Wegener's granulomatosis

Introduction to Wegener's granulomatosis Wegenergranulomatosis (WG) granuloma is a systemic necrotizing vasculitis with complicated clinical manifestations and poor prognosis. It is characterized by granulomatous lesions in the whole respiratory tract, systemic necrotizing vasculitis and small renal Ball - nephritis. Klinger (1931) first reported an example of anatomy as "the boundary type of nodular polyarteritis". Wegner reported 3 cases in 1936 and 18 cases in 1939. According to biopsy and autopsy data, the disease was named "nose." Source granuloma, mainly involving the arteries and kidneys, is named Wegener's granulomatosis. basic knowledge The proportion of illness: 0.02% Susceptible people: no special people Mode of infection: non-infectious Complications: perforation of the nasal septum Vasculitis Mumps Mastitis Orchitis Prostatitis

Wegener granulomatosis

(1) Causes of the disease

The discovery of anti-neutrophil cytoplasmic antibody (ANCA) and immunopathological studies have shown that this disease is an autoimmune disease. More than 2/3 of patients with rheumatoid factor positive also suggest that the immune complex formed by autoimmune reaction is activated. A series of inflammatory responses mediated by complement. The corresponding antigens of ANCA are protein kinase-3 (PR-3) and peroxidase. According to the phenotype of cell staining, the former is called C-ANCA, and the latter is called P. -ANCA, C-ANCA is highly specific in WG, and C-ANCA can also respond to vascular endothelial cells, polymorphonuclear cells, intracellular or cell surface substances of CD4 lymphocytes, and can pass TNF- A and soluble IL-2 receptor stimulate the above cells, further illustrating the vasculitis caused by the immunopathological process of this disease.

(two) pathogenesis

There is considerable evidence to support that Wegener's granulomatosis is an autoimmune disease, and ANCA may be involved in vascular activation and injury, such as WG and anti-PR3 autoantibodies have strong specific relationship, antibody titer and clinical disease Activity-related, and can predict recurrence, the disease responds well to immunosuppressive therapy, but there is also no basis for support. Although anti-PR3 specific antibodies can be detected in the serum of most WG patients, there are still a few patients with negative ANCA. Secondly, in the affected tissues, neither autoantibodies nor autoreactive T cells were found, and no immune complex against PR3 was found. Therefore, it is suggested that even if ANCA has a certain role in the pathogenesis of WG, it is not the most basic. The role.

1. ANCA pathogenic mechanism

(1) Reaction between ANCA and polymorphonuclear granulocytes (PMN): PMN requires the initiation of other pre-inflammatory factors before being activated by ANCA, and expresses many cytosolic antigens on the cell surface, including PR3 and MPO. The cell acquires a target antigen that interacts with autoantibodies. It is still controversial how the activated PMN is activated after interaction with ANCA. Kettritz believes that cross-linking between PR3 and MPO expressed on the cell surface is the basis of activation. Because the F(ab')2 fragment of ANCA activates the activated PMN, but the Fab fragment does not. The other authors failed to confirm the above findings, but found that PMN, FcRIIa and FcIIIRb can also be activated by interaction of the antibody with the Fc receptor. Involved in this process, in addition, blocking antibodies against 2 integrin, particularly CD18, inhibit ANCA-induced PMN activation.

Activated PMN produces toxic oxy groups, which release lysosomal enzymes. In addition, they also secrete inflammatory mediators such as TNF, IL-1, IL-8 and LTB4, and increased expression of activated PMN adhesion molecules, making PMN easy Combined with and penetrating the endothelial cell layer, renal biopsy specimens from WG patients showed activated glomerular PMN, and the number of activated PMN was related to the degree of renal dysfunction. In addition, activated PMN also appeared in the blood circulation, the degree of activation. Related to the activity of the disease.

(2) Interaction between ANCA and monocytes: ANCA can activate monocytes to increase the production of toxic oxy, IL-8 and MIP-1, without activation before activation, but activation can enhance ANCA-mediated Production of toxic oxy groups.

(3) Relationship between ANCA and endothelial cells: Whether endothelial cells express the target antigen of ANCA (especially PR3) is still controversial. Under the stimulation of pre-inflammatory factors, endothelial cells increase PR3 expression and translocate from cytoplasm to On the cell membrane, PR3 can interact with ANCA. PR3-ANCA can induce the up-regulation of endothelial cell adhesion molecules and IL-1, tissue factor expression. When endothelial cells are incubated with PR3-ANCA, endothelial cells synthesize prostacyclin, PAF, Increased IL-8, increased protein leakage, endothelial cell apoptosis, shedding and lysis.

