: to provide relief of symptoms, including dryness, burning, a sandy-gritty ocular irritation, pain, ocular fatigue, fluctuating or diminished vision, and pressure behind the eye; and to prevent damage to the eye due to ongoing inflammation of the ocular surface, such as sterile keratitis, epithelial erosions, neovascularization and ulceration of the cornea, and scarring of the conjunctiva.
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 in patients with SjD. No studies have assessed the ability of any form of treatment to prevent ocular extraglandular complications such as corneal melt or sterile ulcers. A 2017 systematic literature review summarized results of available published evidence with regard to treatment outcomes [12,13]. In addition, a 2016 consensus panel provided recommendations for the evaluation and management of dry eye associated with SjD [14].
Our general approach is based upon available data from published studies as well as our clinical experience and is generally consistent with previous consensus recommendations [7,14]. The choice of therapies depends primarily upon the severity of the ocular disease, rather than whether or not there is underlying SjD. However, SjD patients need more frequent monitoring as they may not always be symptomatic with worsening of their dry eye [15]. (See 'Initial therapy and mild disease' below and 'Moderate to severe disease' below and "Treatment of moderate to severe dry eye in Sjögren’s disease".)
INITIAL THERAPY AND MILD DISEASE — Initial management in all patients should focus on symptomatic relief and restoration of tear film homeostasis. 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 ocular surface staining or mildly increased tear osmolarity. Management includes:
●Patient education regarding the disease and its complications, including:
•Counseling regarding home, workplace, and other environmental factors that may worsen symptoms and self-management techniques for tear conservation (see 'Tear conservation' below and 'Environmental management' below)
•Instruction regarding the signs and symptoms of blepharitis, which are distinct from those of aqueous tear deficiency and require specific management techniques (see 'Potential harms' below)
●Avoidance of prescription and nonprescription systemic medications that may cause or exacerbate symptoms (see 'Avoidance of medications causing dryness' below)
●Use of artificial tears as needed for relief of symptoms of ocular discomfort (see 'Artificial tears' below)
Tear conservation — All patients with dry eye and Sjögren’s disease (SjD) should generally adopt measures for tear conservation. The use of medications that may worsen symptoms of dryness should be avoided, whenever possible. Physical barriers, such as large-frame glasses to minimize tear evaporation, can be helpful. Video display terminal use is associated with a decreased blink rate and increased incomplete blinks, and thus may worsen dry eye when prolonged [16-19]. The same is true for other activities requiring prolonged visual attention, such as reading and driving. Frequent, short breaks and additional longer breaks from these activities may be beneficial; other proposed therapies include efforts to increase the blink rate and the increased use of artificial tears. However, the degree of benefit of these interventions for dry eye related to computer use and other forms of prolonged visual attention is uncertain [19] (see 'Artificial tears' below). The use of these strategies is widely supported by experts in dry eye and is consistent with our clinical experience [7,20,21]. However, formal study of the effectiveness of these techniques is lacking, although they have no foreseeable clinically significant risks. (See 'Environmental management' below and 'Avoidance of medications causing dryness' below and 'Physical barriers' below.)
Environmental management — Exposure to environments that exacerbate dry eyes should be minimized, and preventive strategies should be employed when such avoidance is impractical. Artificial tears should be used regularly to help prevent complications and to increase comfort before entry into dry environments and then with increased frequency as compared with use in more humid environments. (See 'Artificial tears' below.)
The following environments may be problematic:
●Dry or windy outdoor environments
●Dry indoor environments
●Areas with polluted air and other irritants, including the presence of smokers
●Hospital operating and recovery rooms [22] (see 'Perioperative management' below)
The use of humidifiers is helpful in bedrooms and other rooms in which the patient spends a lot of time. The regular use of warm compresses over the eyes can also provide symptomatic relief by improving meibomian gland secretions.
Perioperative management — An ocular lubricant should be used as a preventive measure prior to surgery. During any surgery requiring general anesthesia, it is important to prevent ocular drying by instilling an over-the-counter ocular ointment and then gently taping the eyelids shut.
