Vasculitis: clinical approach, pathophysiology and treatment

Systemic vasculitides constitute a heterogeneous group of diseases characterized by inflammation of blood vessels. Classification of the disease is mandatory for the assessment of prognosis and the institution of treatment. Secondary forms of vasculitis should be distinguished from primary vasculitides, as infections or other conditions underlying the secondary forms require a different approach. The presence of anti-neutrophil cytoplasmic antibodies (ANCA) directed against either proteinase 3 or myeloperoxidase strongly suggest one of the pauci-immune small vessel vasculitides. Their role in the pathogenesis of such vasculitides has been suggested by clinical and experimental data but has not been proven. Treatment of severe systemic vasculitides consists of cyclophosphamide in combination with corticosteroids but this regimen has many adverse effects. Less toxic regimens as well as new treatment modalities based on insight into the pathophysiology of systemic vasculitides have been developed and are currently being tested in multicentre European studies.     

Cutaneous vasculitis: approach to diagnosis and systemic associations

The starting point in the evaluation of vasculitis is the clinical examination. The character and location of the primary lesions determine the type of biopsy specimens and additional tests needed to classify vasculitis. The most common causes of cutaneous vasculitis are drug reactions, infectious diseases, reactions to inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease, or association with malignant disease, especially lymphoproliferative disorders. Direct immunofluorescent techniques and leukocyte monoclonal antibody studies are useful for the diagnosis of selected cases of vasculitis. The clinical and histopathologic data help delineate an approach for further investigation of potentially associated systemic disorders or underlying causes. Although some cases of cutaneous vasculitis are not associated with systemic disorders, this possibility should never be assumed but considered only as a diagnosis of exclusion after careful examination of each patient.     

Pulmonary lesions in Wegener's granulomatosis

Pulmonary lesions are the commonest and prognostically unfavourable visceral pathology in Wegener's granulomatosis. The author discusses clinically and reongenologically detectable lesions associated with this systemic vasculitis with special reference to its most severe forms (alveolar bleeding and infectious complications frequently caused by active immunosuppressive therapy). Diagnostic (including early) and modem therapeutic modalities of Wegener's granulomatosis are considered.     

Wegener's granulomatosis--a diagnostic challenge

Wegener's granulomatosis is a systemic vasculitis characterized by necrotizing granulomatous lesions in the upper and lower respiratory tracts, glomerulonephritis and vasculitis involving other organs. Limited forms have been described in which some features of the disease may be absent. Four patients with this disease are being reported with special emphasis on differences in presentation, the ensuing diagnostic problems, and individual outcome. In three, the disease began as a limited form with upper respiratory tract and eye involvement, while in one patient, onset was systemic including affection of the lower respiratory tract. The mean delay from first symptoms to diagnosis was 20 months--much longer for the three limited forms than for the one with systemic onset, in whom the condition was recognized after 2 months following initial misdiagnosis of respiratory and urinary tract infections. One patient developed endocarditis and required aortic valve replacement. Immunofluorescence revealed antineutrophil cytoplasmic antibodies in all, three showing a cytoplasmic pattern and antibodies to proteinase 3, and the fourth a perinuclear pattern and antibodies to myeloperoxidase. Upper respiratory tract biopsies were not specific. Kidney biopsies were performed in all the patients and were crucial for definitive diagnosis and treatment of the disease, which was successful in three patients.     

Headache and Vasculitis

Although headaches are common in the general population and have many causes, headaches secondary to inflammatory processes in the blood vessels in the Central Nervous System (CNS) are not so common. The most common types of vasculitis that are associated with headaches include primary CNS vasculitis, systemic necrotizing arteritis, granulomatous vasculitis, and systemic collagen diseases. It is important to differentiate between “true” vasculitides and a condition known and reversible cerebral vasoconstriction syndrome (RCVS). While treatment for many of the vasculitides consists of anti-inflammatory medications, this approach may produce significant complications in RCVS. It is up to the clinician to judiciously use imaging and laboratory data to reach the proper diagnosis and therefore offer the correct treatment to these patients.     