(4) In summary, the mechanisms involved in ANCA-associated vasculitis are as follows:

1 Cytokines released by local infection cause up-regulation of endothelial cell adhesion molecules and initiate neutrophils and/or monocytes.

Neutrophils and/or monocytes that have been activated in the 2 cycle express ANCA antigen on their cell surface.

3 activated neutrophils and/or monocytes adhere to endothelial cells, which are subsequently activated by ANCA, and activated neutrophils and/or monocytes release toxic oxy and lysosomal enzymes, which lead to Endothelial cell damage eventually leads to necrotizing inflammation.

4ANCA-activated neutrophils and/or monocyte degranulation release protease 3 and myeloperoxidase, PR3 and MPO activate endothelial cells, damage and even apoptosis, and secondly, antibody-bound PR3 and MPO are planted. The antigen forms an immune complex in situ and then attracts other neutrophils.

5ANCA-activated monocytes produce MCP-1 and IL-8, and the release of these chemotactic substances can expand the extent of monocyte and neutrophil recruitment, which may lead to granuloma formation.

2. Infection factors may also lead to WG:

(1) The initial symptoms of many WG patients are similar to infectious diseases, and patients often see symptoms due to respiratory symptoms.

(2) Bronchoalveolar lavage in patients with WG shows that patients usually present with neutrophil alveolitis.

(3) Several infections are known to be associated with certain types of vasculitis. In humans, the occurrence of vasculitis is associated with hepatitis B, hepatitis C, Epstein-Barr virus, parvo-B19 and HIV infection, however only Vasculitis occurs in less than 1% of infected patients, suggesting that the characteristics of the host determine the expression of the disease.

(4) Subra reported that two patients with subacute endocarditis had positive C-ANCA, one patient reduced the C-ANCA titer by antibiotic treatment, and the other patient had C-ANCA disappeared by antibiotics and surgical treatment. But some people believe that the theory of persistent infection as a stimulant of vasculitis is untenable:

1 Until today, histopathological studies of airway biopsy specimens (including special staining of microorganisms and culture of bacteria, acid-fast bacilli, fungi, mycoplasma and respiratory viruses) have failed to confirm the presence of pathogenic microorganisms.

2 In patients with hepatitis B and hepatitis C-associated vasculitis, the use of immunosuppressive therapy, although the condition has improved significantly, and the virus they carry is significantly increased.

In recent years, we have found that Wegener's granulomatosis is associated with two specific microorganisms: parvovirus B19 and Staphylococcus aureus. Stegeman found that long-term carriers of Staphylococcus aureus are associated with recurrence of the disease, Staphylococcus aureus. Carrier recurrence rate is 8 times that of non-carriers. TMP/SMX can reduce the recurrence of airway and nasal cavity in patients with remission. The superantigen (SAg) produced by staphylococci may be an important trigger for WG, SAg It can stimulate both self-reactive T cells and autoreactive B cells to participate in the pathophysiology of vasculitis. Finkel found anti-B19 and IgM responses in a patient with WG for nearly 4 years, confirmed by nested PCR. Viremia, intravenous immunoglobulin, patient symptoms are significantly improved.

3. Mechanism of granuloma formation In other diseases, granuloma is usually mediated by sensitized CD4 T cells (which produce Th1 cytokines), and similar inflammation occurs in WG. There is a hypothesis that tissue damage and Whether vasculitis is mediated by a distorted (abnormal) Th1 immune response, several studies support this hypothesis: in WG and related vasculitis, cytokine production is qualitative and quantitative, in WG patients, Increased levels of serum IL-1, IL-2, IL-6 and TNF-, increased production of TNF- in circulating monocytes, reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization and immunization Histochemical techniques have led to an increase in the production of glomerular IL-1 and TNF- in patients. Recently, Ludviksson discovered the level of IFN- produced by CD4 T cells in patients with WG patients' peripheral blood lymphocytes. 10 to 20 times higher, the production of TNF- was also significantly increased. On the contrary, there was no significant difference in the levels of Th2 cytokines (IL-4, IL-5 or IL-10). Ludviksson also observed whether it was active or remission. Period, the production of IL-12 in mononuclear cells increased, while IL-12 was fine. To Th1 cells (may produce IFN-) substantially inducing agent.

