Dry syndrome is a chronic inflammatory autoimmune disease involving exocrine glands throughout the body, mainly invading the lacrimal and salivary glands and manifesting as dryness of the eyes and mouth; however, extra-glandular systems such as the respiratory, digestive, urinary tract, nerves, muscles, and joints can be damaged. Dry syndrome was first described systematically by ophthalmologist Herlrik Sjogren, so it is now named after him, that is, Sjogren syndrome. The disease is divided into two categories: primary and secondary, and the latter refers to the dry syndrome that occurs in another clearly diagnosed connective tissue disease (CTD) such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. This chapter mainly describes primary dry syndrome . The prevalence of primary desiccation syndrome in our population is 0.3%-0.7%, and the prevalence in the elderly population is 3%-4%, and there are obviously more female patients than male.
Etiology and pathogenesis
Etiology
The etiology of pSS is still unclear, and most scholars believe that it is the result of the interaction of multiple etiologies, such as infectious factors, genetic background, and endocrine factors that may be involved in the development and perpetuation of the disease. Some viruses such as EBV, hepatitis C virus, and HIV may have a non-directive etiology. Viruses can induce autoimmune reactions or even cause autoimmune diseases by molecularly mimicking cross-reactivity or by exposing susceptible individuals or their tissues to hidden antigens during the infection process. For example, autoantigen cytosolic lining protein (α-fodrin, a kind of skeletal protein in mouse salivary gland), which is related to glandular secretion function and T cell proliferation, anti-α-fodrin antibody can appear in the serum of dry syndrome. If SSA and SSB are not cleared at the time of apoptosis, they may become auto-antigens in susceptible individuals. Epidemiological investigations have demonstrated a higher incidence of the disease in patient families than in the normal population. No recognized HLA susceptibility genes have been identified in genetic testing investigations.
Pathogenesis
The main basis for the pathogenesis and continuity of the disease is immune dysfunction. The ductal epithelial cells of salivary gland tissue may act as antigen-presenting cells, presenting their own (foreign) antigens and MHC molecular complexes, which are recognized by T-cell receptors and lead to activation and proliferation of T and B cells, which differentiate into plasma cells and produce large amounts of immunoglobulins and autoantibodies. The antigen-presenting cells and activated T cells produce a large number of inflammatory cytokines that cause an immune inflammatory response. At the same time, the function of NK cells decreases. It has been proposed that inflammatory cytokines in the salivary gland cause functional changes in the receptors of undamaged salivary gland epithelial cells, which are unable to receive information from local nerves and thus cannot secrete saliva.
Pathological changes
The disease mainly involves the exocrine glands composed of columnar epithelial cells. The pathology is represented by lesions of the salivary and lacrimal glands, which are characterized by massive lymphocytic infiltration of the glandular interstitium, dilation and narrowing of the glandular duct lumen, and destruction and atrophy of the epithelial cells of the minor salivary glands, which are severely impaired. Similar lesions involve exocrine glands of other systems, such as the skin, respiratory mucosa, gastrointestinal mucosa, vaginal mucosa, and tissues of internal organs with exocrine glandular structures, including renal tubules, bile ducts, and membrane glandular ducts. Vascular damage is also a fundamental lesion of the disease, including infiltration of small vessel walls or perivascular inflammatory cells, sometimes embolization of the lumen, and inadequate local tissue blood supply. Both of these lesions, especially inflammation of the exocrine glands, are the basis for the specific clinical manifestations of the disease.
Clinical manifestations
I. Local manifestations
( I ) Dry mouth disease due to salivary gland lesions caused by the following common symptoms.
(1) 70%~80% of patients complain of dry mouth, and in severe cases, the oral mucosa, teeth and tongue become sticky so that they need to drink water frequently when speaking, and solid food must be sent down with water or fluids when eating.
(2) Rampant caries: that is, multiple caries with uncontrollable development, manifesting as gradual blackening of teeth, followed by small pieces falling off, and finally leaving only the residual roots. It is seen in about 50% of the patients. It is one of the characteristics of this disease.
