Systemic vasculitis

Introduction to systemic vasculitis Vasculitis is a group of heterogeneous diseases characterized by inflammation and destruction of blood vessels. The clinical manifestations vary depending on the type, size, location and pathological characteristics of the affected vessels. Vasculitis can be a single disease. The disease can also be one of the clinical manifestations of a disease, such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, tumor, infection; it can be systemic, causing multiple systemic organs Dysfunction, which can also be confined to an organ, can be called vasculitissyndrome in view of the complexity and diversity of vasculitis. The prognosis of vasculitis depends on the size, number and location of the affected blood vessels. basic knowledge Sickness ratio: 0.0012% Susceptible people: no specific population Mode of infection: non-infectious Complications: thrombosis Aneurysms

Causes of systemic vasculitis

Infection factor (45%):

The etiology of systemic vasculitis is quite complicated, and the etiology of infectious vasculitis caused by infection is relatively clear, such as certain pathogenic microorganisms, bacteria, viruses, rickettsia, spirochetes, fungi, etc.

Physical and chemical factors (40%):

Another chemical substance, drug, other allergen, tobacco, etc., these pathogenic antigens or toxic substances or their metabolites can directly damage vascular endothelial cells to cause vascular inflammatory changes or mediate immune abnormal reactions, such as infectivity In vasculitis, pathogens proliferate in a large amount in the blood vessel wall, and inflammatory cell aggregation and vascular inflammatory response can be induced before or at the same time as the immune response is initiated.

Other factors (15%):

Another type of vasculitis is a vasculitis response mediated by immune abnormalities, and its etiology is unclear. From the difference in immune pathogenesis, it can be roughly divided into the following cases.

1. Immune complex mediates the deposition of immune complexes on the vessel wall, attracts and activates complement, kinins, plasmin, neutrophils, mononuclear macrophages, vascular endothelial cells, platelets, etc., releasing inflammatory Media, causing vascular inflammation, intravascular thrombosis and even vascular necrosis or rupture, some of these pathogenic immune complexes are formed outside the blood vessels, free from the blood, and then deposited on the blood vessel wall of certain specific parts, some are An in situ immune complex formed in situ by the vessel wall.

2. The antibody directly mediates that certain autoantibodies have strong affinity for vascular endothelial cells or other components of blood vessels and can be tightly bound to directly form antigen-antibody complexes, directly inducing activated T cells or phagocytic cells. When attacking, causing vascular inflammation, such as pulmonary hemorrhagic-nephritis syndrome, antibodies against the alveolar septum directly attack the type II immune response damage formed by the renal basement membrane.

3. Anti-neutrophil cytoplasmic antibody-mediated antineutrophil cytoplasmic antibody (ANCA) is a generic term for antibodies against neutrophil cytoplasmic granules and lysosomal components in monocytes, such as Antibodies against protease-3 antibody (PR-3-ANCA), myeloperoxidase (MPO-ANCA), lactoferrin and cathepsin G, which directly activate the release of inflammatory mediators in these two cells. Vascular inflammation, such as Wegener's granulomatosis, Churg-Strauss syndrome, etc. are all related to this.

4. T cell-mediated T cells can recognize variant autoantigens and transplant antigens, attacking mutant cells or grafts, causing tissue damage or granulomatous inflammation, such as giant cell arteritis and acute graft rejection.

In clinical systemic vasculitis, the above-mentioned immune pathogenesis can exist alone, but most of the cases are complex or mainly based on one mechanism, and have other conditions, thus bringing the classification of systemic vasculitis It is very difficult, and some vasculitis causes are still unknown. The etiology and pathogenesis of arteritis, giant cell (arterial) arteritis, etc. are still unclear, and the current knowledge about the pathogenesis and etiology of vasculitis is still very Imperfect, sometimes even contradictory, I believe that as the research progresses, the mystery of the onset of systemic vasculitis will be uncovered.

Pathogenesis

It is generally believed that the main pathogenesis of systemic vasculitis is related to factors such as direct damage to the blood vessels by the infectious agent and inflammatory response mediated by immune abnormalities.

Many pathogen infections can cause inflammatory reactions in the vessel wall and direct damage to the vessel wall, or trigger vasculitis due to pathogen metabolites. More often, pathogen antigens and antibodies form immune complexes that deposit in the vessel wall, starting The immune response causes infiltration, aggregation and necrosis of inflammatory cells in the vessel wall.

