Pediatric Sjogren's Syndrome

Introduction to pediatric Sjogren Sjögrenssyndrome (SS) is a chronic inflammatory disease of autoimmune exocrine glands. It can affect other organs at the same time, resulting in a variety of clinical manifestations, but with dry eyes (xerophthalmiaorkeratoconjunctivitissicca) and dry mouth (xerostomia) as the main symptoms. basic knowledge Sickness ratio: 0.05% Susceptible people: children Mode of infection: non-infectious Complications: keratitis, chronic bronchitis, diabetes insipidus, arthritis

Causes of Sjogren's Syndrome

(1) Causes of the disease

Genetic factor

(1) Histocompatibility antigen: In recent years, the frequency of some major histocompatibility complex (MHC) genes has increased in patients with Sjogren's syndrome, and human MHC is also called human. Human leucocyte antigen (HLA), associated with Sjogren's syndrome, is HLA-DR3, HLA-B8. This correlation may vary from race to race and is reported to be associated with HLA-B8 in Western European Sjogren's syndrome. Related to DR3, DRW52, HLA-DR5 in Greece, HLA-DR53 in Japan, HLA-DR8 in China, and DRW52 in male patients, HLA gene and Sjogren's syndrome itself There are also correlations between antibody production and clinical manifestations. For example, Sjogren's syndrome with HLA-DR3 and DQ1/DQ2 has high titers of anti-SSA, SSB antibodies, clinical symptoms, and vasculitis. These results suggest that some class II HLA genes may be genetic markers of susceptibility to Sjogren's syndrome. They play an important role in the pathogenesis, clinical manifestations and disease persistence of Sjogren's syndrome, but in non-dry synthesis A large number of healthy people in the levy also have HLA-DR3 or DR8. Therefore, the genetic basis is only one of the causes of Sjogren's syndrome. It is necessary to have other factors involved in the disease to cause the onset of Sjogren's syndrome.

(2) Family history: Sjogren's syndrome patients have sisters, mothers and daughters at the same time, which also suggests that there are genetic factors in the cause of the disease.

2. The virus believes that a variety of viruses may be associated with the onset of Sjogren's syndrome and the persistence of the disease, such as Epstein-Barr virus, herpesvirus type 6, cytomegalovirus, retrovirus, and the like.

(1) Epstein-Barr (EB) virus: It is a common herpesvirus that infects humans. It has the property of activating B cells with high proliferation. It is characterized by hyperglobulinemia, which can be converted into B lymphocyte tumors. In patients with syndrome, the early antigen (EA) and DNA of Epstein-Barr virus in the lacrimal gland, salivary gland, and renal tubular epithelial cells indicate that Epstein-Barr virus is actively replicating in Sjogren's syndrome patients, which continuously activates B cell proliferation and differentiation. The disease continues to linger; other scholars have also detected the DNA of Epstein-Barr virus from normal human salivary gland biopsy specimens, so it is suspected that Epstein-Barr virus is the cause of this disease.

(2) retrovirus: human immunodeficiency virus (HIV) infected with retrovirus may have dry syndrome, parotid gland swelling and other symptoms of Sjogren's syndrome, and 30% of patients with Sjögren's syndrome in serum An antibody to the HIV component P24gag protein was detected; in HTLV-1 (human T lymphocytic leukemia virus, another retrovirus), Sjogren's syndrome-like symptoms also appeared, so some people think that HIV infection may be Sjogren's syndrome. However, although HIV patients have mouth and dry eyes, they do not have anti-SSA and SSB antibodies in serum. They are not related to HLA-DR3. In addition, some SLE patients also have anti-P24 antibodies in their serum, so they cannot explain HIV or HTLV. -1 is the direct cause of Sjogren's syndrome.

(3) Hepatitis C virus: The US literature reports that hepatitis C virus has no significance in Sjogren's syndrome, unless accompanied by mixed cryoglobulinemia or other diseases, such as membrane proliferative nephritis, a report in France found in the original In the Sjogren's syndrome, hepatitis C virus infection is about 10%. These viruses can occur in the salivary glands of the lips, and it is considered that hepatitis C virus infection is one of the causes of Sjogren's syndrome. Italian scholars believe that Hepatitis C virus is dry. There is no effect on the autonomic organ damage of the syndrome. The form of lymphocyte lesion damage in chronic hepatitis C is different from that of primary Sjogren's syndrome.