In addition, patients should be allowed to bring their topical medications for dry eye from home if they are unavailable in the hospital; these medications should be available as needed.
The level of humidity in operating rooms and in postoperative units may be very low, which increases the risk of dry eye complications, including corneal abrasions. Dryness is also worsened when non-humidified oxygen is administered by facemask. (See "Treatment of moderate to severe dry eye in Sjögren’s disease", section on 'Lubricant ointments'.)
Certain ophthalmologic surgical procedures may also pose special risks. (See 'Risks of ophthalmologic procedures' below.)
Avoidance of medications causing dryness — Medications used for treatment of other conditions (eg, antidepressants, antihistamines, anticholinergics, diuretics, and neuroleptics) may worsen symptoms of dryness [23], and alternatives should be sought whenever possible. The degree to which such medications are relatively contraindicated depends upon the severity of disease for which the drug is being administered and upon the amount to which the drug worsens dryness in the dose used in a given patient. The use of multiple drugs that, individually, may have modest drying effects can also be problematic.
Dryness of the eyes is often caused by the use of drugs with anticholinergic side effects, such as the tricyclic antidepressants and many others (table 1) [23]. The range of medications and the adverse effects of drugs with anticholinergic activity are discussed in detail separately (see "Drug prescribing for older adults", section on 'Anticholinergic activity'). In addition, potent oral analgesics can decrease corneal sensitivity and thereby exacerbate dry eye.
Chronic use of prescription eyedrops (such as medications for glaucoma) that contain preservatives may also be bothersome for patients with SjD. Thus, dry eye patients who require these medications may need to switch to preservative-free formulations and use preservative-free artificial tears. (See 'Choice of formulation' below.)
Physical barriers — Moisture-conserving eyewear can be employed to conserve the tear film. These may be most helpful in particular situations, such as when traveling into dry and/or windy environments such as airplanes or long air-conditioned car rides, during which humidity is low; and while exercising, especially jogging or biking, during which increased air movement on the ocular surface and decreased blink rate are encountered.
Examples of moisture-conserving eyewear include:
●Side shields, which can be fitted to glasses, reducing the evaporation rate of normal or artificial tears
●Wraparound sunglasses, which are more socially acceptable to many patients than goggles
●Ski or swim goggles, which also reduce evaporation
However, the use of such physical barriers is often socially unacceptable, except to more severely affected patients when other measures are insufficient and to those with frequent or persistent exposure to adverse environments.
Certain types of custom-made, large-diameter contact lenses (eg, Prosthetic Replacement of the Ocular Surface Ecosystem [PROSE]) may benefit selected patients with severe dry eye [24] but are generally not used in patients with mild disease. Bandage contact lenses facilitate symptomatic improvement but may increase the risk of corneal infection and should only be used short-term for non-healing corneal epithelial issues. Contact lenses, other than bandage lenses, should never be worn overnight (see "Treatment of moderate to severe dry eye in Sjögren’s disease", section on 'Therapeutic contact lenses'). In addition, contact lenses only protect the cornea. The conjunctiva, responsible for making the mucin layer of the tear film, is left unprotected.
Artificial tears — We recommend the regular use of artificial tears in most patients with SjD, including patients with all levels of disease severity. Patients may select these from the many available tear preparations, which differ in their composition, preservatives, osmolarity, and viscosity [20,25], and which are typically available without prescription (see "Artificial tears (Ophthalmic lubricants: solutions, gels, ointments): Drug information" and "Hydroxypropyl methylcellulose: Drug information"). Patients should try several different agents to identify the one that provides the most comfort, regardless of the theoretical advantage of the composition of one agent over another. (See 'Artificial tear formulation' below and 'Choice of formulation' below.)
The frequency of use should be guided by the need for symptomatic relief, such as reduced symptoms of irritation and improved visual acuity. Artificial tears may be used indefinitely; however, tears containing preservatives should generally not be used more than four times daily. Patients using other topical ocular medications (eg, for glaucoma) should switch to preservative-free alternatives whenever possible (see 'Choice of formulation' below and 'Potential harms' below). Similarly, we discourage use of preservative-free tear supplements more than eight times per day, due to a concern that this may disrupt the mucin layer and thereby aggravate the dry eye.