Steroidal vasculitis in patients with bronchial asthma: specific features of platelet function and antithrombogenic vascular activity

Severe forms of bronchial asthma (BA) are encountered now more and more frequently. Therefore, number of patients treated by course steroids in BA exacerbation and patients on continuous basic therapy with systemic glucocorticosteroids(GCS) grows. Pathogenesis of steroid vasculitis (SV) is though to be related with GCS effect on the skin, hemostasis and directly on the vessels. We studied platelet function and antithrombogenic activity of vascular wall (AAVW) in patients with steroid-dependent BA (SDBA) in development of cutaneous hemorrhagic syndrome (CHS). We examined 30 patients with SDBA and cutaneous vasculitis and 19 SDBA patients free of this vasculitis. A control group consisted of 29 healthy volunteers. Assessment of ADP-induced platelet aggregation, AAVW demonstrates enhanced functional activity of platelets and definite impairment of antithrombogenic endothelial activity in patients with SDBA and CHS. We came to the conclusion that AAVW affection is involved in pathogenesis of SV in SDBA patients.     

Immunologic mechanisms in systemic vasculitis.

Thirty-four patients with systemic vasculitis were studied to determine the possible type and frequency of associated immunologic abnormalities. The patients were divided into three clinical groups--those with systemic vasculitis without respiratory tract involvement, those with systemic vasculitis with respiratory tract involvement (particularly Churg-Strauss vasculitis and Wegener's granulomatosis), and those with limited vasculitis without visceral involvement. A diminished level of serum complement was found in half the patients with systemic vasculitis without respiratory tract involvement. These patients usually had diffuse skin disease that often was associated with the presence of rheumatoid factor and cryoglobulinemia and most likely represented an immune-complex induced disease. The serum IgE often was elevated in patients who had systemic vasculitis with respiratory tract involvement, particularly those with Churg-Strauss vasculitis and Wegener's granulomatosis, and may be a clue to the pathogenesis in this group of patients.     

Various aspects of the pathogenesis of systemic vasculitis

Based on the reported data and observation of 86 patients with different forms of systemic vasculitis (SV) the authors analyzed the leading pathogenetic mechanisms of generalized vascular injuries seen in these diseases. The data presented attest to the role of disorders of immunoregulation, immune complex reactions, an increase in the blood coagulation potential, a rise of platelet and red cell aggregation in the pathogenesis of the main clinical syndromes of SV. At the same time the authors describe in detail the microcirculatory disorders seen in the main disease entities and discuss the concrete reasons for the development of capillarotrophic insufficiency and marked tissue hypoxia. Close interaction of the main pathogenetic factors of SV and the character of the disorders determine the necessity of a differentiated approach to the problems of the treatment of patients depending on the disease entity and the leading pathogenetic components.     

Systemic vasculitis

The systemic vasculitides are characterized by inflammation of blood vessel walls. Vessels of any type, in any organ can be affected, resulting in a broad spectrum of signs and symptoms. The heterogenous nature of vasculitides presents a diagnostic challenge. The American College of Rheumatology classification criteria and the Chapel Hill Consensus Conference nomenclature are the most widely used to distinguish different forms of vasculitis. The Chapel Hill Consensus Conference nomenclature defines 10 primary vasculitides based on vessel size (large, medium, and small). The diagnosis relies on the recognition of a compatible clinical presentation supported by specific laboratory or imaging tests and confirmatory histology. Antineutrophilic cytoplasmic antibody testing has been of particular benefit in defining a subgroup of small vessel vasculitides. Treatment is based on clinical presentation and the pattern of organ involvement. Glucocorticoids are the primary treatment for many forms of vasculitis. Additional immunosuppressive agents, including methotrexate and cyclophosphamide, are sometimes required. Newer approaches, such as the use of anti-tumor necrosis factor or B cell therapies, are being tried in resistant cases. Patients can experience considerable treatment-related toxicity, especially infection from immunosuppressive therapy and adverse effects from steroids (e.g., osteoporosis, diabetes mellitus, cataract). Vitamin D and calcium prophylaxis are recommended in patients on long-term steroid therapy.     