In summary, when WG patients are exposed to environmental stimuli (such as infection) and/or autoantigen-induced excessive macrophage IL-12 response, resulting in increased Th1 cytokine (TNF-, IFN-) production, TNF- , IFN-, initiates and maintains granulomatous vasculopathy, a process that can be affected by ANCA, which promotes the activation of neutrophils, endothelial cells, and monocytes.

Wegener granulomatosis prevention

Primary prevention

(1) Strengthen nutrition and enhance physical fitness.

(2) Prevent and control infection and improve autoimmune function.

(3) Avoid wind and cold, avoid excessive fatigue, avoid alcohol and tobacco, and avoid spicy food.

(4) Protect eye goggles and nose protection during outdoor activities.

2. Secondary prevention

Early diagnosis, understanding of the eye, nasal infection, good clinical observation, early detection of damage to various systems, early treatment, mainly control of the eye, nasal infection.

3. Three levels of prevention

Pay attention to lung, kidney, heart and skin lesions, and pay attention to the occurrence of secondary Staphylococcus aureus infection. In addition, the nervous system and digestive system may also be involved. The application of traditional Chinese medicine may have the effects of regulating immunity, clearing away heat and detoxifying, promoting blood circulation and removing blood stasis. .

Wegener granulomatous complications Complications, nasal septal perforation, vasculitis, mumps, orchitis, prostatitis

Nasal mucosal erosion, necrosis, cartilage and bone destruction can occur, often causing perforation of the nasal septum or sagging nose due to collapse of the nasal bone and cartilage, but also papules, blisters, ischemic ulcers and subcutaneous nodules, subcutaneous nodules Necrotizing granulomatous vasculitis, may also be associated with joint effusion, a small number of patients may also have mumps, orchitis and prostatitis.

Wegener's granulomatosis symptoms Common symptoms Small vascular fibrosis Necrosis Renal failure Freckle hemoptysis No urinary nasal mucosal ulcer Movement disorder Chest pain Hematuria uveitis

The disease is slow onset, systemic symptoms have general discomfort, fatigue, weakness, anorexia, weight loss and fever. Fever is often associated with upper respiratory tract infections, especially secondary infections of the paranasal sinuses, and can also occur in patients without significant active infections. And a primary symptom of the disease occurs, about 2 / 3 of the patients with nasal, pharyngeal, oral symptoms and fever as the first symptom, with joint pain, sputum mass, skin, lung, ear involvement symptoms less Occasionally, nephritis is an early manifestation without other systemic symptoms. Individual patients have unexplained high fever as the first symptom. More than 2/3 of the patients have primary lesions in the nasopharynx, oral cavity, primary joints, skin, lungs and eyes. Rarely, according to pathological features, pathogenesis and clinical manifestations, the disease can be divided into a weekly body and a limited type (incomplete type), the latter is divided into three subtypes.

Body type

(1) Respiratory system: Most patients have refractory upper respiratory symptoms. The typical clinical manifestations are continuous increase of nasal secretions or prolonged pus and nasal discharge. Nasal mucosal ulcers and paranasal sinus pain can occur at the same time. Sustained upper respiratory tract infection or paranasal sinusitis, which can last for weeks to months, can also be severe nasal congestion, nosebleeds and nasal pain, gangrenous rhinitis can occur after nasal mucosal destruction, and nasal mucosal erosion can also occur , necrosis, cartilage and bone destruction, often cause nasal septum perforation or saddle nose due to nasal bone and cartilage destruction collapse, some patients began to have no upper respiratory symptoms, and manifested as cough, hemoptysis, shortness of breath, chest pain and chest discomfort Respiratory symptoms, individual patients with intercostal muscle pain, severe asthma, accompanied by eosinophilia, transient lung infiltration, auscultation when the lungs are dry, wet voice, is migratory.

(2) Skin: About half of the patients have skin damage, which is also one of the early manifestations of this disease. The clinical manifestations are different. It can be caused by allergic vasculitis, purpura, ecchymosis, pimples, blisters, ischemic ulcers. And subcutaneous nodules, subcutaneous nodules are typical of necrotizing granulomatous vasculitis, sometimes skin lesions appear as exudative erythema multiforme, telangiectasia and bleeding points, the above lesions are mostly located in the face, limbs, especially The extension of the joint is more common, and the elderly with long course may have pigmentation and scar formation.

