Schegren’s syndrome is an autoimmune disease characterized by progressive destruction of the exocrine glands, resulting in dryness of the mucous membranes and conjunctiva with various autoimmune signs. If the lesion is limited to the exocrine gland itself, it is called primary Schegren’s syndrome; if it is associated with other autoimmune diseases, it is called secondary Schegren’s syndrome.
The histopathological features of Schegren’s syndrome are: atrophy of the salivary gland parenchyma, infiltration of interstitial lymphocytes, and formation of myoepithelial islands. Clinical manifestations include dry eyes, dry mouth, enlargement of salivary glands and lacrimal glands, rheumatoid arthritis and other connective tissue diseases. Zhang Lei, Department of Maxillofacial Surgery, Peking University Oral Hospital
In addition to history taking and general physical examination, commonly used examinations include: ink smear test to detect lacrimal gland secretion function, rosacea staining to detect dryness of corneal epithelium, salivary flow measurement, salivary gland angiography, nuclear function measurement, and lip gland biopsy. Laboratory tests may include accelerated blood sedimentation, increased r-globulin and serum IgG, and positive autoantibodies.
Treatment is mainly symptomatic. Artificial saliva or tears, saliva promoters, tongue electrical stimulation, acupuncture, immunomodulators, and Chinese herbal medicine can relieve symptoms or stop the progression of lesions. Surgical removal of the affected parotid gland may be considered for tumor-like types or solitary lesions with significant secondary infection. Water channel gene therapy is being investigated experimentally, and oral care, prevention and treatment of Candida albicans infection and dental caries are necessary.
Schegren’s syndrome is an autoimmune disease characterized by progressive destruction of the exocrine glands, resulting in dryness of the mucosa and conjunctiva with various autoimmune signs. If the lesion is limited to the exocrine gland itself, it is called primary Sjögren syndrome; if it is associated with other autoimmune diseases, such as rheumatoid arthritis, it is called secondary Sjögren syndrome.
[Etiology]
The exact etiology and pathogenesis of Sjögren’s syndrome are not well understood. According to some research findings, the following three conditions may be associated with the onset of the syndrome.
1. immunoregulatory defect (immunoregulatory defect) One is an abnormally active cellular immune system, manifested by monocyte infiltration with predominantly activated T cells. The other is a multigenic B-cell activation, causing r-globulinemia, elevated circulating immune complexes and autoantibody production.
2. Viral diseases alter the antigenicity of the cell surface and become stimulated by acquired antigens, stimulating B-cell activation, antibody production and causing an inflammatory response.
3. The first two conditions act together as a result of both the exogenous factor of acquired exogenous stimuli and the intrinsic factor of specific genetic factors that predispose to infection.
Histopathological manifestations are characterized by three features: parenchymatous atrophy, interstitial lymphocytic cell infiltration and myoepithelial cell island formation. According to the severity of inflammation; the lesions can be divided into three stages: ① early stage is periductal lymphocytic infiltration and focal alveolar atrophy. In the middle stage, lymphocytic infiltration and atrophy of the glandular parenchyma are more obvious, and epithelial metaplasia and myoepithelial cell proliferation appear in the ductal system. (iii) Myoepithelial island formation: At the beginning, the ductal lumen remains in the epithelial island, and with the increase of lymphocyte infiltration, the residual ductal lumen disappears, the epithelial island appears glassy, and the outer basement membrane is gradually destroyed, which is the terminal lesion. In addition to the major salivary glands, the minor salivary glands also show similar histological changes: ductal dilatation, lymphocytic infiltration, atrophy of the alveoli, destruction of the glandular lobules and marked sclerosis of the glandular body. However, myoepithelial islands in the minor salivary glands are rare. The severity of the lesions parallels that of parotid lesions.
