Sjögren’s syndrome (SS) is a chronic autoimmune exocrine gland disease primarily targeting the lacrimal and salivary glands. The basic pathology involves lymphocytic infiltration around the ducts, leading to loss of secretory function, resulting in keratoconjunctivitis sicca and xerostomia.
It is the second most common autoimmune rheumatic disease, with an estimated prevalence of 0.1–4.8%. In Japan, the peak age is in the 50s, with a female-to-male ratio of 14:1 (9:1 in international reports). Primary SS accounts for about 70% and secondary SS for about 30%.
Classification
Primary SS (pSS) occurs alone, while secondary SS is associated with other autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It is further classified into glandular SS (stage I: only sicca symptoms) and extraglandular SS (stage II: with systemic organ involvement). Stage III is when malignant lymphoma develops.
Extraglandular manifestations occur in 30–70% of patients with pSS. These include respiratory, renal, skin, joint, autoimmune thyroiditis, and gastrointestinal symptoms. Neurological symptoms are reported in 2–60% of cases. Additionally, 5% develop non-Hodgkin lymphoma (B-cell origin).
pSS may initially present with atypical systemic symptoms without sicca symptoms.
Gao Y et al. reported a case of a 35-year-old woman who presented to the emergency department with limb weakness, severe hypokalemia (1.7 mmol/L), and acute myopathy (CK 7586 U/L)1). She had no typical ocular or oral dryness, and was ultimately diagnosed with pSS-related renal tubular acidosis (SS-RTA).
History
Henrik Sjögren (1899–1986) recorded the first case in 1930 and published it as a doctoral thesis in 1933. It gained international recognition after Bruce Hamilton translated it into English in 1943.
Primary SS occurs alone, while secondary SS is associated with other autoimmune diseases such as rheumatoid arthritis and SLE. In Japan, primary SS accounts for approximately 70% of cases. Patients positive for anti-Ro/La antibodies (seropositive type) have a higher risk of extraglandular symptoms.
Ocular Symptoms
Oral symptoms
Neurological symptoms (central nervous system: CNS)
Neurological symptoms (peripheral nervous system: PNS)
Optic neuritis / Optic neuropathy
Optic neuritis: Can be unilateral or bilateral. In a study of 82 patients, 13 had decreased visual acuity due to optic neuritis, and 1 became blind.
Subclinical optic neuritis: VEP testing detected abnormalities in 61% of examined patients. Subclinical optic neuritis was diagnosed in 12 patients via VEP.
Retrobulbar optic neuropathy: 4 out of 7 cases were asymptomatic and diagnosed only by VEP.
Cranial Nerve Disorders
Trigeminal nerve disorder: The most common cranial nerve symptom, accounting for about 50% of cases. Usually unilateral, predominantly in the maxillary branch (V2). Presents with numbness, sensory abnormalities, and dysesthesia.
Facial nerve palsy: The second most common after trigeminal nerve involvement. Bilateral palsy has also been reported.
Oculomotor nerve palsy: Diplopia and eye movement disorders. Recurrent III and VI nerve palsies, as well as multiple cranial nerve palsies involving III, V, VI, VII, IX, and X simultaneously, may occur.
Optic neuritis (unilateral or bilateral), trigeminal nerve disorders (facial numbness or sensory abnormalities), diplopia due to oculomotor or abducens nerve palsy, and supranuclear ophthalmoplegia may occur. VEP testing can also detect subclinical optic neuritis without symptoms.
Autoimmune mechanism
Etiology
Genetic predisposition, immunological factors, and environmental factors are involved. Environmental factors such as EBV, HTLV-I, and HCV infection have been implicated.
Risk factors
Mechanism of tear reduction
The main type is aqueous tear-deficient dry eye due to inflammatory destruction of the lacrimal gland, but immunological inflammation and blink-related friction also play a role.
Several diagnostic criteria are used in different countries. The main criteria are shown below.
