Comorbidities

Comorbid Conditions

Dry eye syndrome (DES) is frequently associated with a variety of comorbid conditions that complicate its management and affect patient quality if life (QoL). Perhaps the most significant comorbidity is Sjögren syndrome (SS); however, other autoimmune disorders are also associated with DES. In addition, DES can be caused by iatrogenic factors, principally certain topical and systemic medications for other conditions. Ocular surface diseases such as allergic or infectious conjunctivitis and anterior blepharitis can both mimic and exacerbate DES symptoms. This section provides an overview of these common comorbidities and briefly discusses the strategies with which they can be managed.

Autoimmune Disorders and Dry Eye Syndrome

Systemic diseases, and especially autoimmune rheumatic disease (ARDs), are common comorbidities of DES. The most common ARD associated with DES is Sjögren syndrome (SS), with up to 95% of patients with SS also experiencing DES. Other ARDs which are frequently associated with ARD include rheumatoid arthritis(RA; DES prevalence, 38-47%), systemic lupus erythematosus (SLE; DES prevalence, 13-39%), and systemic sclerosis (SSc; DES prevalence, 37-79%). With all of these ARDs, DES is the most frequent ocular manifestation.

Sjögren syndrome is characterized by immune-mediated damage to salivary and lacrimal glands, leading to dryness of the mouth (xerostomia) and eyes (xerophthalmia), as well as other mucosal surfaces in the airways and the digestive tract. It can occur alone (primary SS) or together with other autoimmune diseases like rheumatoid arthritis (secondary SS). Sjögren syndrome predominantly affects women (female:male ratio of 9:1) and is most often diagnosed in the fifth decade of life. Like with most ARDs, the exact etiology of SS is unknown, but is likely multifactorial, involving both genetic and environmental factors. Certain human leukocyte antigen (HLA) alleles, including DRB103:01, DQA105:01 and DQB1*02:01, are known to be associated with SS susceptibility, as are certain environmental triggers – above all Epstein-Barr virus (EBV) infection. Autoantibodies against the ribonuclear antigens Ro/SSA and La/SSB (which can be released from host cells by EBV infection) are a prominent marker of SS and are believed to be the main mediators of its pathological effects. Together with other dysregulated parts of the immune system (T lymphocytes, natural killer cells, pro-inflammatory cytokines), SS autoantibodies cause lacrimal gland dysfunction, which in turn leads to tear film defects and DES symptoms. Lacrimal gland histopathology in Sjögren's syndrome dry eye (SSDE) differs from that of NSDE by the marked presence of infiltrating lymphocytes, which are absent in non-Sjögren's syndrome dry eye (NSDE) (Figure 6-1). Neither SSDE nor NSDE are associated with significant fibrosis, which is visible in lacrimal glands of patients with graft-versus-host disease (GVHD) (Figure 6-1).

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Rheumatoid arthritis is an ARD characterized by the production of autoantibodies against IgG (rheumatoid factor) and citrullinated proteins (ACPAs), which results in synovial inflammation, immune cell infiltration and joint damage. Like other ARDs, RA predominantly affects women (female:male ratio of 3:1). Although RA co-occurs with SS in 4-50% of cases, symptoms of DES are common in RA even when it occurs on its own. In patients with RA, DES appears to develop as a consequence of locally increased pro-inflammatory cytokines, including IL-1a, IL-6, IL-8 and TNFα.

Systemic lupus erythematosus (SLE) is an ARD which most often affects women of child-bearing age; the adult female/male ratio of SLE ranges from 6:1 to 10:1. Anti-double-stranded DNA (anti-dsDNA) are the characteristic autoantibodies associated with SLE; hypocomplementemia (low C3 and C4 complement levels) is also common. As the name indicates, SLE is systemic and affects almost all organs and tissues, including the eyes. Symptoms of DES are common, and their intensity correlates with SLE disease activity. SLE damages the cornea, lacrimal glands, and meibomian glands, reducing tear production and tear film stability.

