Diagnosis and evaluation of vasculitis
Vasculitis: Aims of Therapy/Guest Editor: R. Watts
W. L. Gross,
A. Trabandt and
E. Reinhold-Keller
Department of Clinical Rheumatology, University of Lübeck and Clinic of Rheumatology, Oskar Alexander Strasse 26, 24572 Bad Bramstedt, Germany
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Introduction
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Vasculitis is inflammation of a vessel wall. The systemic vasculitides represent a highly heterogeneous group of clinicopathological entities. Vasculitis has many causes, although it produces only a few histological patterns of vascular inflammation. The clinical expression depends on the site, type and size of vessels involved. Vessels of any type in any organ can be affected, which is reflected in the wide variety of signs and symptoms. Clinically the systemic vasculitides range from benign, locoregionally restricted processes (e.g. cutaneous leucocytoclastic angiitis) to systemic vasculitis leading to life-threatening conditions [e.g. pulmonary renal syndrome in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis]. Many patients develop their disease against a background of non-specific symptoms, such as malaise, weight loss, fever and night sweats (so-called B-symptoms), which reflect constitutional symptoms. More specific symptoms derive from the type of vessels involved; this has led to the well-known classification scheme of primary systemic vasculitides (Table 1
). However, in clinical practice vasculitic syndromes do not respect vessel size boundaries. In addition, discrete vasculitides with indistinguishable clinical presentations due to the predominant involvement of small vessels have a very different prognosis and require different therapies. For example, a patient with purpura caused by HenochSchönlein purpura has a clearly better prognosis and needs less aggressive therapy than a patient with purpura caused by microscopic polyangiitis (MPA), which is likely to progress to life-threatening organ failure if not treated by immunosuppressives. So, in addition to the clinical picture, one needs to take into account the histology and immune phenomena in the blood and tissues, and a broader differential diagnosis to avoid missing secondary vasculitides or vasculitis-like syndromes (Table 2
).
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Classification
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In 1952, Zeek [34] became the first author to incorporate a clinicopathological assessment based on the size of the vessels involved in the inflammatory process in her classification of necrotizing vasculitis. A number of alternative classification systems were proposed later and a major break was made in the 1990s with the 1990 American College of Rheumatology criteria (ACR 1990 criteria); and the elaboration of a uniform terminology for naming, defining, classifying and diagnosing vasculitic disorders at the Chapel Hill Conference 1992 (1992 CHC definitions). The 1990 ACR criteria were reviewed in 1996 by Hunder [3]. The 1992 CHC definitions now include immunodiagnostically significant markers [e.g. ANCA in Wegener's granulomatosis (WG)] and immunohistological findings (e.g. IgA-dominant immune deposits in HenochSchönlein purpura) which are specific for certain diseases and were described by Jennette et al. [4]. The major problem with previous classification schemes was the lack of standardized diagnostic terms and definitions. As a consequence, different names had been applied to the same disease and the same name to different diseases. Therefore, the CHC committeecomprised of internists, rheumatologists, nephrologists, immunologists and pathologists who have in common extensive experience with diagnosing vasculitidesproposed the names and definitions given in Table 3
.
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TABLE 3. Names and definitions of vasculitides adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitisa
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Immunopathogenesis
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Most of the vasculitic syndromes are mediated by immunopathogenic mechanisms (immune vasculitides) and most immune vasculitides are idiopathic (= primary vasculitis). The immunopathogenic mechanisms of vasculitides have been classified into the four types of hypersensitivity reaction described by Coombs and Gell [35]; this classification was reviewed recently [5]. Accordingly, clinicopathological and immunohistochemical studies have led to the terms allergic angiitis (I), antibody-mediated angiitis, including the new group of ANCA-associated vasculitides (II), immune complex vasculitis (III), and vasculitis associated with T-cell-mediated hypersensitivity (IV) (Table 4
). Eosinophilia and elevated IgE in the blood and tissues (in situ) are characteristically associated with allergic angiitis and granulomatosis (ChurgStrauss syndrome; CSS); in ANCA-associated vasculitides (AAV) few or no immune deposits are found in situ (pauci-immune vasculitis). By contrast, immune complex deposits in situ are the hallmark of immune complex vasculitis, which is frequently associated with low complement levels. Granulomatous arteritis is characterized by an inflammatory infiltrate induced by Th1 cells. The predominant immune phenomena in systemic vasculitides associated with the major hypersensitivity reaction type are given in Fig. 1
.
