Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease of the exocrine glands, primarily characterized by dryness symptoms due to impaired secretion of the lacrimal and salivary glands. In 1933, Swedish ophthalmologist Henrik Sjögren first reported a group of patients with ocular and oral dryness as “sicca complex.”
SS is classified as follows:
Primary SS (approximately 70%): Not associated with collagen disease. It is further divided into glandular SS (stage I), with only dryness symptoms, and extraglandular SS (stage II), with systemic organ involvement. Among extraglandular SS, those that develop malignant lymphoma are considered stage III.
Secondary SS (approximately 30%): Complicated by collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and mixed connective tissue disease.
The estimated number of patients in Japan is 500,000 to 1,000,000, with the highest prevalence in the 50s age group. The male-to-female ratio is 1:14, with a predominance in women. Patients range from children to those in their 80s.
Dry eye associated with SS is classically described as aqueous tear deficiency. However, recent studies suggest that pathological changes induce comprehensive tear dysfunction, including alterations in meibomian gland function 1). Compared to non-SS aqueous tear deficiency patients, the SS group had higher evaporation, reduced meibomian gland expressibility, and insufficient oil layer 1).
QHow is dry eye in SS different from ordinary dry eye?
A
Ordinary dry eye is primarily due to reduced tear film stability, often of the evaporative type. In SS, the lacrimal gland is immunologically destroyed, leading to a marked decrease in tear secretion. Additionally, conjunctival epithelial damage is prominent, and even after punctal occlusion to increase tear volume, conjunctival damage is difficult to improve. Meibomian gland dysfunction also coexists, adding an evaporative component 1).
The main complaint is a sensation of dry eyes. It is accompanied by foreign body sensation, burning sensation, eye fatigue, and photophobia. Xerostomia often coexists. Because conjunctival sensation is dull, subjective symptoms may be mild if only the conjunctiva is affected.
In severe cases, there is a risk of corneal scarring, ulceration, infection, and perforation. Filamentary keratitis presents with severe foreign body sensation worsened by blinking, blepharospasm, and tearing.
Ocular surface findings: Keratoconjunctival epithelial damage (positive fluorescein staining) is observed. Conjunctival epithelial damage characteristic of SS is prominent with rose bengal or lissamine green staining. There is a decrease in the tear meniscus and conjunctival injection.
Goblet cell changes: In the early stage, goblet cells may increase. In severe or chronic cases, goblet cell loss and squamous metaplasia are observed.
Filamentary keratitis: Filaments composed of degenerated epithelial cells and mucus adhere to the corneal surface.
SS can affect multiple organs beyond the eyes and mouth. Systemic involvement is seen in 10–20% of patients5).
Neurological disorders: Peripheral neuropathy occurs in 2–25% of patients and is a representative extraglandular symptom of SS4). It presents with various phenotypes including sensorimotor polyneuropathy, small fiber neuropathy, autonomic neuropathy, and trigeminal neuropathy4). Autonomic neuropathy is characterized by cholinergic dysfunction, presenting with orthostatic hypotension, gastrointestinal symptoms, and urinary disorders4).
Pulmonary involvement: Bronchiectasis, lymphocytic interstitial pneumonia (LIP), and pleural effusion have been reported5). Pleural effusion is rare, with only about 10 cases reported in the past 30 years, but it suggests severe extraglandular involvement5).
Malignant lymphoma: Non-Hodgkin lymphoma develops in 4–9% of pSS patients5). Purpura, hypocomplementemia, cryoglobulinemia, and persistent parotid swelling are risk factors5).
Lymphocyte infiltration: T cells infiltrate around the ducts of lacrimal and salivary glands, causing inflammation with epithelial cells. B cells join to form lymphoid follicles.
Autoantibodies: Anti-SS-A/Ro and anti-SS-B/La antibodies are characteristic. Functional inhibitory antibodies against M3 muscarinic receptors are also involved in lacrimal secretion disorders2).
Costimulatory molecules: Ox40/Ox40L are elevated on peripheral blood mononuclear cells and correlate with clinical outcomes and treatment response.
Environmental and genetic factors
Viral infection: EBV genome is detected as type I in the lacrimal glands of SS patients. Involvement of HTLV-1 and HCV is also suggested.
Genetic predisposition: Polygenic pattern. The concordance rate in monozygotic twins is only 20%, indicating a strong influence of epigenetics and environmental factors5).
Cytokines: IL-6 and TNF-α are elevated in tear fluid. IL-6 correlates with disease severity, BUT, Schirmer values, and goblet cell density.