(3) Adult mumps: about 50% of patients have intermittent painful swelling of the parotid gland, unilateral or bilateral, which may subside in about 10 days. A few have submandibular gland enlargement, and less frequently sublingual gland enlargement. Some of them are accompanied by fever. Some of them have persistent enlargement of the parotid gland and should be alerted to the possibility of malignant dialectal tumor.
④ Tongue: It may manifest as tongue pain, dry and cracked tongue, atrophied and smooth tongue papillae, oral cavity may appear ulcerated or secondary infection.
( II ) dry keratoconjunctivitis this due to the lacrimal gland secretion of mucin reduced and dry eyes, foreign body sensation, less tears and other symptoms, severe cases cry without tears, some patients have recurrent chemical service infection, conjunctivitis, keratitis, etc. at the edge of eye risk.
( C ) Other superficial parts such as nose, sclerotia, trachea and its branches, mucosa of digestive tract, exocrine glands of vaginal mucosa can be involved, making them secrete less and show corresponding symptoms.
In addition to dryness of the mouth and eyes, systemic symptoms, such as weakness and low fever, may also appear. About 2/3 of patients have systemic damage of exocrine glands. The manifestations are
( I )
The pathological basis of cutaneous skin lesions is the damage of local blood vessels. The characteristic manifestation is a purpura-like rash, mostly on the lower extremities, which is a red papule with clear borders of the size of a grain of rice. It does not discolor under pressure and appears in batches. Each batch lasts for about 10 days and may fade on its own with brown pigmentation.
( 2 ) Skeletal muscle joint pain is more common. Only a small percentage of joints are swollen, but they are not severe and transient. Destruction of joint structures is not a feature of the disease. Myositis is seen in about 5% of patients.
( C ) Kidney Domestic reports about 30%-50% of patients have renal damage, mainly involving the distal tubules, manifested as type I tubular acidosis. This is followed by a decrease in blood potassium due to excessive renal tubular excretion and, in severe cases, periodic hypokalemic muscle paralysis. When renal tubular excretion of calcium ions increases, calcium is deposited in the renal tissue and nephrocalcification occurs. Calcium salts are deposited in the urinary tract and become kidney stones. Chondromalacia occurs when large amounts of calcium ions are excreted. Nephrogenic uremia also occurs due to impaired water reabsorption by the renal tubules, which manifests as polyuria and polyhydramnios. The ammonium chloride loading test shows that about 50% of patients have a subclinical form of renal tubular acidosis. Proximal renal tubular damage is less common. A small proportion of patients showed more pronounced glomerular damage, manifested as massive proteinuria, hypoalbuminemia or even renal insufficiency.
( IV ) Respiratory system Most patients have no respiratory symptoms. Some develop dry cough and recurrent secondary infections due to reduced secretion of glands in the trachea and its branches. Small bronchial involvement may present with large traces of lung. Interstitial lung lesions are the most common respiratory lesion in this disease (about 15%). Mild cases are mostly asymptomatic, presenting only with abnormal pulmonary function and may remain stable over time. A small percentage of patients present with progressive short, hypoxemia and pulmonary CT showing interstitial fibrosis, and those with extensive lesions often die due to secondary infection and/or respiratory failure.
( V ) The gastrointestinal tract can present with atrophic gastritis, decreased gastric acid, due to lesions of the exocrine glands of its mucosa.
Chronic diarrhea and other nonspecific symptoms. Liver damage is seen in approximately 20% of patients, with clinical manifestations of jaundice and elevated transaminases. There is disagreement as to whether the cause of liver damage is direct involvement of the small intrahepatic bile ducts or a combination of primary biliary cirrhosis or autoimmune hepatitis. The pathology of liver biopsy is diverse, with changes of chronic active hepatitis such as lymphocytic infiltration in and around the intrahepatic small bile duct wall and destruction of the border plate being more prominent. Chronic membranous adenitis is also not uncommon.
( VI ) The incidence of neurological involvement is about 5%. Peripheral nerve damage is the most common. Both central and peripheral nerve damage are associated with vasculitis.
( vii ) Hematologic system The disease may present with leukopenia or (and) thrombocytopenia, and bleeding may occur in severe cases of low platelets. Patients with this disease have significant reactive hyperplasia of lymphoid tissue and have a significantly higher chance of developing non-Hodgkin’s lymphoma than the normal population. Lymphomas are most often found in the mucosa-associated lymphoid tissue, salivary glands, and cervical lymph nodes. Multiple myeloma may also occur as a result of high monoclonal proliferation of B cells.