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TABLE 4. Predominant immune phenomena in primarily systemic vasculitides delineate to the major hypersensitivity reaction types
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Immunodiagnostic approach
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Primary systemic vasculitides were reclassified based on ANCA serology, the presence of immune deposits in situ, and the size of the vessels involved. WG, MPA and CSS were subsumed in the group of ANCA-associated vasculitides, which are characterized clinically by a WG, CSS or non-granulomatous MPA inflammation commonly involving the respiratory tract and earnosethroat (ENT) region and by a necrotizing pauci-immune (= no or minimal immune deposits) vasculitis typically affecting small- to medium-sized vessels.
ANCA are a heterogeneous group of autoantibodies that can be subdivided by indirect immunofluorescence tests (IFTs) and by enzyme-linked immunosorbent assays (ELISAs). IFTs can distinguish two major fluorescence patterns on ethanol-fixed human granulocytes: one of these patterns, classic cANCA, is highly specific for WG, while the other, perinuclear pANCA, is commonly seen in MPA (rarely in WG), but may be detected in a wide variety of other autoimmune conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis, Felty's syndrome and chronic inflammatory bowel diseases with associated disorders).
The clinical utility of cANCA as a diagnostic marker for WG was recently confirmed in a large prospective European study undertaken with sera from vasculitis patients (sensitivity 60%, specificity 95%) [7]. However, when employed as a routine screening method for WG (defined according to ACR criteria) in patients with suspected vasculitis, the sensitivity of cANCA in a recent prospective single-centre study on 346 consecutive patients was only 28% (specificity for WG: 98%). The sensitivity rose to 83% if only biopsy-proven WG was considered [8]. A meta-analysis of 15 studies comprising 13 652 patients (including 736 cases of WG) yielded a pooled sensitivity of 66% and a specificity of 98% [9]. Taken together, these data show that the value of cANCA testing is limited by a rather low sensitivity; the greatest utility of cANCA testing may be in patients with suspected, but not yet proven, WG. This view is supported by a recent analysis of ANCA results in a large routine laboratory (Regional Immunology Laboratory, Belfast, UK). The overall positive predictive value for primary systemic vasculitides was 38% for all cANCA and only 20% for all pANCA. Specificity improved when only antinuclear antibody (ANA)-negative samples with a high ANCA titre were considered (cANCA 90%, pANCA 60%) [10]. In most, but not all cases, titres correlated with disease activity. Rising titres should alert the clinician to an increased risk of exacerbation, but are generally not regarded as an indication for intensifying therapy [11].
ELISAs are used to specify further the target antigens of ANCA, namely proteinase 3 (PR3; cANCA-positive samples have a 99% specificity for WG) [7], myeloperoxidase (MPO; 80% specificity for MPA) [7], as well as less important target antigens such as cathepsin G, lactoferrin, lysozyme and human leucocyte elastase, which are not specific for any particular vasculitic disorder. Whether anti-bactericidal permeability increasing protein (BPI) ANCA offer further diagnostic perspectives in vasculitis is still unclear [1214].
So, ANCA are not specific for ANCA-associated vasculitides and despite the high specificity of cANCA/PR3-ANCA for WG and of MPO-pANCA for MPA, an increasing number of false-positive PR3-/MPO-ANCA have been described [11]. More recently, we and others have observed PR3-ANCA in subacute bacterial endocarditis, a condition sometimes associated with vasculitis [15]. Still, because ANCA test results are usually available before histological analyses are completed, ANCA serology remains the most important tool in the diagnostic repertoire for ANCA-associated vasculitides, especially in seriously ill patients suspected of having vasculitis. Under life-threatening conditions, therefore, therapy should be commenced based on clinical and serological findings! An overview of predominant immune phenomena in systemic vasculitides associated with the hypersensitivity reaction types (and the serological markers) is given in Table 5
.
The incidence of ANCA in CSS is much lower than in WG and MPA, and their immunodiagnostic significance is limited [7]. However, active CSS is characterized by increased eosinophils in conjunction with strongly elevated IgE and eosinophil cationic protein values [17].