[Clinical presentation]
Schegren’s syndrome is most often seen in middle-aged and older women, with varying lengths of time between the onset of symptoms and the time of consultation. The main symptoms include dry eyes (xerophthalmia), dry mouth (xerostomia), swelling of salivary gland and lacrimal gland, rheumatoid arthritis and other connective tissue disease. (1).
1. Oral manifestations Due to atrophy of salivary gland alveolar cells, saliva secretion is reduced and dry mouth occurs. In mild cases, there are no obvious conscious symptoms, but in more severe cases, the tongue, cheeks and throat are burning, the mouth is sticky and the taste sensation is abnormal. In severe cases, speech, chewing and swallowing are difficult. Dry food is not easy to swallow, and it is necessary to drink water when eating. When speaking for a long time, the tongue movement is not flexible. If the patient wears a full denture, it often affects its seating.
Oral examination shows that the oral mucosa is dry, and the mouth mirror adheres to the oral mucosa and cannot slide. The salivary pool at the floor of the mouth disappears. The mucosa of the lips and tongue is red, the surface of the tongue is dry and cracked, the filiform papillae on the back of the tongue are atrophied, and the surface of the tongue is smooth and flushed with a “glazed tongue”. Some patients develop oral mucosal disease, and the rate of oral Candida albicans infection increases significantly. Due to the loss of saliva cleaning, dilution and buffering effect, the incidence of caries increases significantly, and it is often violent caries.
2. Ocular manifestation (ocular manifestation) Due to the invasion of lacrimal gland, tear secretion stops or decreases, the epithelium of cornea and bulbar conjunctiva breaks the ring, causing dry keratoconjunctivitis (keratoconjunctivitis sicca). The patient’s eyes have a foreign body, abrasive or burning sensation, photophobia, pain, and visual fatigue. There is little or no tearing when emotional or irritated. A thick mucus-like gel-like discharge is often present in the conjunctiva of the inferior fornix, which can be held with tiny forceps and pulled into thin strips. The enlarged lacrimal gland may cause difficulty in opening the eyes and a narrowing of the lid fissure, especially in the lateral portion, resulting in a triangular eye. When the enlargement is severe, it can block vision.
Swelling of salivary glands is most common in parotid glands, but can also be accompanied by enlargement of submandibular glands, sublingual glands and minor salivary glands. Most of them are bilateral, but they can also occur unilaterally. The parotid glands are diffusely enlarged (diffuse swelling) with inconspicuous borders, smooth surface and no adhesions to surrounding tissues. In the absence of secondary infection, the gland is firm to palpation without pressure, and there is little or no salivary secretion at the ductal opening when the gland is squeezed. Due to the decrease in saliva, secondary retrograde infection can be caused, and the parotid gland is repeatedly swollen with slight tenderness. When the gland is squeezed, there is cloudy snow-like saliva or pus flow. In a few cases, nodular masses can be palpated in the gland, one or more, or a single larger mass with a moderately soft texture, often with poorly defined boundaries and no pressure pain, which is tumor-like Sjögren syndrome.
4. manifestations of other exocrine gland involvement In addition to salivary glands and lacrimal glands, there may also be involvement of upper and lower respiratory secretion glands and skin exocrine glands. The mucosa of the nasal cavity is dry and crusty, and the nasal septum is even perforated. The larynx and bronchi are dry, with hoarseness and chronic dry cough. Involvement of sweat and sebaceous glands results in dryness or atrophy of the skin.
Connective tissue diseases: about 50% of patients have rheumatoid arthritis and about 10% have systemic lupus erythematosus (SLE). In addition, there may be scleroderma, polymyositis, etc.
6. other complications Interstitial lymphocyte infiltration can lead to tubular insufficiency, reduced urinary concentration capacity, and hypotonic urine. Creatinine clearance is reduced and renal tubular acidosis occurs, but chronic renal failure rarely occurs. Eustachian tube obstruction can cause otitis media, and lesions can also involve nerves, muscles, and blood vessels, with peripheral neuritis of sensory nerves, manifesting as numbness, tingling sensation, or sensory hypersensitivity, and muscle lesions manifesting as polymyositis or myasthenia gravis. Vascular lesions include small arteritis, cyanosis of the hands and feet, and Raynaud phenomenon. The thyroid gland may also present with Hashimoto’s thyroiditis.
