Sjogren’s syndrome (SS) is a systemic autoimmune disease that affects the secretory glands, especially the lacrimal and salivary glands. The disease is also known as autoimmune exocrine gland epithelial cell infection or autoimmune exocrinopathy because the immune inflammatory response is mainly manifested in the epithelial cells of the exocrine glands. The disease is divided into two categories: primary (pSS) and secondary (sSS), the former refers to SS without another clearly diagnosed connective tissue disease (CTD); the latter refers to SS occurring in another clearly diagnosed CTD, such as: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), etc.
The prevalence of dry syndrome in China is 0.29%~0.77%, and the prevalence in the elderly population is 3%~4%, with nearly 10 million patients worldwide. The disease is more common in women, the ratio of men to women is 1:9~1:20. The age of onset is mostly 40~50 years old, but it is also seen in children. In addition to dry mouth and dry eyes due to damaged salivary glands and lacrimal glands, other exocrine glands and other organs outside the glands are also involved and symptoms of multi-system damage occur, such as pulmonary fibrosis, liver cirrhosis, renal tubular acidosis, etc. The likelihood of lymphoma is 44 times higher than that of the normal population. Through the observation of our long-term outpatients, we found that about 63.8% of the patients were not diagnosed in time, mainly due to the lack of attention of the patients and the low awareness of the disease among the population and even medical workers.
Clinical characteristics
The onset of the disease is insidious, and most patients have difficulty in stating a clear time of onset.
1. Local manifestations
(1) Dry mouth: due to salivary gland lesion, the lack of salivary mucin causes the following common symptoms: ① 70%~80% of patients complain of dry mouth, but it is not always the first symptom or the main complaint. 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. (3) Mumps, 50% of patients show intermittent alternating parotid swelling and pain, involving unilateral or bilateral. Most of them can subside 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 The oral mucosa appears ulcerated or secondary 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 infection of the eyelid margin, conjunctivitis, keratitis, etc.
(3) Other superficial sites such as the nose, hard palate, trachea and its branches, mucosa of the digestive tract, and exocrine glands of the vaginal mucosa can be involved, causing less secretion and corresponding symptoms.
2. systemic manifestations In addition to dryness of the mouth and eyes, patients may also develop systemic symptoms such as malaise and 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, as rice-grain-sized red papules with clear borders, which do not fade when pressed and appear 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: not serious, does not cause ulceration of the finger end or the corresponding tissue atrophy.
(2) Skeletal muscle: arthralgia is more common. Only a small proportion of the disease is characterized by joint swelling, but it is not severe and is transient. Destruction of joint structures is not a feature of the disease. Myositis is seen in about 5% of patients.
(3) Kidney: Domestic reports show that about 30% to 50% of patients have kidney damage, mainly involving the distal renal tubules, manifested 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 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 can lead to respiratory failure and death in a minority of cases. Early interstitial lung lesions are not apparent on lung X-rays and can only be detected by high-resolution lung CT. Another 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 can have non-specific symptoms such as atrophic gastritis, decreased gastric acid, and dyspepsia due to lesions of the exocrine glands in its mucosal layer. About 20% of patients have liver damage, especially some patients with combined autoimmune hepatitis or primary biliary cirrhosis. 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: The disease may present with leukopenia or/and thrombocytopenia, and in severe cases of low platelets may be accompanied by bleeding. The incidence of lymphoma in this disease is about 44 times higher than that in the normal population. Angioimmunoblastomatous lymphadenopathy (with macroglobulinemia), non-Hodgkin’s lymphoma, and multiple myeloma have been reported in pSS patients in China.
Clinical ancillary examinations
(1) Ocular examination.
1) Schirmer (filter paper) test (+), i.e. ≤5mm/5min (>5mm/5min in normal subjects).
2) Corneal staining (+), >10 staining spots in each eye.
3) tear film fragmentation time (+), i.e. ≤10 seconds (>10 seconds in normal subjects).
(2) Stomatological examination.
1) salivary flow rate (+), i.e., only ≤1.5 ml of naturally flowing saliva was collected in 15 minutes (>1.5 ml in normal subjects)
2) parotid gland imaging (+), i.e., spillage of contrast from the terminal gland is seen as a punctate, globular shadow.
3) salivary gland nucleography (+), i.e. poor absorption, concentration and excretion of nuclein from the salivary glands.
4) Histological examination of the lacrimal gland biopsy (+), i.e. 50 lymphocytes aggregated in 4 mm2 tissue is called a foci, and any foci showing ≥1 lymphocytes is (+).
(3) Laboratory tests: help to diagnose and evaluate the activity and prognosis of the disease. A variety of autoantibodies can be detected in the serum.
1) anti-SSA antibodies: the most common autoantibodies in this disease, seen in 70% of patients.
2) Anti-SSB antibodies: claimed to be the marker antibody of the disease, seen in 45% of patients.
3) Mitochondrial antibodies: are of interest for liver injury. The IgG antibodies of the M2 subtype are the most significant, and most of the patients with positive antibodies are complicated by cholestatic cirrhosis.
In 2005, Fox published an article in the lancet stating that antibodies of diagnostic significance in SS include anti-SSA, anti-SSB, RF and ANA (see Table 1).
Therapeutic approaches
Current treatment for pSS is aimed at relieving symptoms, halting disease progression, and prolonging patient survival; there is no cure for the disease.
The ideal treatment for pSS is not only to relieve patients’ symptoms of dry mouth and eyes, but also to terminate or inhibit the abnormal immune reactions occurring in patients, protect patients’ organ functions, and reduce the occurrence of lymphoma. pSS treatment includes three levels ① saliva and tear replacement therapy to improve symptoms; ② enhance the residual function of pSS exocrine glands to stimulate saliva and tear secretion; ③ systemic medication altering the immunopathological process of pSS, and ultimately protecting the exocrine glands and organ functions of patients.
The main treatment includes: (1) For patients with mild symptoms, i.e., mild symptoms of dry mouth and eyes, no extra-glandular organ involvement, normal or only mildly elevated serum antibodies and immunoglobulins, hydroxychloroquine, leucovorin and other mild botanicals can be used for treatment. (2) Azathioprine, cyclosporine, leflunomide, etc. should be given to moderate to severe patients with systemic injury such as organ involvement, and cyclophosphamide may be considered for severe visceral involvement, as well as early control of the patient’s B-cell hyperfunction state. (3) Emphasize the regular application of hormones: small doses of hormones can be given to patients with obvious symptoms, and timely dose reduction will not bring about significant adverse effects. It should be emphasized that patients with hormone application should be added with appropriate amount of immunosuppressant, and blindly think that no hormone will delay the disease. (4) Symptomatic and other treatment: local treatment for dry mouth and dry eyes of patients with dry syndrome should be emphasized, and these measures are important to relieve symptoms and reduce complications. For those who have broad-spectrum or high-titer autoantibodies in the serum and do not respond well to medical treatment, immunosorbent plasma replacement therapy can be considered, but the indications must be strictly controlled to avoid the abuse of this method.
In addition, biological agents such as Rituximab (melphalan, anti-CD20 monoclonal antibody) and Epratuzumab (humanized anti-CD22 monoclonal antibody) can clear the active auto-reactive B cells in SS patients and have proven to be promising in not only improving the patient’s symptoms but also correcting immunological abnormalities.
Some herbs may have some effect on the disease to relieve symptoms such as dry mouth and eyes or joint pain, but the immunosuppressive effect is unclear and blind use is harmful. Moreover, herbal medicines have certain side effects, and care should be taken to monitor any damage to the liver, kidneys and gonads during application.