3. The level of estrogen in patients with sex hormone Sjogren's syndrome is elevated, and most patients with Sjogren's syndrome are women, which is presumed to be associated with elevated estrogen.

(two) pathogenesis

Cellular immunity

(1) Lymphocytes:

1 Peripheral blood: the total number of lymphocytes and the number of CD4 and CD8 subpopulations of T lymphocytes, the ratio is 70% to 80% of Sjogren's syndrome patients are normal, but their functions may be abnormal, it has also been reported that CD8 is reduced The number of T cells with inhibitory function in CD8 is reduced, resulting in a large proliferation of B cells. CD5 B-labeled lymphocytes increase by up to 30% to 40% in dryness syndrome (normally only 15% to 25%). The cells belong to poorly differentiated or incompletely mature cells, which spontaneously secrete IgM-RF and anti-single-stranded DNA antibodies (anti-SS-DNA antibodies), so there is a significant differentiation of T and B lymphocytes in the blood surrounding Sjogren's syndrome. Mature and dysfunctional.

2 In the labial gland: a large number of lymphocyte clusters can be seen in the interstitial tissue of the parotid gland, which is mainly composed of T cells, and T cells in the T cells with the activated marker 4B4 /CD45RO predominate. 4B4 cells are activated T cells with complementary memory function. Most of the cells in the labial gland and ductal epithelial cells express HLA-DR molecules, further indicating T and B cells in the labial gland of Sjögren's syndrome. Both ductal epithelial cells were activated, and the same changes were seen in the small lacrimal gland tissue of the conjunctiva of Sjogren's syndrome.

(2) Natural killer cells: Natural killer cells are a group of extremely large lymphocytes. The number of natural killer cells in the peripheral blood of Sjogren's syndrome is normal, but the function is decreased, and monocytes in their exocrine glands (lip glands) Such cells are absent from infiltrating lesions.

2. The prominent manifestations of patients with humoral immune Sjogren's syndrome are hyperglobulinemia and various autoantibodies, reflecting the high hyperfunction of B lymphocyte function and the inhibition of T lymphocyte suppression.

(1) Hyperglobulinemia: gamma globulin in 95% of patients has increased to varying degrees, most of which are polyclonal, immunoglobulin IgG, IgM, IgA can be increased, with IgG increasing the most See, IgM or IgA is also not uncommon, it can also be increased in monoclonality, a small number of patients can appear or chain fragments in urine, hyperglobulinemia in Sjogren's syndrome compared with other connective tissue diseases such as systemic lupus erythematosus and Rheumatoid arthritis is more prominent, and B lymphocytes also have the function of synthesizing a large number of immunoglobulins in the local tissues of the labial glands.

(2) Autoantibodies: Due to the proliferation of B lymphocytes, this disease produces a variety of autoantibodies.

1 anti-SSA (Ro) antibody and anti-SSB (La) antibody: they are closely related to Sjogren's syndrome, and can also occur in some patients with systemic lupus erythematosus, all of which are of IgG type. The antigen recognized by anti-SSA antibody is intracytoplasmic. The small RNA (hy5RNA) is linked to the 60kD and 52kD protein components, both of which belong to the ribonucleoprotein complex. 80% of the antibodies that act on 52kD are from Sjogren's syndrome serum, and the antibodies that act on 60kD are often from SLE. About 85% of Sjogren's syndrome has antibodies against 52kD and 60kD. The anti-SSB antibody recognizes 47kD protein, which is different from the 60kD and 52kD proteins. Anyone with anti-SSB antibody has anti-antibiotics. SSA antibody, because the SSB molecule and SSA are linked together, the SSB RNA may be linked to a variety of proteins, including 70kD, SnRNP A and B/B proteins, SSA 60kD protein, anti-SSA, SSB antibody to Sjogren's syndrome The diagnosis has played a big role.