Immune abnormality-mediated inflammatory responses include various forms, such as immune complex-mediated mediation, direct mediation of antibodies, mediators of vascular endothelial cell injury activation, and anti-neutrophil cytoplasmic antibody mediated, resulting in immune complex deposition. In the blood vessel wall, activation of complement, leading to vascular inflammation, necrosis, or inflammatory mediators, neutrophil cytoplasmic antibodies bind to target antigen components in neutrophils, leading to neutrophil activation, oxygen free Base and degranulation, causing respiratory explosion, resulting in damage to vascular endothelial cells, inflammation of the blood vessel wall, necrosis.

Pathology: The pathology of systemic vasculitis varies with the type, location, size and stage of the affected blood vessels, but the basic pathological changes are focal full-thickness necrotizing changes of the small and medium arteries. The lesions may be segmental, lesions. The site may have thrombosis or aneurysmal expansion, and the healing lesion may have fibrous tissue and endothelial cell proliferation, which may lead to stenosis of the lumen.

Systemic vasculitis prevention

Primary prevention: smoking cessation is an important measure to prevent and treat vasculitis. Comprehensive domestic and foreign data, 80% to 95% of patients smokers. Clinical observations show that smoking cessation can relieve pain and stabilize the disease. The symptoms of smoking are aggravated, so patients should be patiently advised not to smoke.

Systemic vasculitis complications Complications thrombosis aneurysms

The lesion may have thrombosis or aneurysmal expansion, and the healing lesion may have fibrous tissue and endothelial cell proliferation, which may lead to stenosis of the lumen.

Systemic vasculitis symptoms common symptoms systemic vasculitis hypertension eosinophilia low complement vasoactive vascular allergic inflammation reticular leukoplakia liver function abnormal hemoptysis erythrocyte sedimentation increased rapid hematuria

1. Clinical manifestations of systemic vasculitis The following conditions often suggest the possibility of systemic vasculitis without a definite explanation.

(1) General conditions: fever, weight loss, fatigue, fatigue.

(2) Musculoskeletal: joint pain, arthritis.

(3) Skin: palpable purpura, nodules, urticaria, reticular bluish, superficial phlebitis, ischemic skin lesions.

(4) nervous system: headache, stroke, single or multiple neuritis.

(5) head and neck: sinusitis, nasal cartilage, otitis, iritis.

(6) Kidney: nephritis, kidney infarction, high blood pressure.

(7) Lung: hemoptysis, pulmonary nodules, pulmonary infiltrates, pulmonary phlebitis.

(8) Laboratory abnormalities: anemia, increased erythrocyte sedimentation rate, abnormal liver function, hematuria, ANA positive, RF positive, blood-cold globulin-positive, low-complementemia, ANCA antibody-positive, angiotensin-converting enzyme activity increased.

The above performance is not specific, but also in infections, tumors, etc., but in the unexplained circumstances, these conditions provide some clues for the diagnosis of systemic vasculitis: 1 suggest non-specific manifestations of vasculitis (anemia, blood sedimentation) Fast); 2 prompt visceral involvement range (urine, kidney function, liver function, ECG, chest X-ray, paranasal sinus X-ray); 3 in addition to idiopathic vasculitis, hepatitis B, connective tissue disease, kidney Sick and so on.

2. Abnormal findings of common vasculitis biopsy.

3. The clinical manifestations of vasculitis vary depending on the type, location and extent of the affected blood vessels. The onset may be occult or acute, and the extent and extent of the lesions may vary, some of which are fatal multiple organs. Involved, the disease develops rapidly and is difficult to control, and some only show mild skin damage. The clinical manifestations of various vasculitis can overlap, and the same disease varies greatly in different patients or the same patient at different times. General condition and main clinical manifestations of vasculitis.