(3) The urinary system has different degrees of kidney damage, which is a common manifestation of the body's body shape. Although some patients may have no obvious symptoms of nephropathy, once renal damage occurs and is not treated properly, it usually develops rapidly. Renal failure, clinical and urinalysis in patients with no nephritis characteristics, renal biopsy found a histological changes in focal nephritis, renal damage manifested as hematuria, proteinuria, some patients with characteristics of nephrotic syndrome At the same time, there are a large number of red blood cell casts, transparent casts and granular casts. Following these changes, there may be oliguria or anuria, accompanied by a sharp decline in creatinine clearance and other laboratory changes in renal insufficiency.

(4) nervous system: about 1/3 of patients may have neurological manifestations, symptoms caused by vasculitis or granulomatous injury, such as coma, hemiplegia, subarachnoid hemorrhage, cranial nerve palsy, meningitis, Exercise disorders and brainstem lesions, peripheral nerve involvement is similar to typical nodular polyarteritis, and is also asymmetrical composite mononeuritis, which occurs due to neurovascular dystrophy.

(5) Five senses: About 2/3 of the patients have ocular symptoms, and their clinical features range from mild keratitis to severe scleritis. Some patients present with granulomatous sclera and uveitis, which can cause scleral softening. Pupils, secondary eyelid ptosis can also occur, due to the spread of paranasal sinus inflammation or primary intragranular granulomatous vasculitis, retinal artery thrombosis, nasolacrimal duct obstruction, corneal ulcer And eye pain, serous otitis media is also a common manifestation of this disease, usually secondary to obstruction of the Eustachian tube, but can also occur in the ear structure such as tympanic granulomatous destruction, some patients with deafness can be the origin of the disease symptom.

(6) Others: Some patients may have stomach, duodenal ulcer, granuloma formation, abdominal pain that does not locate, hematemesis and bloody stools, liver, splenomegaly, and abnormal liver function.

About 15% of patients may have heart involvement, manifested as pericarditis, fociitis and coronary arteritis, and may be associated with heart failure, myocardial infarction and refractory arrhythmias.

Most patients may have joint pain, may be associated with joint fluid, joint symptoms reflect the activity of the lesion, a small number of patients may also have mumps, orchitis and prostatitis.

2. Limited type

(1) Type I or above is mainly caused by respiratory tract and lung lesions. The onset of pharyngeal swelling and pain may cause multiple masses in the posterior pharynx, which may cause difficulty in swallowing, pain, and varying degrees of hemorrhage. Shadow or nodular shadows, manifested as cough, phlegm, hemoptysis and chest pain, this type has no kidney disease.

(2) Type II is mainly nasal, pharyngeal, oral or ocular lesions, often above respiratory symptoms, sinusitis or ocular lesions are the first symptoms, ocular lesions are intraorbital masses, exophthalmos and corneal ulcers, clinical and Pathology is easily misdiagnosed as "inflammation of the sacral pseudotumor". The identification of Wegener's granulomatous eye lesions and intraorbital inflammatory pseudotumor is shown in Table 1. The ocular lesions are divided into two types: 1 adjacent type: more The upper respiratory tract lesions spread to the corpus callosum to form granuloma, the eyes are heavier, there may be para-aluminal edema, fundus hemorrhage and venous dilatation, 2 foci: bilateral peripheral corneal peripheral typical ulcer, by necrotic vessels Caused by inflammation of the ciliary vascular atresia, often with corneal lesions.

(3) type III: this type of central nervous system, skin damage or reticuloendothelial system hyperplasia as the first symptom, manifested as coma, urinary incontinence, rash, high fever, hepatosplenomegaly, generalized lymphadenopathy, cardiac symptoms or simple Sympathetic symptoms of kidney disease.

Wegener granuloma examination

1. Patients with blood routine and 1/3 of erythrocyte sedimentation rate have moderate anemia; mild to moderate leukocytosis, sometimes the total number of white blood cells can reach (10-20)×109/L, and the neutrophils counted up significantly. See leukopenia, there may be thrombocytopenia, but in the active phase of thrombocytopenia, occasionally eosinophilia, all patients with erythrocyte sedimentation rate increased to varying degrees.

2. Urine routine can be seen with proteinuria, hematuria, tubular urine.

3. The stool routine occult blood test is occasionally positive.

4. Some patients with biochemical examination have abnormal liver function. When uremia occurs, blood BUN is elevated, and other blood biochemical abnormalities of uremia are observed. Protein electrophoresis shows that 7 globulin is elevated.