An approach to diagnosis and initial management of systemic vasculitis.

Systemic vasculitis occurs in a heterogeneous group of primary disorders or can be a manifestation of infection, an adverse drug reaction, malignancy or a connective tissue disease. A vasculitic process should be suspected in patients with unexplained ischemia or multiple organ involvement, especially when such features as polymyalgia rheumatica, inflammatory arthritis, palpable purpura, glomerulonephritis or multiple mononeuropathy are also present. The clinical features of systemic vasculitis depend on the organs involved and, in turn, organ involvement is largely influenced by the size of the affected blood vessels. The diagnostic work-up should be tailored to the clinical situation and geared toward a tissue or angiographic diagnosis, bearing in mind that the findings from these studies are not always pathognomonic. Emphasis should also be placed on exclusion of a secondary process. The diagnosis of the specific type of vasculitis may be made on the basis of the clinical features and the histopathologic or angiographic findings. Initial therapy for most types of systemic vasculitis consists of high-dose corticosteroids, with the addition of immunosuppressive therapy in certain patients.     

Role of therapeutic plasma exchanges in systemic vasculitis

Therapeutic management of systemic vasculitides is based on glucocorticoids (GCs), in combination or not with immunosuppressive and/or immunomodulatory agents. Plasma exchange (PLEX) has been used in some vasculitides, with various levels of evidence. Indeed, it is part of the first-line therapy in patients with anti-glomerular basement membrane (GBM) antibodies and in patients with severe hepatitis B related polyarteritis nodosa (PAN). PLEX might also be considered in some selected patients with ANCA-associated vasculitis and cryoglobulinemia vasculitis. Studies support the use of PLEX as second line therapy in refractory Kawasaki disease. Finally, there is not robust data to support the use of PLEX in unselected patients with non-HBV-related PAN or IgA vasculitis. Additional studies are required to address its role in these settings.     

Intravenous immunoglobulin in the therapy of systemic vasculitis

The current therapy of the systemic vasculitides with corticosteroid and cytotoxic drugs is successful in controlling disease in the majority of patients but is limited by adverse effects; drugs must also be continued in the long-term as relapse frequently follows their withdrawal. Autoantibodies to neutrophil cytoplasmic antigens (ANCA) are associated with systemic vasculitis and have been implicated in its pathogenesis. Interest in the use of pooled immunoglobulin (IVIg) in the therapy of vasculitis has followed the detection of antiidiotype antibodies to ANCA in IVIg and the success of IVIg in the treatment of Kawasaki disease, an ANCA positive childhood vasculitis.We have given IVIg to 12 patients with vasculitis, nine resistant to standard therapy, which led to clinical remission in eight and a partial response in four. Benefit was sustained in eleven although two had late relapses at 6 and 9 months. Clinical improvement was matched by falls in ANCA and C-reactive protein. The possible mechanisms underlying the therapeutic effect of IVIg in vasculitis are discussed.     

系统性血管炎常用指标对疾病活动评估的意义

目的寻找对系统性血管炎(SV)患者疾病活动度有评估意义的指标。方法回顾分析SV患者24例(病例组)及对照组20例的相关指标,对比分析两组免疫球蛋白(IgA、IgG、IgM)、C反应蛋白(CRP)、红细胞沉降率(ESR)、补体(C3、C4)的特点,计算两组血清免疫球蛋白与CRP、ESR、补体之间的相关系数,并应用Logistic回归分析计算上述指标与SV疾病活动度的相关性。结果病例组三种免疫球蛋白较对照组升高,IgA差异有统计学意义(P0.05),IgG、IgM差异无统计学意义;病例组CRP、ESR均值高于对照组,差异有统计学意义(P0.01);两组间C3、C4差异无统计学意义。病例组IgA与ESR呈正相关,IgM与C4呈负相关,CRP与ESR呈显著正相关;对照组仅IgG与CRP呈正相关。Logistic回归分析提示ESR与疾病活动有显著相关性。结论 CRP、ESR是系统性血管炎疾病活动的良好指标,免疫球蛋白升高对疾病活动有一定的提示意义,可以作为补充。     

