**Background:** Dry eye disease (DED) is a common condition affecting millions worldwide, with a prevalence of 5%–50% depending on definition and population. Aqueous-deficient dry eye (ADDE) is a subtype characterized by decreased tear production from the lacrimal gland, seen in up to one-third of DED cases. ADDE can be comorbid with systemic autoimmune processes or secondary to environmental insults, and if untreated, can cause chronic irreversible lacrimal gland damage and severe visual impairment. This review aims to summarize the etiologies, diagnostic approaches, and management strategies for ADDE, proposing a pathophysiology-based classification and treatment algorithm.
**Methods:** The authors conducted a narrative review of the literature on ADDE, focusing on etiologies, diagnostic tests, and treatment options. They classified ADDE causes into immune-mediated (Sjögren's syndrome, graft-versus-host disease), conjunctival cicatrization (Stevens–Johnson syndrome, mucous membrane pemphigoid, drug-induced cicatrizing conjunctivitis), neurogenic (neurotrophic keratitis, diabetes, hypothyroidism), and alacrimia (congenital or acquired). Diagnostic methods discussed include Schirmer test (cutoff <10 mm or <5 mm), tear meniscus height measurement by OCT (normal 0.19–0.34 mm; cutoff 0.2 mm gave 98.3% sensitivity and 96.7% specificity), lacrimal gland examination, ocular surface staining (fluorescein, lissamine green), tear film breakup time, meibomian gland assessment, and blood work for systemic disease (anti-Ro/La antibodies). Management strategies include lubricants, topical immunosuppressants (cyclosporine A 0.05%–0.1%, lifitegrast 5%), secretagogues (diquafosol 3%, rebamipide 2%, cevimeline, pilocarpine, varenicline nasal spray), autologous serum, punctal occlusion, scleral contact lenses, and disease-specific systemic immunomodulation for Sjögren's syndrome and mucous membrane pemphigoid.
**Key Results:** The review reports that Schirmer test values <10 mm indicate aqueous deficiency, and tear meniscus height <0.2 mm by OCT has high diagnostic accuracy. In Sjögren's syndrome, corneal staining with fluorescein and conjunctival staining with lissamine green (>5 on Oxford score) was 91.1% sensitive and 83.9% specific for identifying keratoconjunctivitis sicca. For treatment, cyclosporine 0.05% increased tear production and reduced staining in 877 subjects with ADDE (Schirmer <5 mm). Lifitegrast improved corneal staining and symptoms in 718 subjects with DED (Schirmer <10 mm). Diquafosol improved ocular surface staining and symptoms in 15 ADDE patients over 6 months. Autologous serum (20%) reduced symptoms and corneal staining in 20 patients with severe ADDE (mean Schirmer 3.8 mm). Punctal plugs improved symptoms in 54% of 80 DED patients. Minor salivary gland transplantation improved Schirmer values by 2–4 mm in cicatricial ADDE.
**Clinical Implications:** Early identification of ADDE is crucial to prevent chronic lacrimal gland damage and visual impairment. Ophthalmologists play a key role in diagnosing underlying systemic diseases like Sjögren's syndrome, as dry eyes may be the first manifestation. A multidisciplinary approach involving rheumatologists, dermatologists, and hemato-oncologists is often necessary. Treatment should be individualized based on etiology, with disease-specific systemic immunosuppression for progressive conditions like mucous membrane pemphigoid. Emerging therapies such as mesenchymal stem cell therapy and bioengineered lacrimal glands hold promise for severe, refractory cases.