Two types of rheumatoid factor (RF): RF is an autoantibody that binds to the IgG-FC segment. It occurs in various autoimmune diseases such as Sjogren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus. The positive rate of IgM-RF in Sjogren's syndrome is about 50%, lower than RA (70%), higher than SLE (30%), and the RF positive rate accounts for more than 90% in our Sjogren's syndrome cases. IgM-RF also It can occur in some tumors, infections and other non-rheumatic diseases, where it only represents the body's immune disorder, but no specificity.

3 Others: anticardiolipin antibody (ACA) (25%), anti-mitochondrial antibody (20%), low titer anti-double-stranded DNA antibody (anti-ds-DNA antibody) (10%), anti-RNP antibody, and the like.

4 anti-organ antibodies: patients with Sjogren's syndrome can also appear anti-thyroid duct antibody, anti-thyroid antibodies, anti-corporeal cell antibodies.

(3) immune complex: about 80% of Sjogren's syndrome has circulating immune complexes, which are formed by a large number of autoantibodies and antigens combined and due to reticular endothelial system clearance dysfunction, serum cryoglobulin appears, often representing There is damage outside the gland.

(4) Cytokines: The cytokines (IL-1, IL-6, TNF-, IFN-) secreted by blood lymphocytes around Sjogren's syndrome and the serum cytokine levels were not abnormal. The levels of IL-2 and TNF- in serum decreased, and mR-NA expression of IL-1, IL-6, TNF- and IFN- was expressed in labial epithelial cells and mononuclear cells, suggesting that cytokines are involved. Sjogren's syndrome local, the pathogenesis of labia.

(5) Abnormal immune function, T, B lymphocytes in peripheral blood have obvious differentiation, maturation, and functional abnormalities. The animal model of Sjogren's syndrome has premature thymic decline and decreased T lymphocyte function. B lymphocyte hyperfunction appears in a variety of autoantibodies that produce immune damage, and human Sjogren's syndrome may have a similar pathogenesis.

3. Pathology The salivary glands of the disease, the lacrimal gland and any organs in the body can be affected. There are two main pathological changes.

(1) Exocrine gland inflammation: There is a large amount of lymphocytes, including plasma cells and monocytes, infiltrating between the exocrine glands composed of columnar epithelial cells. This aggregated lymphocyte infiltrative lesion is a characteristic pathological change of this disease. Appears in the salivary glands (including the small parotid glands of the lips, ankles), lacrimal glands (including the small lacrimal glands of the conjunctiva), renal interstitial, interstitial lung, digestive tract mucosa, hepatic portal, bile ducts and lymph nodes, eventually leading to local The epithelial cells of the ducts and glands proliferate, followed by degeneration, atrophy, destruction, and the loss of their proper function by replacing the fibrous tissue. Some people in the salivary gland and the lacrimal gland have a large amount of lymphocyte infiltration called pseudo-lymph. Tumor (Figure 1, 2).

(2) vasculitis: caused by cryoglobulinemia, hyperglobulinemia or immune complex deposition, is the pathological basis of this disease complicated by glomerulonephritis, peripheral and central nervous system lesions, rash, and Raynaud's phenomenon.

Pediatric Sjogren Syndrome

The current cause is not fully understood, but it is related to EB virus infection and is related to genetic factors. Active prevention and treatment of EB virus infection should have positive effects in preventing this disease.

In addition to specialist treatment, patients with Sjogren's syndrome should have less tear secretion. They should wear protective glasses, avoid light and shelter from the wind, and keep indoors moist. Because saliva secretion is less, it is necessary to use beneficial toothpaste, mouthwash after eating, periodontitis, Mold in the mouth should be treated promptly. Patients with Sjogren's Syndrome should take the initiative to inform the doctor of the condition regardless of where they go to prevent accidents due to dry airway and mucus clogging during and after surgery.

Actively treat other connective tissue diseases.