Systemic vasculitis examination

1. Anti-neutrophil cytoplasmic antibodies against neutrophil cytoplasmic antibodies (ANCA) Since the first detection of patients with acute glomerulonephritis (RPGN) in 1982, research on ANCA has been increasing, on ANCA It is becoming clearer that it has been confirmed that ANCA includes an autoantibody profile whose target antigens include various substances such as protease-3 (PR-3), myeloperoxidase (MPO), elastase, lactoferrin. Protein, cathepsin G, bactericidal/permeability-enhancing protein (BPI), azurin, lysosome, -glucuronidase, -enolase, defensin, and human lysosomal-associated membrane proteins They have different physiological functions, and different target antigens exhibit different fluorescence models.

The physiological function of ANCA target antigen may play a role in the pathogenesis of ANCA-related diseases. Most ANCA target antigens are present in neutrophil granules, especially in azurophilic granules, and various stimuli lead to neutrophil activation. Degranulation, causing the expression of various proteases on the surface of neutrophils and releasing them into the extracellular environment. The protease in the extracellular environment can interact with the ANCA present in the circulation. The majority of the physiological functions of the ANCA target antigen depend on them. Proteolytic activity, but some potential functions are not related to this activity (Table 8), suggesting that different domains of the ANCA target antigen are responsible for different biological functions, and experiments have confirmed that the target antigen epitopes targeted by ANCA from different patients exist. Certainly, in theory, ANCA binds to the antigen to antagonize the activity of the target antigen, but clinical observations show that the antigen-antibody binding interaction is heterogeneous, therefore, the ANCA-specific reaction epitope and the definite antibody are determined. Combined with the effect on the function of the target antigen, the role of ANCA in the pathogenesis of vasculitis can be better clarified.

At present, there are two main methods for ANCA detection. Indirect immunofluorescence (IIF) is the most common and original detection method, but IIF can not distinguish specific antigens. Clinically, it is often used as screening test, enzyme-linked immunosorbent assay. (ELISA) is used to further distinguish the specific antigen of ANCA. As a confirmation test of ANCA, it is usually detected by direct method or sandwich method. Other detection methods such as radioimmunoassay, immunoblotting or immunoprecipitation have also been used for the detection of ANCA. However, it is rarely used for routine detection. The classical c-ANCA and p-ANCA are defined according to the immunofluorescence model of ethanol-fixed neutrophils. The neutrophil cytoplasm is diffusely granulated and stained in the nucleus. The heavy stain between the leaves is cytoplasmic (c-ANCA), and its target antigen is mainly PR-3. It is a neutral serine protease located in neutrophil azurophilic granules, with 228 amino acid residues. The base composition has a molecular weight of 26,800. The ANCA mentioned in the previous literature refers to c-ANCA. The neutrophil surrounding the nucleus of the nucleus is a perinuclear type (p-ANCA), and its target antigen is mainly Myeloperoxidase, consisting of 2 heavy chains Two light chains are composed, and the molecular weight is 133,000-155,000. IIF can be different in the method of fixing the cell substrate when detecting ANCA. The substrate fixed by formaldehyde is c-ANCA when tested. Without p-ANCA, this is because many ANCA antigens in the cytoplasm of the cell, such as MPO, cannot be released from the azurophilic granules, so they are expressed as a uniform fluorescent staining model in the cytoplasm, ie c-ANCA, but fixed with ethanol. At the time, substances such as MPO can be released from the azurophilic particles and adsorbed around the nucleus due to its strong positive charge to form p-ANCA. This transformation of the fluorescence model contributes to p-ANCA, atypical ANCA. Identification with ANA, because formaldehyde-fixed specimens can destroy nuclear antigen and prevent ANA binding, ANA homogenous fluorescence model can be expressed as peri-nuclear or perinuclear/homogeneous fluorescence on ethanol-fixed neutrophils. The model is difficult to judge when both p-ANCA and ANA are positive. The above cases are detected by formaldehyde-fixed specimens. The true p-ANCA is c-ANCA, while the ANA false-positive is negative.

Since the first report of ANCA, the range of diseases involved has also increased, such as inflammatory bowel disease, autoimmune liver disease, infection, malignant tumors and other connective tissue diseases (Table 9), but still with its blood vessels There are many studies on the relationship between inflammation, especially c-ANCA and Wegener's granulomatosis, and the relationship between p-ANCA and microscopic polyangiitis. The detection rate of c-ANCA in Wegener's granulomatosis is between 80% and 90%. %, its sensitivity is related to the type of disease and activity, the initial inactive Wegener granuloma has the lowest positive rate, and the typical positive rate of activity is about 100%, so c-ANCA is Wegener granulation Another important clinical significance of c-ANCA is that its titer is related to the activity of the disease. When the condition is stable, the titer is decreased, and the titer is increased when the disease is active. p-ANCA is mainly seen under the microscope. Inflammation, Churg-Strauss syndrome and necrotic crescentic glomerulonephritis, the titer is also related to the disease activity, can be used to guide treatment, to judge the efficacy, the significance of ANCA in other diseases needs to be further clarified.