Laboratory and other tests
Mild anemia (25%), leukopenia (6%-33%), eosinophilia (5%-25%), and mild thrombocytopenia may occur. Blood sedimentation is increased (80%-94%).
Immunological examination: about half of the cases have decreased albumin and increased peak globulin, mainly in the γ globulin part, but also have increased α2 and β globulin. Immunoglobulins are mainly increased IgG and IgM, about 3/4 patients are positive for rheumatoid factor, often IgM type; anti-nuclear antibodies are positive (17%-68%), anti-dsDNA antibodies are rare, macroglobulin and cold globulin can be positive, there is a high viscosity syndrome; anti-thyroglobulin and anti-gastric wall cell antibodies are positive (30% each), anti-human globulin test and anti-mitochondrial antibodies are positive (10 Anti-salivary gland duct epithelial cell antibodies (ASDA) were positive in 25% of primary SS and 70% to 80% of SS combined with rheumatoid arthritis, and β2-microglobulin was increased in serum and saliva. The serum concentration can be used as an indicator of disease activity. DIF shows IgG deposits in the basal and parabasal layers of the epidermis. Peripheral blood T lymphocytes were decreased, marked by decreased Ts, increased Ia-positive T lymphocyte population, and low lymphocyte transformation test and active petal formation test. Circulating immune complexes are increased; CH50 and C3 are increased or normal, and may be decreased in the presence of vasculitis. About 2/3 of patients have defective reticuloendothelial system Fc receptor function. When benign lymphocytic proliferation of SS transforms into malignant lymphoma, hypergammaglobulinemia may become hypogammaglobulinemia and autoantibody titers decrease or become negative.
C. Ophthalmic examination
1, tear flow rate (Schirmer test) with filter paper to determine the tear flow, 5 × 35mm filter paper, bend at 5mm, put into the lower conjunctival sac, 5 seconds after observation of tear wetting filter paper length, <10mm for below normal;
2, tear film crushing time (BUT test) <10 seconds for abnormal;
3, corneal staining corneal 2% fluorescein or 1% Congo red or 1% Bengal rose red live staining (staining points <10 normal). More than 10 points are abnormal.
IV. Oral examination
1.Saliva secretion measurement of sugar content test with sucrose pressed into tablets, each tablet 800mg, placed in the center of the back of the tongue, record the time required for complete dissolution, normal <30 seconds; more than 30 seconds is abnormal.
2.Salivary flow rate was measured by using a small suction cup attached to a hollow duct and adsorbed at the opening of the unilateral parotid duct with negative pressure to collect salivary secretion, normal >0.5m1/min.
3.Parotid gland imaging is performed with 40% iodine oil to observe the morphology of the gland, whether there is destruction and atrophy, the residence time of the contrast agent in the parotid gland, narrowing or dilatation of the parotid duct; parotid gland isotope 131 iodine or 99mTc scan is performed to observe the distribution of radioactivity, whether the secretion and concentration are delayed or reduced to understand the secretory function.
4. Biopsy of the parotid gland with more than one mononuclear cell infiltrating lesion in a 4 cm2 tissue block.
Diagnosis
Classification criteria of dry syndrome
I. Oral symptoms: 1 or more of the 3 items
1.Sensation of dry mouth daily for more than 3 months;
2.Recurrent or persistent enlargement of parotid gland in adulthood;
3.Swallowing dry food with the help of water.
II. Eye symptoms: 1 or more of the 3 items
1.Feeling unbearable eye sensation daily for more than 3 months;
2.Repeated sand in the eye or gritty sensation;
3.Need to use artificial tears 3 times or more per day.
III. Ocular signs: Positive for any 1 or more of the following tests
1. Positive Schirmer’s test (≤5mm/5min);
2. Positive corneal staining.
Ⅳ, histological examination: pathology of the lower lacrimal gland showed lymphocytic foci ≥1 (at least 50 lymphocytes gathered in the interstitium of the lacrimal gland per 4 cm2 of tissue was considered a foci).