The use of artificial tears in patients with SjD is supported by several randomized trials that included patients with SjD and moderate to severe dry eye [26-31]. These trials showed symptomatic relief and improvements in damage to the corneal epithelium compared with baseline measurements. One compared hyaluronate and carboxymethylcellulose eyedrops, showing that both improved symptoms and corneal surface findings [28]. A different trial demonstrated greater benefit from hyaluronate compared with saline eye drops [29], and another trial showed greater improvement with hypotonic compared with isotonic hyaluronate [26].
Controlled trials of artificial tears in patients with mild to moderate dry eye (not excluding SjD) have also shown therapeutic benefits [32]. In a comparison trial of artificial tears containing carboxymethylcellulose versus carboxymethylcellulose and hyaluronic acid in 394 dry eye patients, there was equivalent benefit in terms of improving ocular symptoms, ocular surface staining, and tear break-up times [33]. In a study of 99 dry eye patients, both lipid- and non-lipid-based artificial tears had similar benefits [34].
The trials of artificial tears are limited by their small size and by the use of only a few selected agents. Additionally, it is unclear which of the many available preparations provides the greatest improvement and which ingredients or formulations are most effective in improving subjective and objective outcomes that are clinically important [20,35].
Artificial tear formulation — Artificial tears and lubricants are generally available without a prescription and may be in the form of liquid eyedrops, gels, or ointments. Gels and ointments often blur vision during use and are usually not required in patients with mild disease. However, they may be particularly useful when applied in the evening before sleep. (See "Treatment of moderate to severe dry eye in Sjögren’s disease", section on 'Lubricant ointments'.)
Typically, the major components of artificial tears include:
●A form of cellulose (eg, hypromellose or carboxymethylcellulose), which is a major component of many artificial tear products, beneficial for replacement of the aqueous layer, and helps maintain viscosity.
●Preparations containing high concentrations of sodium hyaluronate are an alternative to carboxymethylcellulose in artificial tear products marketed in Japan, Europe, Russia, Australia, and parts of Asia, but not the United States [36]. This naturally occurring high-molecular weight glycosaminoglycan binds water molecules and is viscoelastic, thereby improving ocular surface hydration and reducing surface friction. In the United States, there are a few topical preparations that contain low levels of sodium hyaluronate as an excipient rather than as an active ingredient [37].
●Spreading agents (eg, polyvinyl alcohol, polyethylene glycol, dextran), which are contained in many drops and which help the aqueous layer to spread over the hydrophobic corneal and conjunctival epithelium and to prevent evaporation.
●Mucolytic agents (eg, acetylcysteine), which are useful in more severely affected patients when there is an overproduction of mucus that accumulates as filaments in the eye. However, an objectionable smell may limit use of these agents.
●Preservatives (eg, benzalkonium, thimerosal, chlorobutanol, chlorhexidine, polysorbate 80), which prevent bacterial contamination and which prolong shelf life. However, these may lead to local irritation and worsening of ocular surface findings. Benzalkonium is the preservative most commonly in use today, but is also the one most likely to aggravate dry eye disease through various toxic effects on the ocular surface, particularly on goblet cells [38]. Thus, the long-term and/or frequent use of tear supplements containing benzalkonium should be avoided.
Choice of formulation — Patients can initially use drops containing hypromellose (0.3 percent) or carboxymethylcellulose (0.25 to 0.5 percent; or hyaluronic acid [0.1 to 0.18 percent], where available) as needed and up to every two to four hours (eg, Tears Naturale II, Liquifilm Tears, Liquifilm Forte, Tears Plus, Isopto Tears, and Viscotears). These drops also generally include a spreading agent and a preservative. The frequency of use varies with the degree of dryness, with the specific product used, and with the ambient humidity and other environmental factors. These tears differ in viscosity, also affecting how long they last following an application. Higher-viscosity drops require less frequent application, but they may cause visual blurring and can increase the risk of blockage of the meibomian glands, with resultant posterior blepharitis. (See "Artificial tears (Ophthalmic lubricants: solutions, gels, ointments): Drug information" and "Hydroxypropyl methylcellulose: Drug information".)