2. Anti-endothelial cell antibody (AECA) was first discovered by immunohistochemical detection of kidney specimens. It has been nearly 30 years old and has been found to include vasculitis. AEEA can be detected in a variety of rheumatic diseases such as systemic lupus erythematosus and systemic sclerosis, and AECA may play a role in the pathogenesis of these diseases. AECA has multiple subtypes of IgG, IgM and IgA. Mainly through the F(ab)2 segment of its immunoglobulin binding to different parts of the endothelial cell membrane, the properties of the AECA target antigen on endothelial cells have not been completely determined, but it is certainly heterogeneous. AECA can be used with various sources of endothelium. Cellular responses, from aorta (aorta), veins (umbilical vein, saphenous vein) to various small veins, such as the kidneys, skin, omentum, and microvessels of the brain. Moreover, AECA is species-specific and is derived from humans. There is a cross-reaction between calves and rat AECA. AECA produced by endothelial cells from different sources of macrovascular and microvascular may play different roles in pathogenesis, so it is learned. According to this, AECA is divided into two categories, namely, macrovascular-derived AECA and microvascular-derived AECA.

It is known that AECA is involved in the pathogenesis of various diseases, especially in relation to vasculitis. In Wegener's granulomatosis, the growth and decline of AECA titer is related to the activity of the disease, and the disease itself can be used Activity is different from concurrent infection, renal insufficiency, or side effects of drugs. In Kawasaki disease, AECA can be used as a labeled antibody, which has diagnostic significance, and its titer is also positively correlated with disease activity, in systemic erythema. In lupus and antiphospholipid syndrome and systemic sclerosis, AECA is closely related to pulmonary hypertension, neurological disease, finger ulcer, Raynaud's phenomenon and pulmonary interstitial fibrosis. Similar reports have been reported in dermatomyositis. The detection rate of the disease.

AECA is a heterogeneous antibody that targets a group of antigens expressed by endothelial cells. Its properties are not fully understood. The AECA and its recognized antigens may not be identical in different diseases. The EC release of different lesions is different. The antigen stimulates the body to produce ACEA against the antigen. The antigen recognized by the AECA may be a continuously expressed antigen, an antigen expressed after activation or an implanted antigen, and some antigens may be expressed or up-regulated after the endothelial cells are activated by cytokines, and some antigens may also be It is a cellular component that adheres to the inner membrane of endothelial cells, such as DNA and/or DNA-histone complexes, as well as PR-3 and MPO. Almost all AECA recognizes vaginal proteoglycans that are constitutively expressed by endothelial cells, heparin-like. Molecules and other components, and are not related to blood group antigens and MHC class I and II molecules, but the antigens recognized by AECA in each disease are not identical, and have a correlation with the primary disease. Table 11 gives some Clear antigenic components recognized by AECA.

AECA has a variety of detection methods, using human umbilical endothelial cells (HUVEC) as a substrate, which can be tested by ELISA, immunofluorescence, flow cytometry, immunoblotting and complement-mediated cytotoxicity assays. An IgM type antibody of AECA was detected.

In the large family of AECA, there are corresponding antibodies against different structures of endothelial cells, and there are correlations between different antibodies and corresponding diseases and specific clinical manifestations. With the advancement of endothelial cell isolation and culture techniques, further Comparative analysis of the similarities and differences of biochemical properties of endothelial cells derived from large blood vessels and small blood vessels. Endothelial cells from different sources have certain commonalities in structure, such as monolayer structure, which can produce factor VIII, prostacyclin (PGI2) and Weibel-Palade. The corpuscles, but their antigenic heterogeneity is more interesting, and further clarification of these questions will help to understand the pathological significance of AECA and also contribute to the study of the pathogenesis of vasculitis.