Pediatric Sjogren's syndrome Complications keratitis chronic bronchitis diabetes insipidus arthritis

Glandular skin: may occur in the parotid or submandibular gland, may be complicated by lymphoma, reticuloma, malignant lymphoma. Purpura, Hashimoto's thyroiditis, Raynaud's phenomenon, allergic vasculitis; patients with less sweat or even no sweat.

Eyes: keratitis, decreased vision or even blindness;

Respiratory system: chronic bronchitis and interstitial pneumonia;

Digestive system: atrophic gastritis; hepatosplenomegaly, chronic active hepatitis;

Urinary system: distal renal tubular acidosis and hypokalemia, renal diabetes, diabetes insipidus, kidney disease, glomerulonephritis, etc.;

Central nervous system: causing epileptic seizures, mental disorders;

Joint muscles: joint muscle pain, arthritis, myositis, etc.

Symptoms of Sjogren's Syndrome in Children Common Symptoms Dry Eyes, Parotid Gland, Hand, Foot and Cleft Palate, Dry Joint, Pain, Tongue, Nasal Bleeding, Hepatosplenomegaly, Keratitis, Renal Glucose

Sjogren's syndrome is often slow, and the initial symptoms are not obvious. Many patients do not seek medical treatment due to symptoms such as dry mouth or dry eyes, but often come from other symptoms such as joint pain, rash or fever.

Dry mouth

Due to the reduction of saliva, children have less saliva, but no symptoms. In severe cases, they often drink water frequently. When they enter solid food, they must be sent with water. About 50% of the patients' teeth are gradually blackened and powdery or small pieces fall off. Only the residual root is called sputum, which is one of the characteristics of xerostomia. The tongue is dry, has splits, the tongue nipple shrinks, the tongue is smooth, the tongue is painful, ulcers can appear, and the parotid or submandibular glands can be repeated, alternating on both sides. Swelling, especially in the parotid gland, is more common in children.

2. Dry eyes

Due to the reduction of lacrimal gland secretion, the eye is dry, "sand sensation", burning sensation, severe tears without tears, severe dry eyes can cause filamentous keratitis, causing serious foreign body sensation, red eyes, fear of light and decreased vision blindness.

3. Other parts of the exocrine gland

Glands such as the nose, throat, throat, trachea and bronchial mucosa can also be involved, leading to nasal dryness, nosebleeds, hoarseness, chronic bronchitis and interstitial pneumonia in the lower respiratory tract, esophageal dysfunction in the digestive tract, stomach acid Reduced secretion and atrophic gastritis, 35% of patients with anti-gastric cell antibody positive, 18% to 44% of patients have hepatosplenomegaly, transaminase increased, 40% of pathological changes to chronic active hepatitis, patients may have renal tubular dysfunction, serious There is distal renal tubular acidosis and hypokalemia, in addition, renal diabetes, diabetes insipidus, kidney disease, glomerulonephritis and the like can also occur.

4. Skin mucosa

There may be purpura-like rash, nodular erythema, vulvar secretion glands often affected, vulvar skin and vaginal dryness and atrophy.

5. Other organ lesions Some patients have anti-thyroid antibodies in the serum, clinically can be complicated by Hashimoto's thyroiditis, may also be accompanied by vasculitis with Raynaud's phenomenon and skin ulcers, but also peripheral nerve involvement manifested as lower extremity numbness, feeling Obstruction, central nervous system involvement can be manifested as epileptic seizures or mental disorders, and patients can also be complicated by monoclonal B-cell lymphoma.

6. Joint muscles

70% of patients have joint pain, but only 10% have arthritis, and some patients may have myositis.

Examination of pediatric Sjogren's syndrome

Blood routine

Half of patients may have mild positive cell-positive anemia, and some patients may have mild leukopenia, eosinophilia, mild thrombocytopenia, and increased erythrocyte sedimentation rate.

2. Biochemical examination

Half of the patients may have a decrease in plasma albumin and an increase in globulin. The globulin is elevated to a multi-plant peak type, mainly in the gamma globulin part, and may also be increased or beta globulin. The globulin can be as high as 40 to 60 dl, and it is more obvious in patients with polymyositis and systemic sclerosis.

