Overview
Dry syndrome (Sjogren’s syndrome, SS) is a chronic inflammatory autoimmune disease that mainly involves exocrine glands. It is also known as autoimmune exocrine gland epithelial cell inflammation or autoimmune exocrinopathy because the immune inflammatory response is mainly manifested in the epithelial cells of the exocrine glands. In addition to dry mouth and eyes due to decreased function of salivary glands and lacrimal glands, other exocrine glands and other organs outside the glands are also involved, resulting in multisystem damage. The disease is characterized by a variety of autoantibodies and hyperimmunoglobulinemia in the serum. The disease is divided into two categories: primary and secondary, the former refers to dry syndrome without another clearly diagnosed connective tissue disease (CTD). The latter refers to the dry syndrome that occurs in another CTD with clear diagnosis such as systemic lupus erythematosus (SLE), rheumatoid arthritis and so on. This guideline mainly describes primary dry syndrome.
Primary dry syndrome is a global disease, the prevalence of which is 0.3%~0.7% in our population, and the prevalence of which is 3%~4% in the elderly population. The disease is more common in women, and the ratio of men to women is 1:9~20. The age of onset is mostly from 40 to 50 years old. It is also seen in children.
Clinical manifestations
The onset of the disease is insidious, and it is difficult for most patients to say when the disease started. The clinical manifestations are diverse. The severity of the disease varies greatly.
1.Local manifestations
(1) Dry mouth: due to salivary gland lesions, the lack of salivary mucin causes the following common symptoms.
(1) 70%～80% of patients complain of dry mouth, but it is not necessarily the first symptom or the main complaint. In serious cases, the oral mucosa, teeth and tongue are sticky so that it is necessary to drink water frequently when speaking, and it is necessary to send down with water or liquid food when eating solid food, and sometimes it is necessary to get up and drink water at night.
Rampant dental caries is one of the characteristics of this disease. About 50% of the patients have multiple caries which is difficult to control the development, and it shows that the teeth gradually become black, then small pieces fall off, and finally only the residual roots remain.
(iii) In adult mumps, 50% of patients present with intermittent alternating painful swelling of the parotid gland, involving unilaterally or bilaterally. Most of them resolve on their own in about 10 days, but sometimes the enlargement persists. 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 lymphoma.
④The tongue shows painful tongue, dry and cracked tongue, and atrophied and smooth tongue papillae.
⑤ Oral mucosa appears to be ulcerated or secondary to infection.
(2) Dry keratoconjunctivitis
This is due to the decrease of mucin secreted by the lacrimal gland and presents with symptoms such as dry eyes, foreign body sensation, few tears, and in severe cases, painful crying without tears. Some patients have recurrent purulent infections of the eyelid margin, conjunctivitis, and keratitis.
(3) Other superficial areas such as nose, hard palate, trachea and its branches, mucosa of digestive tract, and exocrine glands of vaginal mucosa can be involved, causing less secretion and corresponding symptoms.
2.Systemic manifestations In addition to dry mouth and eyes, patients may also have systemic symptoms such as weakness and low fever. About 2/3 of patients have systemic damage.
(1) Skin
The pathological basis of skin lesions is local vasculitis. There are the following manifestations ① Allergic purpura-like rash: mostly seen in the lower extremities, it is a rice-grain sized red papule with clear borders, does not fade when pressed, and appears in batches. Each batch lasts for about 10 days and can fade on its own with brown pigmentation. ②Erythema nodosum is less common. (3) Raynaud’s phenomenon is not serious and does not cause ulceration of the finger end or atrophy of the corresponding tissue.
(2) Skeletal muscle
Arthralgia is more common. Only a small percentage of joints are swollen, but most of them are not serious and transient. Destruction of joint structures is not a characteristic feature of the disease. Myositis is seen in about 5% of patients.
(3) Kidney
In China, renal damage is reported in about 30% to 50% of patients, mainly involving the distal tubules, and manifests as hypokalemic muscle paralysis due to type I renal tubular acidosis, and in severe cases, renal calcification, kidney stones and chondromalacia. Nephrogenic dysuria, which manifests as polyhydramnios and polyuria, is also frequently seen in patients with renal tubular acidosis. A subclinical form of renal tubular acidosis can be seen in about 50% of patients by ammonium chloride loading test. Proximal renal tubular damage is less common. A small proportion of patients present with more pronounced glomerular damage, with clinical manifestations of massive proteinuria, hypoalbuminemia and even renal insufficiency.