Revised Diagnostic Criteria of the Japanese Ministry of Health and Welfare Research Group (1999): SS is diagnosed when 2 or more of the 4 items are positive.
| Item | Examination content |
|---|---|
| ① Biopsy pathology | Labial/lacrimal gland biopsy: ≥1 focus per 4 mm² |
| ② Oral examination | Sialography Stage 1 or higher, or decreased salivary secretion + scintigraphy |
| ③ Ophthalmic examination | Schirmer test ≤5 mm/5 min + rose bengal van Bijsterveld score ≥3, or Schirmer test ≤5 mm/5 min + positive fluorescein staining |
| ④ Serological test | Anti-SS-A/Ro positive or anti-SS-B/La positive |
2002 American-European Consensus Group Criteria: 4 or more of 6 items (IV and VI mandatory).
2012 SICCA criteria: Requires 2 out of 3 items based on objective measurements.
Exclusion criteria: History of head and neck radiation, hepatitis C, AIDS, lymphoma, sarcoidosis, graft-versus-host disease (GVHD), IgG4-related disease.
When optic neuritis is present, anti-SS-A and anti-SS-B antibody tests are performed to confirm SS. Differentiation from MS, NMOSD (check anti-AQP4 antibodies), SLE, and sarcoidosis is important.
In Japan, according to the 1999 revised criteria of the Ministry of Health and Welfare, diagnosis is made when two or more of the following four items are positive: biopsy pathology, oral examination, ophthalmological examination (Schirmer test I method + keratoconjunctival staining), and serum autoantibodies (anti-SS-A/Ro, anti-SS-B/La). If neuro-ophthalmic symptoms are suspected, VEP, MRI, and cerebrospinal fluid examination are added.
Standard treatment is shown below.
Prescription examples are as follows.
Preservative-free eye drops are recommended.
Other management
For hypokalemia associated with SS-related renal tubular acidosis (SS-RTA), serum potassium correction is performed with oral potassium citrate (1.46 g/dose, 3 times daily)1).
Punctal plugs or surgical punctal occlusion can be used to retain tears. In severe cases that do not improve, autologous serum eye drops may be used. If inflammation is severe, preservative-free steroid eye drops may be used for a short period.
Mechanism of CNS Lesions
Direct infiltration of mononuclear cells: Inflammatory infiltration and damage to the CNS.
Vascular damage: Anti-neuronal antibodies and anti-Ro antibodies are involved in increased risk.
Ischemia due to small vessel vasculitis: Ischemic changes cause secondary nerve damage.
Mechanisms of PNS lesions
Vascular/peripheral inflammatory infiltration: Inflammatory cell infiltration around peripheral nerves.
Vasa vasorum vasculitis: Vasculitis of the vasa vasorum leads to ischemia.
Anti-neuronal antibodies and anti-M3 antibodies: Direct immunological damage to nerves.
Pathophysiology of optic neuritis: Caused by a combination of demyelination and ischemic vasculitis.
Lymphocyte infiltration into renal tubular epithelium → interstitial nephritis → distal renal tubular acidosis 1). Renal involvement in SS patients occurs at a rate of 0.3–33.5%, typically appearing 2–7 years after SS diagnosis. In severe hypokalemia (≤2.0 mmol/L), acute myopathy occurs via intracellular potassium shift → Na-K pump imbalance → cell edema → muscle degeneration → CK release into blood 1).
In a study of 82 pSS patients, subclinical optic neuritis was detected by VEP in 12 patients. VEP abnormalities were found in 61% of the patients tested. These results suggest the use of VEP as a systematic screening tool for optic neuritis in pSS patients.
NMOSD-like optic neuritis plus transverse myelitis has been reported in anti-AQP4 antibody-positive pSS patients, and the actual state of SS-NMOSD comorbidity is being investigated.
Evaluation using confocal microscopy can detect early nerve damage in pSS objectively, even when nerve density is normal, by observing budding and increased dendritic cells.
Gao Y et al. reported that severe hypokalemia (1.7 mmol/L) associated with SS-RTA can present as the initial symptom of acute myopathy (CK 7586 U/L)1). This suggests that it may be a clue to detecting atypical pSS lacking sicca symptoms.