Furthermore, endothelial cell damage in active AAV is indicated by markedly increased serum thrombomodulin (sTM) values [17]: in CSS, high levels of sTM correlate closely with the soluble interleukin-2 receptor, which has been shown to be a promising seromarker of disease activity in WG [18].
Because intermittent infections are a major differential diagnostic problem in seriously ill AAV patients (Table 6
), a marker that distinguishes between the two conditions is urgently needed. Procalcitonin was recently shown to be normal in active autoimmune rheumatic disorders, but strongly elevated in concomitant bacterial infections and sepsis [19]. However, these findings have yet to be confirmed [20].
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Diagnosis
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A detailed patient history, physical examination and focused laboratory investigation are vital in diagnosing vasculitic disorders. The goals of the work-up include identification of a cause of the disease and/or the underlying immunopathogenetic mechanism, classification of the disease, and determination of the disease activity and extent. The latter is all the more important as stage-adapted treatment and assessment of the treatment's efficacy are only possible if there are uniform and reproducible measures of the extent and activity of organ involvement in the vasculitic disease. A prerequisite for this is a standardized evaluation of the clinical, radiological and laboratory findings by an interdisciplinary team of expert physicians (internal medicine, neurology, ophthalmology, dermatology, radiology, etc.).
Semi-quantitative scoring systems were recently developed for the standardized assessment of disease activity and extent. On the basis of the extended (ENT, lung, kidney) ELK classification [21, 22], a disease extent index (DEI) was established by our group [23]. This instrument has been well accepted by German vasculitis centres because it can be easily and quickly applied pro- and retrospectively and is valid, reliable, sensitive to change, and highly reproducible (Table 7
). The DEI may also be of prognostic value in therapeutic trials. Pulse cyclophosphamide treatment, for example, proved to be less effective in patients with a DEI >7 at the start of treatment [23]. In addition, a vasculitis activity score (Birmingham vasculitis activity score; BVAS) has been developed, validated and computerized [25]. Because of its magnitude, the BVAS is used more often in clinical studies than in daily clinical practice. Whether the two scores are complementary or could be substituted one for the other remains to be elucidated.
Laboratory tests should be used to ascertain the type of vasculitis, the organ systems affected, and the extent of organ involvement. However, many of these tests are non-specific; the erythrocyte sedimentation rate (ESR) and acute-phase proteins like C-reactive protein (CRP) only indicate that inflammation is present, but do not reveal its exact aetiology. A low complement level may be present in patients with immune complex vasculitis (e.g. cryoglobulinaemia) and the presence of cANCA (PR3-ANCA) strongly suggests a diagnosis of WG. Some differential diagnostic features of several forms of small vessel vasculitides are given in Table 5
.
The definite diagnosis of systemic vasculitis, however, is dependent on the demonstration of vascular involvement by either biopsy or angiography. Biopsy specimens should be obtained only from clinically involved accessible tissue. Arteriograms are helpful in identifying and characterizing vasculitis of the medium-sized or larger arteries, e.g. in Takayasu arteritis.
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Diagnostic route
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The first step towards arriving at a diagnosis is to recognize what kind of vessel or vessels is predominantly involved. The second step is to find out whether other symptoms are present which seem to be unrelated to the pathological sequelae of vasculitis, i.e. to find out whether there are granulomatous lesions in the ENT region in WG or, more importantly, whether there are exogenous factors which may have triggered the vasculitic process, i.e. drugs, infections or neoplastic manifestations (Table 8
). This search must be carried out very carefully with regard to the clinical investigation, starting with close examination of the patient's history and environment. Then imaging procedures have to be carried out in order to determine the disease extent. Various laboratory markers will additionally reflect or accord with the clinical impression with respect to disease activity (Table 5
). A biopsy should next be taken from a site of tissue involvement in order to avoid false negative results, which is frequently the consequence of biopsies taken blind. After all, the question whether the disease is really one of the group known collectively as primary systemic vasculitis, or a secondary form (Table 8
), or an infection-induced process, or something entirely new, must be answered. The increase in the number of cases of vasculitis due to growing awareness, better diagnostic tools, etc., has been accompanied by a parallel increase in the number of vasculitic syndromes associated with infections, immunodeficiencies, etc. Recently, granulomatous vasculitis affecting small cutaneous blood vessels and purpura due to leucocytoclastic vasculitis and associated with the herpes virus were observed [26, 27]. Moreover, a neurobrucellosis mimicking cerebral vasculitis [28] and a WG-like syndrome were identified as a case of primary immunodeficiency due to a defect of the MHC gene complex class I processing and presentation pathway [29].