(4) Lung
Most patients have no respiratory symptoms. Those with mild involvement present with a dry cough and those with severe involvement present with shortness of breath. The main pathology of the lungs is interstitial lesions, with some developing diffuse interstitial lung fibrosis, which may result in respiratory failure and death in a minority. Early interstitial lung lesions are not apparent on lung X-rays and can only be detected by high-resolution lung CT. A small percentage of patients develop pulmonary hypertension. Those with pulmonary fibrosis and severe pulmonary hypertension have a poor prognosis.
(5) Digestive system
The gastrointestinal tract may show non-specific symptoms such as atrophic gastritis, decreased gastric acid, and dyspepsia due to lesions of the exocrine glands in its mucosal layer. Approximately 20% of patients have liver damage, and the clinical spectrum varies from jaundice to no clinical symptoms with liver function impairment. Liver pathology is diverse, with changes such as infiltration of small intrahepatic bile duct walls and their surrounding lymphocytes and destruction of the border plate being prominent. Chronic pancreatitis is also not uncommon.
(6) Nerve The incidence of involvement of the nervous system is about 5%. Peripheral nerve damage is the most common, and either central or peripheral nerve damage is associated with vasculitis.
(7) Hematologic system
The disease may present with leukopenia or/and thrombocytopenia, and bleeding may occur in severe cases of low platelets. The incidence of lymphoma in this disease is about 44 times that of normal population. In China, there are reports of angioimmunoblastoma lymphadenopathy (with macroglobulinemia), non-Hodgkin’s lymphoma, multiple myeloma, etc. in patients with primary dry syndrome.
Diagnostic points
1.Symptoms and signs
(1) Oral symptoms
(1) Dry mouth every day for more than 3 months, need to drink water frequently, wake up in the middle of the night to drink water, etc;
(2) Recurrent or persistent enlargement of the parotid gland after adulthood;
③ Difficulty in swallowing dry food, which must be assisted by water;
④ Rampant dental caries, dry and cracked tongue, and oral infection with mycobacteria;
(2) Eye symptoms
① Daily unbearable dry eyes that last for more than 3 months;
(2) Repeated feeling of “sand” blowing into the eye or frosting sensation;
(3) The need for artificial tears three or more times a day;
(3) Other symptoms such as vaginal dryness, dry itchy skin, clinical or subclinical renal tubular acidosis, or other systemic symptoms mentioned above.
2.Auxiliary examination
(1) Eye
(1) Schirmer (filter paper) test (+), i.e. ≤5mm/5min (>5mm/5min in normal subjects);
② Corneal staining (+), with >10 staining points in each eye;
③ tear film fragmentation time(+), i.e. ≤10 seconds (>10 seconds in normal subjects);
(2) Oral cavity
① Salivary flow rate (+), i.e. only natural outflow of saliva ≤1.5ml was collected in 15 minutes (normal subjects >1.5ml);
② Parotid gland contrast (+), i.e., spillage of contrast agent from the terminal gland is seen as a dotted or globular shadow;
④ Salivary gland nuclide examination (+), i.e. poor absorption, concentration and discharge of nuclide from salivary glands;
⑤ Histological examination of lacrimal gland biopsy (+), i.e. 50 lymphocytes aggregated in 4mm2 tissue is called a foci, and any foci showing lymphocytes ≥1 is (+).
(3) Urine PH >6 many times is necessary to further check the indicators related to renal tubular acidosis.
(4) Peripheral blood tests may reveal low platelets or occasional hemolytic anemia
(5) Serum immunological tests
(1) Anti-SSA antibodies are the most common autoantibodies in this disease and are seen in 70% of patients;
② Anti-SSB antibody is said to be the marker antibody of the disease and is seen in 45% of patients;
(3) Hyperimmunoglobulinemia, both polyclonal, seen in 90% of patients.
(6) Others such as pulmonary imaging, liver and kidney function measurements can be found in patients with corresponding systemic damage.
3.Diagnostic criteria
The international classification (diagnosis) criteria of dry syndrome in 2002 are as follows.
Table 1 Items of dry syndrome classification criteria
I. Oral symptoms: 1 or more of 3 items
1.Sensation of dry mouth daily for more than 3 months;
2.Recurrent or persistent enlargement of parotid glands in adulthood;
3.Swallowing dry food with the help of water.
II. Eye symptoms: 1 or more of the 3 items
1.Indestructible dry eyes daily for more than 3 months;
2.Repeated sand in the eye or gritty feeling;
3.Need to use artificial tears 3 or more times a day.