3. Immunological examination

IgM, IgA, and secretory IgA are elevated, and macroglobulins and condensed agglutinin can be found in individual patients. Due to the presence of IgG and its complexes in the blood, blood viscosity sometimes increases. About 3/4 patients are positive for rheumatoid factor, often IgM type; anti-nuclear antibody positive (17%~68%), anti-dsDNA antibody is rare, macroglobulin and cryoglobulin can be positive, hyperviscosity syndrome; anti-thyroid Globulin and anti-gastric cell antibody positive (30% each), anti-human globulin test and anti-mitochondrial antibody positive (10% each); primary SS anti-SS-A antibody positive rate of 70% to 75%, Anti-SS-B antibody was 48% to 60%, while SS combined with rheumatoid arthritis was 9% and 3%, respectively. Anti-salivary ductal epithelial antibody (ASDA) was 25% positive in primary SS, and SS was combined. Rheumatoid arthritis is 70%-80%, 2 microglobulin is increased in serum and saliva (2-M), and serum concentration can be used as an indicator of disease activity. The IgG content in saliva is increased with high levels of IgA and IgMRF. DIF showed IgG deposition on the basal and basal layers of the epidermis. Peripheral blood T lymphocytes decreased, Ts decreased significantly, Ia-positive T lymphocyte population increased, lymphocyte transformation test and active petal formation test were low. Circulating immune complexes are elevated; CH50 and C3 are elevated or normal, and may decrease when vasculitis occurs. About 2/3 patients have Fc receptor function defects in the reticuloendothelial system. When the benign lymphocytosis of SS is converted into malignant lymphoma, hypergammaglobulinemia can be changed to gammaglobulinemia, and the autoantibody titer is decreased. Or overcast.

4. Eye examination:

(1) Rose red or fluorescein staining test: 2% fluorescein or 1% Congo red or 1% Bengal rose red in vivo staining (staining point <10 normal), which can show the overlap of rheumatism with ulcers.

(2) tear film breakage time: BUT test, <10 is abnormal, cornea.

(3) Schirmer test: the tear flow was measured with filter paper, and the X35mm filter paper was bent at 5mm and placed in the lower conjunctival sac. After 5", the length of the wet filter paper was observed. The normal person was above 15mm, and <10mm was lower than normal. ;

The above three positives were consistent with dry keratoconjunctivitis.

Slit lamp examination: Partially peeled corneal epithelial cells, corneal fragments or superficial corneal stroma infiltration can be found.

5. Salivary gland detection

(1) Saliva flow measurement: first put a small cup in the opening of the parotid tube, and then drop a few drops of lemon liquid to the tongue. After 5 minutes, collect the left and right parotid secretions. If it is less than 0.5ml, it will be positive; then chew the paraffin 4g, and The amount of saliva secreted by 10 min was measured, and the normal value was 10 to 20 ml, and the patient was reduced.

(2) Parotid angiography: 40% lipiodol angiography, observation of gland morphology, whether there is destruction and atrophy, contrast agent staying in the parotid gland, stenosis or dilation of the parotid duct, parotid isotope 131 iodine or 99m scan, observe radioactivity Distribution, whether its excretion and concentration are slow or reduced to understand the secretory function. Pathological changes in the gland were observed from the lip or nasal mucosa biopsy.

(3) Gram-spot scanning and radionuclide measurement, the concentration and the 99mTc function are poor, and the acid-stimulated melon is low or even disappears.

(4) Labia gland biopsy: There are more than one mononuclear cell infiltration lesions in the 4mm2 tissue block.

(5) Parotid ECT examination: After radiofrequency injection of 99m intravenously, the parotid gland was scanned in a positive position to observe its shape and size. Since saliva can concentrate 99m, it is possible to collect saliva samples at the same time and measure their radioactivity count to reflect the function of the salivary glands. The salivary gland of this disease is low in function.

6. Histopathology

The lacrimal gland, parotid gland and subgingival gland are infiltrated with a large number of lymphocytes, mainly cells. In severe cases, cell infiltration can resemble the germinal center of lymph nodes, glandular atrophy, and ductal epithelial cells proliferate to form epithelial-myoepithelial cells. The duct is narrowed or dilated and replaced by connective tissue later. Extra-glandular lymphoid infiltration can affect the dysfunction of the lungs, kidneys or skeletal muscles.