Recent advance in vasculitis syndrome

Many classifications of vasculitis syndrome have been proposed. The American College of Rheumatology (ACR) proposed criteria for classification of vasculitis in 1990. In 1994, the nomenclature of systemic vasculitides was proposed by Chapel Hill International Consensus Conference. In this conference, the nomenclature of systemic vasculitides was discussed and confirmed by the committee consisted of 16 investigators from 6 countries. The classification of systemic vasculitides was proposed in concern with the size of involved artery and also with the appearance of antineutrophil cytoplasmic antibodies (ANCA). In Japan, Research committee of intractable vasculitis syndrome, Survey and Research on Specific Diseases, the Ministry of Health and Welfare of Japan proposed diagnostic criteria for vasculitis syndrome. The criteria for ANCA related vasculitis syndrome, temporal arteritis and antiphospholipid syndrome were proposed and a nation-wide survey has been undertaken in this committee (Chairman: Hiroshi Hashimoto). In this review, we describe a recent classification of vasculitides and recent topics on Takayasu arteritis, temporal arteritis, Wegener's granulomatosis and Churg-Strauss syndrome.     

Biological markers of liver fibrosis and activity as non-invasive alternatives to liver biopsy in patients with chronic hepatitis C and associated mixed cryoglobulinemia vasculitis

OBJECTIVE AND METHODS: We assessed the reliability of non-invasive biological scoring indexes (Fibrotest-Actitest [FT-AT], Forns, APRI, age-platelet, platelet, hyaluronic acid) as non-invasive alternatives to liver biopsy (LB) in 138 HCV-infected patients. RESULTS: Thirty-six of 138 (26%) patients had systemic vasculitis, 27% significant serum inflammation, 47% fibrosis (F2F3F4) on LB. The diagnostic value of FT (F2F3F4 vs. F0F1) was assessed by an AUC of 0.83, without difference regarding to systemic vasculitis or serum inflammation. A discordance between FT-AT and the Metavir scoring indexes, present in 29% of patients, was associated with serum hemolysis and male but not with systemic vasculitis or serum inflammation. The other non-invasive biological tests were not influenced by serum inflammation or systemic vasculitis but were less reliable than FT (P 相似文献   

Treatment of vasculitic peripheral neuropathy: a retrospective analysis of outcome

BACKGROUND: Vasculitis of the peripheral nervous system (PNS) is rare. There are no controlled treatment trials, and clinical practice is guided by experience from case series and indirectly by analogy with systemic vasculitis. METHODS: We identified patients (n=212) with possible vasculitic peripheral neuropathy (VPN) from the neuropathology and neurophysiology records of two centres over 28 years. Case-notes were available for 181, from which, 106 cases of clinicopathological VPN were identified. Adequate treatment data were available in 100; follow-up data, in 93. RESULTS: Of 106 cases, 95 had systemic vasculitis and 11 had vasculitis confined to the PNS. Pharmacological treatment (94/100 cases) was corticosteroid-based, and included cyclophosphamide in 54; 17 received additional agents. Initial stabilization was achieved in all but six. One-year survival was 90.3%. Of the nine who died in the first years (mean age 73 years), seven had received cyclophosphamide, and all but two had severe, multisystem vasculitis. The neurological relapse rate was 10%. Only one relapse occurred after cyclophosphamide treatment. Outcome was reported as good in 72% (78% in those who relapsed). DISCUSSION: Death and relapse were infrequent in treated patients. Relapse occurred almost exclusively in patients treated with prednisolone alone. Aggressive early treatment with cyclophosphamide may prevent relapse. The current management approach to VPN appears largely effective, especially if cyclophosphamide is used.     