III. Ocular signs: Positive for any 1 or more of the following tests
1. Schirmer I test (+) (?5 mm/5 points);
2. Corneal staining (+) (?4 van Bijsterveld scale).
IV. Histological examination: pathology of the lower lacrimal gland showed foci of lymphocytes ? 1 (defined as a foci with at least 50 lymphocytes aggregated in the interstitial lacrimal gland in 4 mm2 tissue).
V. Salivary gland damage: Positive for any 1 or more of the following tests;
1. Salivary flow rate (+) (?1.5 ml/15 min);
2. Parotid angiography (+);
3.Salivary gland isotope examination(+)
VI, autoantibodies: anti-SSA or anti-SSB (+) (double diffusion method)
Table 2 Specific classification of the above items
1.Primary dry syndrome: Without any underlying disease, the diagnosis is made if the following 2 items are present.
a. 4 or more of the items in Table 1 are met, but must contain entry IV (histological examination) and/or entry VI (autoantibodies);
b. Positive for any 3 of the 4 entries III, IV, V, VI.
2. Secondary dry syndrome: The patient has an underlying disease (e.g. any connective tissue disease) while meeting any 1 of entries I and II of Table 1 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, lymphoma, nodal disease, GVH disease, and application of anti-acetylcholine drugs (e.g., atropine, scopolamine, bromopamine tylenol, belladonna, etc.).
4. This disease needs to be differentiated from the following diseases
(1) Systemic lupus erythematosus
Dry syndrome is mostly seen in middle-aged and elderly women, fever, especially high fever is uncommon, no zygomatic rash, dry mouth and eyes are obvious, renal tubular acidosis is its common and main renal damage, hyperglobulinemia is obvious, hypocomplementemia is rare, prognosis is good.
(2) Rheumatoid arthritis
The symptoms of joint inflammation in dry syndrome are much less obvious and severe than those of rheumatoid arthritis, and there is rarely joint bone destruction, deformity and functional limitation. Anti-SSA and anti-SSB antibodies are rarely seen in people with rheumatoid arthritis.
(3) Dry mouth in non-autoimmune diseases, such as senile exocrine gland function decline, diabetic or drug-related dry mouth depends on the medical history and the individual characteristics of each disease to differentiate.
Treatment options and principles]
There is no cure for this disease. The main measures are to improve the symptoms, control and delay the progress of tissue and organ damage caused by immune response and secondary infection.
1.Improve the symptoms
(1) It is difficult to reduce dry mouth, you should stop smoking, drinking alcohol and avoid taking drugs that cause dry mouth, such as atropine. Keep the mouth clean, rinse the mouth regularly, reduce the possibility of dental caries and oral secondary infection. Overseas, parasympathetic acetylcholine stimulants such as pilocarpine tablets and similar products can be taken to stimulate the secretion of the salivary glands that have not been destroyed to improve the symptoms of dry mouth. They have certain efficacy but also more adverse effects such as sweating and frequent urination.
(2) Dry keratoconjunctivitis can be treated with artificial tear drops to reduce dry eye symptoms and prevent corneal damage. Some eye ointments can also be used to protect the cornea. Some people abroad use self-serum treated with eye drops.
(3) Non-steroidal anti-inflammatory drugs and hydroxychloroquine can be used for muscle and joint pain.
Hypokalemia: Correction of hypokalemic episodes of paralysis can be done with intravenous potassium supplementation (potassium chloride), and after the condition stabilizes, it is changed to oral potassium salt solution or tablets, which some patients need to take for life to prevent the reoccurrence of hypokalemia. Most patients can still live and work normally after the correction of hypokalemia.
Systemic damage should be treated according to the severity of the damaged organ. Adrenocorticotropic hormone should be given in the same doses as in other connective tissue diseases in cases of combined neurological, glomerulonephritis, interstitial lung lesions, liver damage, low blood cells, especially low platelets, and myositis. Immunosuppressive agents such as cyclophosphamide and azathioprine may be used in combination with other drugs for rapidly progressing disease. Combination chemotherapy is recommended for those with malignant lymphoma in an aggressive and timely manner.
Prognosis
The prognosis of this disease is good. Most of the patients with visceral damage can be controlled to achieve remission after appropriate treatment, but the disease can recur after stopping treatment. Among the visceral damage, those with progressive pulmonary fibrosis, central neuropathy, glomerular damage with renal insufficiency, and malignant lymphoma have a poor prognosis, while the rest of the systemic damage are mostly in remission and even resume daily life and work after appropriate treatment.