V. Salivary gland damage: positive for any 1 or more of the following tests
1. Positive salivary flow rate (≤1.5 ml/15 min);
2. Positive parotid gland imaging;
3. Positive salivary gland radionuclide examination.
VI. Autoantibodies: positive anti-SSA antibody or anti-SSB antibody (double diffusion method).
II. Specific classification of dry syndrome diagnosis
1.Primary dry syndrome: without any underlying disease, the diagnosis can be made with the following ① or ②
① Meet 4 or more of the above classification criteria, but must contain entry Ⅳ (histological examination) and/or entry VI (autoantibodies).
② Positive for any 3 of the 4 entries Ⅲ, Ⅳ, Ⅴ and VI.
2.Secondary dry syndrome: The patient has an underlying disease (any connective tissue disease) while meeting any 1 of entries Ⅰ and Ⅱ of the classification criteria items, and any 2 of entries Ⅲ, Ⅳ and Ⅴ.
3. Must exclude: history of cervical head and facial radiation therapy, hepatitis C virus infection, AIDS, nodular disease, graft-versus-host disease, and application of anticholinergic agents (e.g., atropine, scopolamine, bromopamine tylenol, belladonna, etc.).
Differential diagnosis
1.Systemic lupus erythematosus dry syndrome mostly appears in middle-aged and elderly women, fever, especially hyperthermia is uncommon, no pteroidal erythema, dry mouth and eyes are obvious, renal tubular acidosis is its common and main renal damage, hyperglobulinemia is obvious, hypocomplementemia is rare, good prognosis.
2.The progression of joint inflammation and bone damage in rheumatoid arthritis dry syndrome is much less obvious and serious than rheumatoid arthritis, and rarely causes joint deformity and low function. Rheumatoid arthritis patients rarely appear anti-SSA and anti-SSB antibodies.
SSB antibodies.
3, non-autoimmune diseases of dry mouth, such as senile, diabetic people can appear dry mouth, serum autoantibodies and globulin test can be identified.
4.Diabetes mellitus can have dry mouth symptoms in both diseases, but diabetes mellitus is more obvious with polydipsia, polyuria, polyphagia and wasting, and increased blood and urine glucose, without the eye, oral and laboratory abnormalities of dry syndrome.
5.Familial periodic paralysis both can have paralysis caused by low potassium, which can improve after potassium supplementation, but the disease often does not have other symptoms and laboratory abnormalities of dry syndrome.
Treatment
The disease is not yet curable. The main treatment is alternative and symptomatic. The aim of treatment is to prevent local damage caused by long-term dry mouth and eyes, to closely follow up and observe changes in the disease, and to prevent and control the systemic damage of the disease.
To treat dry mouth symptomatically, we should stop smoking, drinking alcohol and avoid taking drugs that cause dry mouth such as atropine, keep the mouth clean, rinse the mouth regularly, and reduce dental caries and oral secondary infections. Dry keratoconjunctivitis can be treated with artificial tear drops to reduce corneal damage. Eye ointment can also be used to protect the cornea. Non-simplified anti-inflammatory drugs are effective for muscle and joint pain.
Intravenous potassium supplements (potassium chloride) are used to correct acute episodes of hypokalemia.
Some patients need lifelong prevention of hypokalemia recurrence. Most patients can live and work more normally after the correction of hypokalemia.
For patients with combined neurological damage, glomerulonephritis, interstitial pneumonia, liver damage, low blood cells (especially low platelets), myositis, etc., glucose should be given.
The dose of glucocorticoids is the same as that used for other connective tissue diseases. Immunosuppressive agents such as cyclophosphamide and azathioprine may be used in combination with other drugs for rapidly progressing disease. Combination chemotherapy for lymphoma is recommended for those who present with malignant lymphoma.
Prognosis
The disease develops slowly and has a good prognosis. Most of the cases with visceral damage can be controlled after proper treatment. If treatment is not timely, the disease may deteriorate or even become life-threatening. Among the visceral damage, those with progressive pulmonary fibrosis, central neuropathy, glomerular damage with renal insufficiency, and malignant lymphoma have a poor prognosis; among the rest with systemic damage, most of them can go into remission or even recover to the point of daily life and work after proper treatment. Causes of death include concurrent renal failure, infection, and combined lymphoma.