7. X-ray inspection

(1) chest radiograph or CT examination: lung changes are varied, there are extensive reticular, nodular or patchy infiltrates, with the bottom of the lungs, hilar lymph nodes, sometimes with pneumonia, pleurisy Or atelectasis, etc. (Figure 4).

(2) Skeletal radiography: The small joints of the limbs are changed to osteoporosis.

8. Anti-nuclear antibody and anti-nuclear antibody spectrum: anti-nuclear antibody, anti-SSA, anti-SSB antibody positive.

Diagnosis and differential diagnosis of pediatric Sjogren

diagnosis

The disease lacks specific clinical manifestations and laboratory projects for diagnosis. There are many diagnostic criteria in the world, but whether it is suitable for children, it needs to be further determined. Xerostomia and keratitis are the main causes of this disease. Exocrine glands, ie lesions of the salivary glands and lacrimal glands, therefore, they are the objective basis for the diagnosis of this disease, the following three basic points are the basis for the diagnosis of this disease:

1. Diagnostic criteria for xerostomia

(1) Salivary flow rate: The normal value of salivary flow rate is 0.6 ml/min on average.

(2) Parotid gland angiography: The duct and small gland are damaged when there is lesion in the parotid gland.

(3) lip mucosa biopsy: lymphatic infiltration can be seen in the glandular tissue, 50 lymphocytes are clustered into a heap called a foci, and 1 focal lymphocytic infiltration is abnormal.

(4) Radionuclide angiography: When the salivary gland is hypofunction, its intake and excretion are lower than normal.

Any of the above four trials can be diagnosed as xerostomia.

2. Diagnostic criteria for dry keratoconjunctivitis

(1) Schirmers test: The filter paper wetting length 15 mm is normal at 5 min, and 10 mm is abnormal.

(2) tear film breakup time (BUT): an abnormality is shorter than 10 s.

(3) Corneal staining: Under the slit lamp, more than 10 corneal staining points are abnormal.

(4) Conjunctival biopsy: abnormality was observed in the infiltrating cell. Under the slit lamp, the focal lymphocytic infiltration in the superconjunctival tissue of the cornea staining site was abnormal.

Anyone with two abnormalities in the above four tests can be diagnosed as dry keratoconjunctivitis.

3. ANA, anti-SS-A antibody positive, anti-SS-B antibody and RF positive.

Differential diagnosis

Sjogren's syndrome in children must be differentiated from chronic recurrent mumps, infectious mumps and tumors. However, these diseases are not negative for mouth and eye dryness, rash, joint symptoms and anti-nuclear antibody tests.

Viral mumps is often called mumps. It occurs more frequently in children or adolescents. It can be bilaterally or unilaterally affected. White blood cells are not increased but decreased or normal. Local symptoms and suppuration are similar. But there is no tendency to purulent.

Some of the parotid gland tumor dry syndrome (Scholine syndrome) has a mass and no other symptoms. Parotid gland angiography is seen as a tumor-like appearance. It is not easy to distinguish from parotid tumor before surgery. Such as clinical symptoms associated with certain symptoms, such as dry eyes, dry mouth and other connective tissue diseases; and more than one gland, other parotid glands are also swollen; or accompanied by peripheral duct dilatation or accessory glands The distal catheter is dilated, and the emptying function is slow, which helps the identification.

Pediatric Diabetes: Symptoms of polyuria, polydipsia, polyphagia, and weight loss are more than three. The cause of the disease is often due to infection, improper diet and other diseases. : Both diseases can have dry mouth symptoms, but diabetes, polydipsia, polyuria, polyphagia and weight loss are more obvious, blood sugar is increased, and there are no dry eye, oral cavity and laboratory abnormalities.

Familial periodic paralysis: both can have hypokalemia and paralysis, but can be improved after potassium supplementation, but the disease often has no other symptoms of dry syndrome and laboratory abnormalities.

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