What are the differential diagnoses for a patient presenting with xerostomia and keratoconjunctivitis sicca?

Differential Diagnosis of Dry Mouth and Eyes

The most critical diagnosis to identify in a patient presenting with xerostomia and keratoconjunctivitis sicca is Sjögren's syndrome, as approximately 10% of patients with aqueous tear deficiency dry eye have underlying Sjögren's syndrome, which carries increased risk of lymphoid malignancy. 1

Primary Autoimmune/Systemic Conditions

Sjögren's Syndrome (Primary or Secondary)

• Primary Sjögren's syndrome presents with keratoconjunctivitis sicca and xerostomia due to lymphocytic infiltration of lacrimal and salivary glands 2, 3, 4
• Secondary Sjögren's syndrome occurs with concurrent autoimmune disease, most commonly rheumatoid arthritis 3
• Look for: elevated dental caries despite good oral hygiene, antibodies to Ro/SSA and La/SSB antigens (present in up to 90% of cases), and salivary gland biopsy showing lymphocytic infiltration 2, 4
• Critical consideration: Among autoimmune diseases, primary Sjögren's syndrome has the strongest association with lymphoid proliferative malignancy 1

Graft-Versus-Host Disease (GVHD)

• Occurs in patients who have undergone allogeneic stem cell transplantation 1
• Presents with bilateral keratoconjunctivitis sicca, conjunctival injection, chemosis, and pseudomembranous conjunctivitis 1
• Can involve multiple tissues including skin, liver, gastrointestinal system, and lung 1
• Ocular disease is more common in the chronic phase (beyond 3 months post-transplant) 1

Ocular Mucous Membrane Pemphigoid (OMMP)

• Bilateral (often asymmetric) presentation with conjunctival injection, papillary conjunctivitis, and progressive subepithelial fibrosis 1
• More common in women, onset generally over age 60 1
• Progressive chronic course with goblet cell loss leading to severe tear deficiency and xerostomia-like symptoms 1
• Pitfall: Can be drug-induced by pilocarpine and timolol, mimicking idiopathic OMMP 1

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

• Bilateral mucocutaneous necrosis affecting conjunctiva, oral mucosa, and other mucous membranes 1
• Triggered by medications (sulfonamides, barbiturates, phenytoin) or infections (HSV, mycoplasma pneumoniae) 1
• Results in conjunctival scarring, goblet cell loss, mucin deficiency, and severe tear deficiency 1

Endocrine Disorders

Thyroid Disease

• Graves' disease and Hashimoto's thyroiditis both associated with keratoconjunctivitis sicca 1
• Thyroid ophthalmopathy causes exposure keratopathy, upper eyelid retraction, and conjunctival edema 1
• Majority of patients have thyroid eye disease occurring within 18 months of thyroid dysfunction, though timing can vary by years 1

Medication-Induced Causes

Topical Ophthalmic Medications

• Glaucoma medications, topical NSAIDs, antibiotics, antivirals cause keratoconjunctivitis 1
• Preservatives in eye medications are common culprits, especially with multiple medications or frequent dosing 1
• Presents with conjunctival injection, punctal edema, inferior fornix follicles 1
• Gradual worsening with continued use; can lead to corneal ulceration and punctal occlusion 1

Systemic Anticholinergic Medications

• The most prevalent cause of xerostomia in elderly persons is anticholinergic medications 2
• Critical to review: Complete medication list including over-the-counter antihistamines, antidepressants, antipsychotics, and urinary antispasmodics 2

Dupilumab-Associated Disease

• Bilateral conjunctival injection with watery or mucous discharge 1
• Occurs in patients with severe atopic dermatitis, typically within weeks to months of starting dupilumab 1
• Often manageable with treatment and may resolve while continuing medication 1

Age-Related and Mechanical Causes

Age-Related Dry Eye

• Natural aging brings significant changes in saliva and tear film composition regardless of underlying disease 2
• Diagnostic challenge: Xerostomia and dry eyes are common features of old age, making diagnosis of underlying autoimmune disease more difficult in elderly patients 5

Floppy Eyelid Syndrome

• Upper eyelid easily everted with horizontal lid laxity and papillary reaction of superior tarsal conjunctiva 1
• Associated with obesity, sleep apnea, and thyroid disease (commonly Hashimoto's thyroiditis) 1
• Chronic nocturnal eyelid ectropion causes upper tarsal conjunctiva contact with bedding 1

Neoplastic Conditions (Critical Not to Miss)

Sebaceous Carcinoma

• Presents with intense bulbar conjunctival injection and chronic blepharoconjunctivitis 6, 7
• Major pitfall: Commonly misdiagnosed as chronic inflammatory condition 6
• Often has history of multiple chalazion excisions 1

Conjunctival Lymphoma

• Painless "salmon patch" lesions with indolent fleshy swelling 6
• May present as recurrent subconjunctival hemorrhage 7
• Increased risk in patients with autoimmune conditions including Sjögren's syndrome, Hashimoto's thyroiditis, and IgG4-related disease 6

Diagnostic Approach Algorithm

Step 1: Assess for systemic autoimmune disease

• History of rheumatoid arthritis, lupus, or other connective tissue disease suggests secondary Sjögren's 3
• Dental caries despite good hygiene, parotid swelling, or extraglandular manifestations (lung, kidney, skin involvement) suggest primary Sjögren's 4

Step 2: Medication review

• Document all topical eye medications, especially glaucoma drops and frequency of use 1
• Review systemic anticholinergic medications in elderly patients 2
• Recent initiation of dupilumab in atopic dermatitis patients 1

Step 3: History of stem cell transplantation

• Any history of allogeneic transplantation mandates consideration of chronic GVHD 1

Step 4: Acute vs. chronic presentation

• Acute mucocutaneous reaction with skin involvement suggests SJS/TEN 1
• Progressive chronic course over months to years with conjunctival scarring suggests OMMP 1

Step 5: Red flags requiring biopsy

• Any persistent conjunctival lesion, nodule, or recurrent subconjunctival hemorrhage requires biopsy to exclude malignancy 6, 7
• Unilateral presentation with intense injection not responding to standard therapy warrants biopsy for sebaceous carcinoma 6

Step 6: Serologic and objective testing

• Anti-Ro/SSA and anti-La/SSB antibodies for Sjögren's syndrome 2, 4
• Salivary gland biopsy showing lymphocytic infiltration confirms Sjögren's 4
• Thyroid function tests if thyroid eye disease suspected 1
• Ocular staining score and tear film assessment to quantify severity 1