Preservative-free preparations (eg, Tears Naturale Free, Bion Tears, HypoTears PF, Refresh, Moisture Eyes Free, and TheraTears Free) are preferred in patients who develop irritation from frequent use of tears containing preservatives. The irritation related to preservatives can be associated with ocular surface changes involving the cornea and conjunctiva, with abnormal tear film, and with inflammation [39]. Such irritation may occur with use every two to four hours in some patients; thus, patients should generally avoid using drops containing preservatives more than four times daily. Preservative-free tears are typically supplied in single-use dispensers/vials. Potential disadvantages of these fluids are high cost and, for patients with arthritis, difficulty with opening the single-use containers. These products may be available for purchase in bulk at lower cost through the internet.
The benefits of switching from preserved to preservative-free formulations have not been formally evaluated in patients with SjD but have been shown in both retrospective and prospective studies of patients being treated for glaucoma, in whom substantial reductions in irritation symptoms and in signs of meibomian gland dysfunction and conjunctival and corneal damage were seen with reduced usage of preservative-containing drops, particularly after switching entirely to preservative-free drops [39-42]. In one prospective study involving 158 patients, the number of patients with symptoms during treatment was reduced by half after switching to preservative-free medication, and the number of patients with abnormal signs was reduced by 30 to 50 percent [42]. As examples, symptoms of irritation, burning, and stinging and findings of corneal fluorescein staining were both reduced after 6 and 12 weeks with preservative-free drops (from 56 to 31 to 28 percent and from 82 to 53 to 41 percent, respectively).
There are additional differences in individual preparations [20,43]. An example of a tear that has a decreased osmolarity to compensate for higher salt concentrations in the dry eye is HypoTears. Systane drops include a lipid-stabilizing agent. The addition of a mucolytic such as acetylcysteine, which breaks up mucus strands and filaments, should be tried in patients who complain of sticky eyes in the morning or who have mucus filaments on examination. The patient should be warned of its unpleasant smell (like rotten eggs) [44].
Slow-release artificial tear inserts (eg, Lacrisert), which contain hydroxypropyl cellulose but no preservatives, avoid the need for frequent instillation of drops (see "Hydroxypropyl cellulose: Drug information"). However, artificial tear inserts are difficult for many patients with arthritis to place in the lower conjunctival recess. The patient must have enough tears to dissolve the pellet and enough dexterity to place the insert into the eye without damage to the corneal surface. These inserts are usually reserved for bedtime use, since they invariably blur the vision.
Potential harms — There are several problems that can be associated with the use of artificial tears, including irritation due to components of the drops themselves and blepharitis.
●Itching or increased irritation of the eye may occur in some patients with use of drops that contain preservatives, stabilizers, or solubilizers [39]. A preservative that is acceptable to most patients without severe dry eyes may reach a higher concentration in the patient with dry eyes and may be more likely to cause problems. Although these additives extend the lifetime of products, they may produce local irritation and persistent symptoms despite the use of drops, especially if used every two to four hours. If this occurs, an alternative preparation can be tried that is preservative-free or uses a different preservative. The preservatives used in artificial tears that are most responsible for irritation in dry eye patients (eg, benzalkonium chloride) have generally been replaced by less irritating compounds but may still be used in other types of eye drops.
●Posterior blepharitis is caused by clogging, inflammation and subclinical infection (commonly staphylococcal) of the meibomian glands of the eyelid; it can be worsened by contact lens use. Symptoms resemble those of aqueous tear deficiency, but, unlike aqueous tear deficiency, blepharitis is often associated with redness of the lower lids, sometimes excessive tearing, and clogged-up meibomian gland orifices with lid margin telangiectasia. It is important to evaluate the presence of blepharitis in patients with SjD and address it separately from aqueous tear deficiency. The evaluation and treatment of blepharitis are discussed separately. (See "Blepharitis".)
MODERATE TO SEVERE DISEASE — Treatment of moderate to severe disease is discussed in detail separately. (See "Treatment of moderate to severe dry eye in Sjögren’s disease".)