Schirmer test I: The test strip is placed without anesthesia, and ≤5 mm after 5 minutes is considered abnormal. Sensitivity 42% and specificity 76% have been reported.
Corneoconjunctival staining: Fluorescein, rose bengal, or lissamine green is used to evaluate corneal and conjunctival epithelial damage. In SS, conjunctival damage is often prominent.
Tear film tests: Shortened tear break-up time (BUT), increased tear osmolarity, and decreased fluorescein clearance are observed.
Serological tests: Anti-SS-A/Ro, anti-SS-B/La, ANA, and RF are measured. Even if seronegative, SS cannot be ruled out; if clinical suspicion is high, consider labial gland biopsy.
Labial gland biopsy: It is less invasive and more accessible than lacrimal gland biopsy. A “focus” of 50 or more lymphocytes aggregated around ducts is evaluated per 4 mm². Impression cytology shows 97% concordance with labial gland biopsy.
QCan SS be diagnosed even if serum antibodies are negative?
A
Yes. A significant number of patients with SS dry symptoms are seronegative. According to the Japanese 1999 revised criteria, even if serological tests (item 4) are negative, SS can be diagnosed if two of the following three items are met: histopathology (item 1), oral examination (item 2), and ophthalmic examination (item 3). If clinical suspicion is strong, consider labial gland biopsy.
Treatment for dry eye associated with SS is based on three pillars: supplementation, preservation, and secretion enhancement of tears. Since decreased tear secretion is the main pathology, water supplementation is the foundation of treatment.
Mild to Moderate
Artificial tears: Preservative-free artificial tears (e.g., Soft Santear) are instilled 6–7 times a day. In severe cases, preservative-free formulations are used to avoid corneal toxicity from preservatives.
Sodium hyaluronate eye drops: Hyalein Mini 0.1% or 0.3% instilled 6 times a day. They have a tear-retaining effect.
Diquafosol sodium eye drops: Diquas 3% instilled 6 times a day. They promote mucin and water secretion from the conjunctiva. They are also effective for tear-deficient dry eye in SS patients.
Rebamipide eye drops: Mucosta ophthalmic solution UD 2% instilled 4 times a day. They promote mucin production.
Low-potency steroids: Flumetholon 0.1% instilled 1–2 times a day. Used when inflammation contributes to symptom exacerbation (use for the minimum necessary period).
Severe
Punctal occlusion: Punctal plug insertion is performed. The size is measured with a punctal gauge and an appropriate plug is selected. In severe cases, plugs are inserted into both upper and lower puncta. For plug loss or punctal dilation, surgical punctal closure is performed.
Autologous serum eye drops: Improvement in tear film stability and ocular surface staining scores has been demonstrated. They supplement trace substances such as fibronectin that are present in tears.
Scleral contact lenses: They form a tear reservoir and continuously moisten the ocular surface. Improvements in OSDI, corneal and conjunctival staining, and tear osmolarity have been reported 1).
Bandage silicone hydrogel lenses: Continuous wear for 6 weeks yielded better results than autologous serum (comparison over 3 months) 1).
Pilocarpine hydrochloride and cevimeline hydrochloride hydrate are used as oral medications. They are approved for xerostomia in SS, and increases in tear secretion, goblet cell count, and improvement in conjunctival epithelium have also been reported 1). Side effects (sweating, gastrointestinal symptoms) require caution.
In refractory SS, systemic immunosuppressive drugs may be necessary. Methotrexate and cyclophosphamide are considered. Infliximab showed improvement in early pilot studies, but subsequent RCTs did not demonstrate benefit. Prednisolone (30–60 mg/day) is used for severe extraglandular involvement, and may be switched to mycophenolate mofetil after tapering 5). IVIG therapy is effective for severe neuropathy 4).
Topical cyclosporine A inhibits T-cell activation and protects acinar cells from lymphocyte-induced apoptosis. After 6 months of treatment, apoptosis-related markers in the conjunctival epithelium decrease. However, improvements in Schirmer test and tear break-up time are limited; it is mainly used to control ocular surface inflammation.
First-line treatment is lubricating eye drops and ointments. For poor responders, a low-water-content bandage contact lens is used (concomitant antibiotic eye drops are mandatory). Single filaments can be removed with forceps under topical anesthesia. For multiple filaments, 10% acetylcysteine eye drops are applied 3 times daily for 2–3 weeks.
QWhat SS treatments are available in Japan?