The final ARD with significant association with DES, SSc, is characterized by fibrosis and vasculopathy (microvascular damage) of the skin and internal organs. The female:male ratio is 3:1. Fibrosis of the conjunctiva and lacrimal glands is believed to be the primary mechanism of DES development in SSc. The presence of significant fibrosis and comparably less prominent lymphoid infiltration differentiate SSc-related DES from SSDE. Peripheral neuropathy in SSc can reduce corneal sensation, which may decouple the signs and symptoms of DES in patients with SSc.

Iatrogenic Dry Eye Syndrome

A number of medical interventions, above all topical and systemic drugs but also ophthalmic procedures (including surgical procedures), are associated with an increased risk of DES. The topical drugs that have the potential to cause allergic, toxic and pro-inflammatory responses on the ocular surface and therefore cause or exacerbate DES are shown in Table 6-1.

Many systemic drugs, including widely used classes like vasodilators, sulfonylureas, anxiolytics, antidepressants and antihistamines, are also associated with increased risk of DES or DES symptom aggravation (Table 6-2). Potential mechanisms are as variable as the associated drugs, and may include tear production reduction, modulation of nerve input and reflex secretion, pro-inflammatory response activation and direct irritation/damage.

A secondary analysis of data from the Dry Eye Assessment and Management (DREAM) Study found that antihistamines, aspirin, corticosteroids, vitamin D3 and seizure medications were linked to worse DES signs, while diuretics were associated with less MGD. However, these relationships are correlative and the DREAM study included only patients with moderate-to-severe DES; thus, these conclusions cannot be extended to patients with mild DES.

In general, the effects of topical and systemic medications on DES are still understudied, particularly in patients with polypharmacy, in whom additive or synergistic effects may occur. Clinicians should note that medications that cause dry mouth have the potential to also cause DES.

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Management Strategies for Common Systemic and Ocular Comorbidities

Before the correct management approach to a patient with DES can be undertaken, common comorbidities and mimics must be properly diagnosed (see Presentation). If SS or another ARD is suspected, diagnosis involves serologic testing for autoantibodies or other features that characterize the ARD. Management of SS and other ARDs involves both systemic agents (steroids, immunosuppressive agents, biologics that target B lymphocytes – e.g., rituximab, belimumab) and treatments for DES and other local manifestations. Since DES associated with ARDs is typically more severe, advanced treatment options such as oral secretagogues, nasolacrimal reflex (NLR) stimulation and blood product-based eye drops (among others; see Treatment Options) are usually required.

Conjunctivitis, whether allergic or infectious, is a common mimic of DES. Management of allergic conjunctivitis includes allergen avoidance and the use of artificial tears to wash away allergens. Topical antihistamines, mast cell stabilizers and corticosteroids are common treatments. Oral antihistamines may be used but can have drying effects on the ocular surface, potentially exacerbating DES. For viral or bacterial conjunctivitis, topical or oral antimicrobial (antiviral or antibiotic, as appropriate) agents may be used, although most cases are self-limited. Anterior blepharitis (inflammation of the front part of the eyelid) is primarily treated through eyelid hygiene; e.g., using warm compresses to soften and remove scales and debris from the eyelid margins and regular cleansing of the eyelid margins with warm water or commercial eyelid cleansers. Topical antibiotics, such as erythromycin or bacitracin, can be used for bacterial infections, and more severe cases may be treated with anti-inflammatory agents (e.g., corticosteroids or cyclosporine). In cases caused by Demodex infestation, the appropriate first-line treatment is either topical tea tree oil (TTO; pre-formulated wipes with 25% TTO are commercially available) or an ophthalmic solution of lotilaner 0.25%. Lotilaner is the first medication to receive FDA approval (in 2023) specifically for the treatment of Demodex blepharitis. It is a mite-specific GABA-gated chloride channel inhibitor, which paralyzes Demodex parasites, thus killing them. In refractory cases, oral ivermectin (a glutamate-gated chloride channel inhibitor with broad anti-invertebrate activity) can be used.