Electrocardiogram, chest X-ray film, and sinus X-ray film are required for visceral involvement.

Diagnosis and differentiation of systemic vasculitis

Diagnostic criteria

The diagnosis of vasculitis is based on a combination of clinical manifestations, serology, pathology and angiography, and the diagnosis and differential diagnosis of suspected vasculitis:

1 Collecting a complete history and experience is an extremely important step because many clinical manifestations of vasculitis are more diagnostic than laboratory tests, such as eosinophilia and allergies and asthma history suggest Churg-Strauss syndrome An important basis for diagnosis: intermittent dyskinesia or discomfort of the lower jaw and tongue suggests the possibility of giant cell arteritis. Table 7 lists the general conditions and major clinical features of common vasculitis.

2 serological examination, mainly including the determination of autoantibodies, examination of some infectious factors related to vasculitis such as hepatitis B virus, HIV virus, complement and cryoglobulin determination, and the extent and extent of organ system involvement should be determined. Serological examination of certain vasculitis diseases can be confirmed.

3 special traumatic examinations, such as biopsy of the lesion, angiography or examination of bronchoalveolar lavage fluid can provide objective evidence for the diagnosis of vasculitis.

Differential diagnosis

Some diseases have similar manifestations to vasculitis. In addition, most patients with vasculitis usually show non-specific systemic symptoms and/or an organ involvement, so the differential diagnosis of vasculitis is important:

1 Some vasculitis is a well-prevented disease, such as Henoch-Schönlein purpura, usually only symptomatic treatment, secondary to allergic vasculitis of the drug, as long as the relevant drugs are discontinued.

2 Most systemic vasculitis has many important organ involvement, often need to be treated with high doses of glucocorticoids, or with immunosuppressive drugs, plasma exchange, immunoglobulin, etc., the effect of treatment is also different, as shown in Figure 4. The differential diagnosis procedure for vasculitis, each process includes the possibility of diagnosis and exclusion diagnosis. The final step is those without laboratory diagnostic indicators and require biopsy or angiography to exclude other similar diseases.

In clinical practice, biopsy or angiography should be used according to the ratio of risk and benefit. The results of biopsy are related to the size of the specimen and the location of the specimen. The pathology of the biopsy is usually a manifestation of some common vascular inflammation damage. Specificity, therefore, pathological results alone can not lead to a positive diagnosis, angiography is safer than biopsy when the following conditions exist, 1 if the risk of biopsy is greater than angiography, such as imaging findings suggest brain lesions At this time, angiography is safer than biopsy. For some patients with abnormal liver function, angiography may be safer than liver penetration. 2 Some suspected cases of large blood vessel involvement, generally speaking, allergic vasculitis such as Henoch - Schönlen's purpura and other involved blood vessels are very small, angiography may not be able to get a positive result, and aortitis involving the aorta and its main branches are generally not recommended for biopsy, angiography can be easily confirmed.

It is worth noting that the classification criteria for vasculitis developed by ACR in 1990 and the definition criteria for classification of vasculitis developed by the Chapel Hill Conference in 1994 were mainly developed for research purposes, not clinical diagnostic criteria, and they are applicable to various vasculitis diseases. The differential diagnosis between them is not used to confirm whether the patient has vasculitis, but most clinicians currently use them as diagnostic criteria for clinical diseases. Recently, Rao et al. used ACR to define seven vasculitis classification criteria (nodules). Polyarteritis, Churg-Stratus syndrome, Wegener's granulomatosis, allergic vasculitis, Henoch-Schönlen purpura, giant cell arteritis and Takayasu arteritis) and clinical gold criteria (history, symptoms, signs, biopsy or A comprehensive comparison of angiographic diagnosis and diagnosis of 198 patients showed that only 38 cases (75%) met the ACR criteria in 51 clinically diagnosed vasculitis cases, and 15 of them met two or two. More than one ACR classification criteria, 31 (21%) of the other 147 clinically confirmed non-angiitis cases met the ACR vasculitis classification criteria (14 cases met the giant In the case of arteritis, 18 cases were consistent with Wegener's granulomatosis or nodular polyarteritis or both, which indicates that the ACR classification criteria are poorly used for clinical diagnosis, so the diagnosis of vasculitis should emphasize clinical , tissue biopsy and angiography combined.

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