Briefly, the treatment of such patients includes:
●Moderate disease – In patients with moderate episodic or chronic symptoms or with signs of disease such as variable corneal staining, mild debris, or an abnormal Schirmer test, additional measures and some changes in topical therapies are usually required while continuing initial preventive measures. These interventions may include more frequent and preservative-free artificial tears, lubricating ointment at night, topical cyclosporine or lifitegrast, topical steroids, punctal plugging, and other interventions. Patients with dry mouth as well may also be treated with an oral secretagogue, such as pilocarpine or cevimeline. (See 'Initial therapy and mild disease' above and "Treatment of moderate to severe dry eye in Sjögren’s disease", section on 'Moderate disease'.)
●Severe disease – Patients with severe disease, signs of which may include marked or severe punctate corneal erosions, filamentary keratitis, and conjunctival vital dye staining, may require intensification of therapies already being employed or additional interventions, including those used for moderate disease symptoms or signs, moisture goggles or other physical barriers for tear conservation, permanent punctal occlusion, systemic antiinflammatory and immunosuppressive therapies, and other interventions. (See 'Initial therapy and mild disease' above and "Treatment of moderate to severe dry eye in Sjögren’s disease", section on 'Moderate disease' and "Treatment of moderate to severe dry eye in Sjögren’s disease", section on 'Severe disease'.)
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 keratoplasty and blepharoplasty.
Treatment of refractive errors by laser such as LASIK or PRK is contraindicated in patients with SjD. Such procedures may exacerbate preexisting dryness and may lead to corneal melt in patients with SjD [45-47].
Surgeons performing blepharoplasty should be aware of the dry eye syndrome, since elective surgery on the eyelids can mechanically alter the anatomy sufficiently to aggravate a subclinical condition, resulting in full-blown dry eye. This may occur due to interruption of the neural innervations as well as anatomical abnormalities due to inadequate closure and blink leading to excessive evaporation of the tear film [48-51].
Other more common procedures, such as cataract surgery, should be deferred until improvement of the ocular surface and tear film parameters has been achieved [52,53]. In addition, the use of topical nonsteroidal antiinflammatory medications following cataract surgery in patients with significant dry eye, particularly in the setting of SjD, can lead to non-healing ulcers or sterile keratolysis and is thus contraindicated [54-56].
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
●Several approaches should be used to treat dry eye in patients with Sjögren’s disease (SjD). Attention to ambient humidity and other environmental factors, attention to medications that exacerbate dryness that are being used for other indications, and use of physical barriers to avoid drying or irritation of the eyes are important first-line measures. Particular attention to ocular exposure and care should be given to patients undergoing surgical procedures. (See 'Tear conservation' above.)
●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. (See 'Artificial tears' above.)
●In patients with increased irritation of the eye with use of artificial tears containing preservatives, stabilizers, or solubilizers, and in patients requiring artificial tears and other topical ocular medications containing preservatives more than four times daily, an alternative preparation should be tried that is preservative-free or contains a different preservative. (See 'Artificial tears' above and 'Choice of formulation' above and 'Potential harms' above.)
●Blepharitis may complicate SjD, and increased ocular irritation from lid margin inflammation and infection may be misinterpreted as an inadequate response to therapies. It is important to differentiate from aqueous tear deficiency because it requires separate treatment rather than intensification of ocular lubricant therapy. Blepharitis is often associated with redness of the eyelids, episodes of excessive tearing, and evidence of meibomian gland plugging and telangiectasia. Blepharitis can be improved with warm compresses with or without topical/oral antibiotics. (See 'Potential harms' above and "Blepharitis".)
●Patients with SjD may be at increased risk compared with the general population if they undergo certain ophthalmologic procedures, including keratoplasty and blepharoplasty. Treatment of refractive errors by laser such as LASIK or PRK is contraindicated in patients with SjD. Surgeons performing blepharoplasty should be aware of the dry eye syndrome, since elective surgery on the eyelids can aggravate subclinical disease and markedly worsen dry eye. (See 'Risks of ophthalmologic procedures' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to an earlier version of this topic review.
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