First we reported a case of primary immunodeficiency due to a defect of the transporter associated with antigen presentation (TAP) genes, a heterodimeric complex which controls the expression of HLA class I molecules by delivering peptides from the cytosol into the lumen of the endoplasmic reticulum. Since childhood, the 36-yr-old female suffered from recurrent sinusitis/bronchitis. She later developed bronchiectasis and destructive nasal granulomata in conjunction with a generalized vasculitic syndrome that did not improve upon immunosuppression and antibiotics. A severe reduction of MHC class I molecules at the cell surface of the B-cell lines was observed, whereas MHC class II expression was not altered. Isoelectric focusing of metabolically labelled MHC class I molecules revealed that class I heavy chains remained unsialylated, consistent with a block of TAP-dependent translocation. These conclusions were confirmed by further experiments showing that peptide translocation was completely abolished. We also demonstrated that presentation of viral antigens through endogenous class I molecules was severely impaired. Immunoprecipitation and Western blotting of TAP1/2 complex showed that TAP2 was not detectable [29].
In our latest paper we reported five patients with the same genetic defect who displayed a remarkable homogeneity of clinical symptoms and disease course [30]. In conclusion, we described a novel granulomatous syndrome which can be erroneously classified as WG by applying international classification criteria, but which can easily be differentiated from WG by (1) analysing the level of expression of HLA class I molecules in peripheral blood mononuclear cells (PBMC) and (2) cANCA (PR3-ANCA) which will typically be absent in this disease. Our findings illustrate the general principle that an accurate genetic analysis of a defined syndrome can provide a better understanding of the aetiology and pathogenesis of a disease. Adults with otherwise unexplained destructive granulomatous lesions, frequent infections of the respiratory tract with or without bronchiectasis and leucocytoclastic skin vasculitis may suffer from a recessive defect in the HLA class I expression pathway. It is likely that expression of different HLA class I haplotypes by different patients may have an influence on the spectrum of their clinical symptoms and infections. Analysis of patients with defects in the class I presentation pathway is therefore of importance to understand the relationship between susceptibility to infectious diseases, autoimmune disorders and HLA class I haplotype in an outbred population.
In the diagnosis of a patient with suspected vasculitis there are no agreed upon criteria for the various categories of vasculitis. It is noteworthy that the ACR 1990 criteria were not designed for diagnosis. However, the proposed names and definitions for vasculitic disorders proposed in the 1992 CHC definitions [4] are being increasingly used for diagnosis. The diagnosis of vasculitis requires the knowledgeable integration of clinical, histological (immunohistological) and laboratory data. Chest and sinus radiographs by computed tomographic scans and/or nuclear magnetic resonance imaging may reveal occult respiratory tract disease [31, 32]. Confirmation that eyes, ears, nose or throat are involved often requires the expertise of an ENT and/or ophthalmology specialist [33]. In addition, nerve conduction studies can document the severity and progression (or regression) of peripheral neuropathy.
Evidence of conditions that are known to cause vasculitis has to be sought in every interview with the patient. The patient's history should be thoroughly screened for drug hypersensitivity, infection (hepatitis!), rheumatic diseases (including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome), neoplastic disorders, and inflammatory bowel diseases.
Today's thinking about vasculitis is all too often restricted to the group of primary vasculitides. Doctors are less willing to consider those secondary, e.g. to the various conditions depicted in Table 8
. This is probably the reason why in the past year many reports in leading journals have stated that infectious origins should always be considered. Despite the progress that has been made in the field of vasculitis within the past decade, this group of diseases still poses a challenge to doctors and scientists today, and will continue to do so in the future.
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Notes
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Correspondence to: W. L. Gross. 
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Submitted 20 September 1999;
revised version accepted 19 October 1999.