5. Immunological examination of more than half of patients with rheumatoid factor positive, more common IgA increased, may have elevated IgE, normal or slightly elevated complement, can be detected immune complex and C-reactive protein positive, nearly 1 3 patients with HBsAg positive, lupus cells were negative, a few patients were positive for antinuclear antibodies and anti-SS-A, SS-B antibody positive.

Anti-neutrophil granule antibody (ANCA) is specific for the diagnosis of WG, especially C-ANCA, more than 90% of active WG can be positive, and the remission period after treatment can make ANCA negative. This can be measured by ANCA as an indicator of disease activity and efficacy.

X-ray examination usually has no abnormalities in the lungs at the onset stage. In some cases, there is no X-ray change in the lungs. More than half of the patients may have pulmonary interstitial texture enhancement and single or multiple sizes due to pulmonary vasculitis and granuloma formation. Nodules and masses can vary in diameter from a few millimeters to several centimeters. The contours of the masses can be clearly defined, resembling metastatic tumors, and can be blurred and irregular due to peripheral inflammation. Cavities are quite common, 1/3 to 1/ In the case of 2, the cavity can be reduced as the condition improves, and the disease can continue to increase when the disease recurs. When the cavity begins to form, the wall thickness is thick and the inner wall is irregular. Later, it can develop into a thin-walled cavity, which resembles a thin-walled cyst. These manifestations are more diagnostic. Reference value.

CT examination: typical manifestations of multiple nodules of different sizes on both sides, the edges are smooth or slightly blurred, about 1/3 to 1/2 are thick-walled, the inner wall is rough and irregular, and the cavity can be thinned or even completely after treatment. Disappeared, about 20% of patients showed a single nodule, which can show a huge cavity change, and endobronchial lesions can cause obstructive pneumonia or atelectasis.

In addition, a small amount of pleural effusion may occur, but also due to rupture of necrotic lesions, blood pneumothorax, pulmonary hypertension, hilar vascular enlargement, a few cases of hilar lymph node enlargement, myocardial lesions or pericardial effusion, heart shadow The generality is expanded, and like other rheumatism, it is not characteristic.

Other X-ray findings are nasal soft tissue masses, inflammatory changes in the paranasal sinus and nearby bone destruction, and tomography can show laryngeal and tracheal granuloma.

Diagnosis and diagnosis of Wegener's granuloma

diagnosis

The diagnosis of this disease depends on clinical and histopathological findings: 1 typical necrotizing granulomatous vasculitis in the whole respiratory tract; 2 necrotic vasculitis in the lungs and skin; 3 focal necrotizing glomerulonephritis.

The localized Wegener granuloma can not be diagnosed by tissue biopsy alone. Because it is easy to be misdiagnosed as chronic inflammation, it must be combined with clinical manifestation. The following pathological examinations can be performed on suspicious cases: 1 chronic rhinitis and sinusitis accompanied by mucous erosion or granulation Tissue hyperplasia; 2 eyes, ulceration of the oral mucosa, necrosis or granuloma; 3 visible mimic shadows or cavities in the lungs; 4 skin with purpura, erythema, necrosis or ulcers; 5 kidney biopsy positive, which can be clearly diagnosed.

In 1990, the American College of Rheumatology classification and diagnostic criteria have high application value.

Differential diagnosis

Care must be taken to distinguish from other granulomatous inflammations, vasculitic diseases.

1. Pulmonary hemorrhage-nephritis syndrome Pathological examination showed that anti-glomerular basement membrane antibody and fluorescent antibody were detected in vivo to detect linear IgG, which is different from Wegener's granulomatosis.

2. Lymphoma-like granuloma in addition to no upper respiratory tract involvement, there is a renal biopsy to show glomerular lymphoid infiltration, which can be identified with the disease.

3. Idiopathic midline granuloma is a partial destruction of the face and upper respiratory tract. It can be differentiated from the disease by renal biopsy.

4. Other Wegener granulomatosis with eosinophilia should also be distinguished from many primary diseases that cause eosinophilia, especially with allergic granuloma, the latter with fever , paroxysmal asthma, eosinophilia is characterized, histopathological changes are mainly eosinophil infiltration, epithelial cells surrounding the lesion are arranged radially, the affected blood vessels are middle, small arteries, arterioles, veins and capillaries There is no clinical manifestation and X-ray features of paranasal sinusitis. In addition, the pulmonary symptoms and X-ray features of Wegener's granulomatosis are also significantly different from allergic granulomas.

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