[Diagnosis]
In addition to history and general physical examination, the following tests may be performed to aid in the diagnosis.
Schirmer test is used to detect the secretory function of the lacrimal gland. Two pieces of 5 x 35 mm2 filter paper are placed at the junction of the inner 1/3 and middle 1/3 of the lid fissure, and the wetting length of the filter paper is checked after 5 min of eye closure.
2. Tetraiodotetrazolium fluorescein staining, also known as rose bengal staining. A drop of 1% tetraiodotetrazolium fluorescein is placed in the conjunctival sac and immediately rinsed with saline. A bright red stain can be found in the exposed lid area of the cornea, which is typical of a dry corneal epithelium.
3. Saliva flow measurement (sialometry) Saliva secretion is influenced by many factors and the methods and standards are different. A collector (Lashley cup) can be used to collect parotid saliva specifically (Figure 9-18) or simply to collect total saliva. The simplest method is to take 5 grams of white wax and ask the patient to chew it for 3 minutes; less than 3 ml of total saliva is considered reduced secretion.
Figure 9-18
Figure 9-18 Lashley cup used to collect saliva from the parotid gland
4. Salpingography (sialography) is one of the main diagnostic methods for Schegren’s syndrome. Lateral sialography and 5-minute functional sialography are routinely taken during the filling phase. The main manifestations are dilatation of the terminal ducts of the salivary glands (duct ectasia) and hypovolemia (Figures 9-19, 20).
Figure 9-19
Figure 9-19 Filling phase of parotid gland imaging in Schegren’s syndrome
Figure 9-20
Figure 9-20 Parotid gland imaging in Schegren’s syndrome during the emptying phase
In milder lesions, there is no significant change in nuclear uptake and only delayed secretion; in more severe lesions, both uptake and secretion are depressed.
6. laboratory findings: erythrocyte sedimentation rate (ESR) may be accelerated, plasma globulin, mainly r-globulinemia, serum IgG may be significantly increased, IgM and IgA may be increased. Autoantibodies (autoantibodies), such as rheumatoid factor (rheumatoid factor), antinuclear antibody (antinuclear antibody), anti-SS-A (anti-SS-A), and SS-B (anti-SS-B) antibodies may be positive (Table 9-1).
Table 9-1 Possible abnormalities in serological examination of Schegren’s syndrome
Item Abnormal manifestation
Hemoglobin Accelerated
r-globulin Elevated
IgG markedly elevated
IgM may be elevated
IgA may be elevated
Positive rheumatoid factor (RF)
Anti-nuclear antibody (ANA) Positive
Anti-SS-A antibody Positive
Anti-SS-B antibody Positive
Anti-salivary gland ductal epithelial cell antibodies Positive
CD4+ (helper T cells) Increased
CD8+ (suppressor T cells) decreased
7. labial gland biopsy shows lymphocytic and plasma cell infiltration in the glandular lobules, atrophy of the glandular parenchyma, dilation of the ducts, and ductal cell hyperplasia. Unlike the major salivary glands, myoepithelial islands are rare. It should be noted that the lacrimal gland is also one of the target tissues for immune diseases other than Schegren’s syndrome, so similar manifestations can be seen in rheumatoid arthritis and systemic lupus erythematosus, and the diagnosis should be closely related to the clinical picture.
[Treatment]
Symptomatolytic therapy is the main treatment. Dry eyes can be treated with 0.5% methylcellulose drops to relieve the symptoms of dry eyes. For dry mouth, artificial saliva can be used to moisten the mouth to relieve the discomfort.