A
In ophthalmology, diquafosol sodium (Diquas), rebamipide (Mucosta), and sodium hyaluronate (Hyalein) are approved eye drops. Cyclosporine eye drops are not covered by insurance in Japan. Systemic drugs such as cevimeline hydrochloride (Evoxac) and pilocarpine hydrochloride (Salagen) are approved for oral dryness in SS and have been reported effective for ocular symptoms. In severe cases, autologous serum eye drops and punctal plugs are options.
The basic lesion in SS is lymphocytic infiltration of the lacrimal and salivary glands. T cells (mainly CD4-positive helper T cells) infiltrate around the ducts, triggering inflammation with epithelial cells. B cells join to form lymphoid follicles, and fibrosis progresses.
Even in SS patients with marked dryness, biopsy samples show 50% of glandular cells remaining. The decrease in tear secretion cannot be explained solely by gland destruction; impairment of the neurosecretory circuit plays an important role.
In the MRL/MpJ-Faslpr mouse model, inflammatory cytokines such as IL-1β were shown to inhibit neurotransmitter release from nerve endings, reducing lacrimal secretion 2). Protein secretion in response to efferent nerve stimulation was not impaired, but denervation-like hypersensitivity (enhanced intracellular Ca²⁺ response) was observed 2).
In SS, functional inhibitory antibodies against M3 muscarinic receptors exist, which inhibit receptor activation by acetylcholine 2). This discovery led to the development of M3 receptor agonists (pilocarpine, cevimeline).
Observation of the cornea of SS patients using scanning slit confocal microscopy shows no difference in nerve density, but increased nerve sprouts and dendritic antigen-presenting cells are noted 2). Mechanical hypersensitivity of corneal nerves is suggested, thought to be due to abnormal firing during inflammation or regeneration 2). Despite corneal nerve hypersensitivity, tear secretion is reduced, indicating that secretory dysfunction occurs at a different stage from corneal nerve activation 2).
The conjunctival epithelial damage characteristic of SS is not easily improved by increasing moisture through punctal occlusion. This suggests that besides tear deficiency, immunological inflammation and friction from blinking are involved.
QWhy is there no tear production even when 50% of the lacrimal gland remains?
A
In SS, not only destruction of lacrimal gland cells but also neurosecretory dysfunction of remaining gland cells is important. Inflammatory cytokines (such as IL-1β) inhibit neurotransmitter release from nerve endings, interrupting secretory stimulation to gland cells 2). Furthermore, autoantibodies against M3 muscarinic receptors prevent acetylcholine from binding to receptors 2). In other words, it is a state where “the factory remains, but the command system is blocked.”
Monthly autologous panretinal photocoagulation lacrimal gland injection combined with HA eye drops significantly improved corneal staining, Schirmer value, TBUT, and OSDI scores in SS patients compared to HA eye drops alone (90-day RCT, n=30) 1). Although the sample size is small, it is expected as a new intervention for severe SS 1).
Oral administration of IRT5 probiotics (5 strains: L. casei, L. acidophilus, L. reuteri, B. bifidum, S. thermophilus) improved tear production and corneal staining in a mouse model of autoimmune dry eye3). Improvement in histopathological scores of the lacrimal gland was also reported, but no effect on goblet cell density was observed 3). Oral administration of pre/postbiotics also showed significant improvement after 4 months of treatment 3). Human clinical trials have not yet been reported 3).
The prognosis of SS is generally favorable, with most patients remaining stable for a long period. Over a course of more than 10 years, about 30% of patients show no change in symptoms or laboratory findings, while 40% have only abnormal laboratory values. The remaining 30% develop new lesions such as lung disease, kidney disease, or lymphoma. Hypocomplementemia, cryoglobulinemia, and M proteinemia are listed as prognostic markers for severe extraglandular involvement 5).
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Dartt DA. Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases. Prog Retin Eye Res. 2009;28(3):155-177. doi:10.1016/j.preteyeres.2009.04.003.
Markoulli M, Ahmad S, Engel L, et al. TFOS Lifestyle: Impact of nutrition on the ocular surface. Ocul Surf. 2023;29:226-271.
Chaaban N, Shaver T, Kshatriya S. Sjogren Syndrome-Associated Autonomic Neuropathy. Cureus. 2022;14(6):e25563.
Abou Ziki MD, Taoutel R, Hong JC, Podell DN. Severe extra-glandular involvement and pleural effusions complicating primary Sjogren’s syndrome: a case report. J Med Case Rep. 2022;16:374.
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