Rheological changes in the blood and disseminated intravascular coagulation (DIC) in systemic vasculitis

Eighty-six patients with different versions of systemic vasculitis were examined for rheological blood properties and some immunologic characteristics. The relationship between the formation of immune complexes and disorders of rheological characteristics and cell aggregation was established with emphasis on the necessity of correcting these disorders by anticoagulants and deaggregating agents for the treatment of patients with systemic vasculitis to be successful.     

Biological therapies: new treatment options for ANCA-associated vasculitis?

Biological therapies enable us to apply highly selective targeting components to modulate the immune response. Until now, a few controlled studies investigated the efficacy of TNF-α blocking agents in systemic vasculitis have been carried out, but, in general, they were falling short of expectations. However, there is conducive evidence that TNF-α blockers are advantageous in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, at least in selected disease stages. Likewise, although the efficacy of the monoclonal CD20 antibody rituximab in ANCA-associated vasculitis is obvious, the effect on predominantly granulomatous disease activity in Wegener’s granulomatosis is less clear. In addition, interferon-α is used for induction treatment particularly in Churg-Strauss syndrome. Even though the effectiveness and safety of short-term administration was confirmed by case series, severe side effects after long-term treatment relativized the initial results. This review presents the recent data on the use of biologicals in vasculitis and appraises the knowledge in the clinical context.     

Pulmonary vasculitis in the intensive care unit

Pulmonary vasculitis can occur in apparent isolation, as part of a primary systemic vasculitis, or with an underlying systemic inflammatory autoimmune disorder. The presentation of pulmonary vasculitis in the intensive care unit (ICU) can be fulminant and will often overlap with more common disorders that affect the critically ill. Although diffuse alveolar hemorrhage (DAH) is the clinical feature that often initiates the concern for an underlying vasculitis, hemoptysis may not be apparent or its presentation can be mistaken for an alternative disease process. As a result, the diagnosis of pulmonary vasculitis in the ICU may be delayed or be completely unrecognized. A high level of suspicion is essential to obtain a timely diagnosis and for effective therapies to be implemented. There have been significant advances this past decade in diagnostic strategies as well as in the therapeutic options for patients with pulmonary vasculitis. We review here the clinical presentations, diagnostic strategies, and treatment options of the critically ill patients presenting with pulmonary vasculitis. The reader is referred to other resources for a more comprehensive review of specific vasculitic entities.     

Cutaneous and systemic manifestations of drug-induced vasculitis

OBJECTIVE: To evaluate the literature for published cases of drug-induced vasculitis with cutaneous and/or systemic manifestations. DATA SOURCES: The MEDLINE database was searched from 1965 to December 1999 for articles focusing on drugs and vasculitis, using various search terminologies (e.g., Churg-Strauss syndrome, Goodpasture's syndrome, Henoch-Sch?nlein purpura, various drugs suspected to induce vasculitis). Cases were included when they met the established criteria as described in the methodology. DATA SYNTHESIS: Drugs found to be most frequently associated with vasculitis were propylthiouracil, hydralazine, colony-stimulating factors, allopurinol, cefaclor, minocycline, D-penicillamine, phenytoin, isotretinoin, and methotrexate. The interval between the first exposure and appearance of symptoms was reported to be extremely variable (hours to years). Vasculitis has occurred after drug dosage increases and after rechallenge with the suspected drug. In the majority of cases, vasculitis has resolved after discontinuing the drug. Patients with more severe, often life-threatening, manifestations have required treatment with corticosteroids, plasmapheresis, hemodialysis, or cyclophosphamide. Death was the result in 10% of all published cases, with a predominance in patients in whom multiple organ systems were involved. CONCLUSIONS: Clinicians need to be suspect of drug-induced vasculitis to enable prompt diagnosis and treatment. This should improve patient outcomes based on the data referenced for this article.