Salivary stimulant (sialogogue) can promote salivary secretion from the surviving glands, and is often taken orally with sialor, which has the effect of stimulating cholinergic receptors and stimulating salivary secretion, three times a day, one tablet (25mg) each time.
Salivary secretion is regulated by the nervous system, and stimulation of the tongue and palate by low voltage increases the stimulation of salivary secretion. These stimuli are transmitted through the nervous system to the central nervous system, which in turn feeds back to the salivary gland tissue, allowing the surviving salivary gland tissue to perform its function. It is useful for those with less disrupted glandular tissue, but less effective for those with heavy disruption. Traditional acupuncture treatment can also promote salivary secretion and relieve dry mouth symptoms.
Immune dysfunction in patients with Schegren’s syndrome can be treated with immunomodulator. Thymulin (thymulin) 10mg intramuscularly, once every other day, for 3 months as a course of treatment, 2 courses per year. It is effective for patients with recurrent swelling of the parotid gland.
Chinese herbal medicine can relieve symptoms and stop the progression of lesions. The treatment plan should be formulated after identifying the symptoms. The usual treatment rule is “nourish Yin and produce fluid, clear heat and moisten dryness”. Commonly used medicines include Chai Hu, Gardenia jasminoides, Mai Dong, Sheng Di, Sha Shen, Sang Ye, Chrysanthemum and Licorice. Golden lotus flower, oral inflammation clear punch, Qiju Dihuangwan and other Chinese medicines can also be applied.
Immunosuppressants such as quinoline chloride, prednisone, and leucovorin can be considered for patients with secondary Schegren’s syndrome with rheumatoid arthritis or tumor-like Schegren’s syndrome, but the condition is recurrent and the side effects are large, causing stomach discomfort and inhibiting the hematopoietic system. There are reports of pseudolymphoma turning into true malignant lymphoma after cyclophosphamide use, so cyclophosphamide should be used with great caution.
For tumor-like Schegren’s syndrome, surgical treatment can be used to remove the affected gland to prevent malignant transformation. Surgical removal of the affected parotid gland may also be considered in cases of solitary primary lesions with severe glandular destruction or significant secondary infection.
With the development of molecular biology, various gene therapies have emerged. It has been shown that mammalian cell membrane water secretion is controlled by aquaporins (AQP), and five aquaporins have been isolated from mammalian cells and are regulated by five corresponding water channel genes. The adenovirus-mediated AQP5 gene was injected retrogradely into the submandibular gland of rats with 20Gy radiation to the head and neck, and the salivary secretion of the radiation-injured submandibular gland was restored to the level of the normal submandibular gland, while the salivary secretion of the radiation-injured submandibular gland in the control group without gene therapy was only 1/4 of the normal submandibular gland. If successful, it is expected to enter clinical use.
Patients with Schegren’s syndrome often develop oral Candida albicans infection, mucosal inflammation, and dental caries. Therefore, attention should be paid to oral hygiene and protection to reduce the chance of retrograde infection. Candida albicans infection can be applied to the mucous membrane, tongue back surface with mycobacterial glycerin, oral fluconazole, etc. Active prevention and treatment of dental caries, with acute inflammation can be treated with antibiotics. Schegren’s syndrome is generally benign process, but very few patients can develop malignant change. Chused et al. reported that the malignancy of lymphatic and epithelial components is significantly more than that of epithelial component. Chused et al. reported that patients with primary Schegren’s syndrome with parotid swelling and no anti-salivary duct antibodies had a significantly higher incidence of malignant lymphoma than patients with secondary Schegren’s syndrome without parotid swelling and with anti-salivary duct antibodies. For patients with primary Schegren’s syndrome, swollen parotid glands, negative anti-salivary duct antibodies, preexisting hypergammaglobulinemia and progressive decline in IgM, and gradual disappearance of various serum antibodies, the occurrence of malignant lymphoma should be alerted.