Editorial
Classification of systemic vasculitis: Time for an update
La clasificación de las vasculitis sistémicas: es momento de su renovación
Javier Marco-Hernández, Sergio Prieto-González
Corresponding author
Servicio de Enfermedades Autoinmunes, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
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The spectrum of clinical manifestations is very varied and depends mainly on the location of the affected vascular territory.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Sometimes, this clinical heterogeneity between the different types of vasculitis, or even among individuals suffering from the same entity, makes its diagnosis a real challenge. Vasculitis are clinicopathological entities, so the diagnosis is based primarily on clinical suspicion and demonstration of vascular inflammation. Once the diagnosis is established, its classification between the different types is important, since a correct classification has therapeutic and prognostic implications. For this classification, in addition to considering the size of the affected vessel, the combination of epidemiological, clinical, serological, histological and radiological data is required.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The diagnostic criteria of a disease are used to identify patients with a certain pathology among those with very different entities but similar clinical manifestations. On the other hand, the classification criteria are designed to differentiate a patient with a certain entity from others with similar and related pathologies.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> To date there are no diagnostic criteria for any of the entities described in the case of vasculitis. On the other hand, several published studies address the concept of classification and definition of vasculitis. The first classification proposal, published in 1952, described five types of vasculitis, with the main difference relying on the size of the affected vessel: hypersensitivity vasculitis, allergic granulomatous angiitis, rheumatic arteritis, polyarteritis nodosa and temporal arteritis.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Proposed classifications subsequently perfected this pioneering way of differentiating different types of vasculitis, delving into histological findings and incorporating demographic, clinical and analytical data.</p><p id="par0015" class="elsevierStylePara elsevierViewall">In 1990, the <span class="elsevierStyleItalic">American College of Rheumatology</span> (ACR) published the classification criteria for seven types of vasculitis: giant cell arteritis (GCA), Takayasu arteritis (TA), Wegener's granulomatosis (currently granulomatosis with polyangiitis or GPA), Churg-Strauss syndrome (currently eosinophilic granulomatosis with polyangiitis or EGPA), polyarteritis nodosa (PAN), immunoglobulin<span class="elsevierStyleHsp" style=""></span>A vasculitis (IgAV) and hypersensitivity vasculitis (HSV).<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The study cohort used for its development included 807 patients with vasculitis and the methodology consisted in comparing the group of patients with each specific diagnosis with the rest of patients with vasculitis. The sensitivity and specificity of the criteria of each of the vasculitis were high (between 85 and 93.5%, and between 86.6 and 99.7%, respectively), their use is widely extended and accepted, and are still valid today. These criteria have allowed the inclusion of patients in a homogeneous way in epidemiological studies and multicenter clinical trials, a fact that has favoured the expansion of knowledge of these rare diseases and the advancement in their therapeutic management.</p><p id="par0020" class="elsevierStylePara elsevierViewall">These criteria have, however, important limitations. One of the most relevant is that the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCA) are not part of them. This is because the recruitment and collection of data from the patient cohort on which they are based were carried out in the early 1980s, and it was not until 1985 when the relationship between ANCA and vasculitis was described.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Linked to this, microscopic polyangiitis (MPA) was not a widely recognized entity at the time of the study, so it was not included in the classification criteria. In fact, today there are no qualifying criteria for this entity. In addition, there is overlap between the different vasculitis when applying the ACR criteria, and several studies have shown that the same patient can meet the criteria of several entities,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> or that patients with other diagnoses (without vasculitis) can also meet them.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> On the other hand, in the last decade imaging techniques have come to occupy a significant place in the evaluation of a patient with vasculitis, especially in those with large vessel involvement.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–10</span></a> Doppler ultrasound, computed tomography with angiography, magnetic resonance imaging with angiography and positron emission tomography are used systematically in these patients. Apart from the use of arteriography for the study of PAN and TA, imaging techniques were not a common tool in the study of a patient with vasculitis at the time of ACR criteria publication, so their role in these is very limited.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> All this has caused that the sensitivity of the ACR criteria, applied to current patient cohorts, has decreased considerably.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The first Chapel Hill consensus conference (CCCH) on the nomenclature and definition of the most common systemic vasculitis was held in 1994.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In it, an international committee of experts, which included internists, rheumatologists, immunologists, nephrologists and pathologists with extensive experience in the diagnosis and management of patients with systemic vasculitis, agreed on the name and definition of ten systemic vasculitis. In addition to the entities included in the ACR criteria, MPA, cryoglobulinaemic vasculitis (CV) and cutaneous leukocytoclastic vasculitis (CLV) were added. On the other hand, HSV was not considered an entity as such, being reclassified between the MPA and the CLV. The classification was made according to the size of the affected vessel (large, medium or small), although the authors noted that involvement was predominant but not exclusive. In this way, a patient with a GCA characteristically has involvement of the aorta and its main branches (large vessel),<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a> but this does not exclude a potential small vessel involvement, as occurs in some cases in the histological findings of the temporal artery biopsy<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> or in the ophthalmic imaging study.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The definitions were eminently histological, with a detailed description of vascular compromise, which was especially useful for differentiating particular types of vasculitis. As the histological demonstration of vasculitis is not always possible, the consensus conference included, in an appropriate clinical context, the acceptance of surrogate markers of vasculitis (for example, the presence of visceral artery aneurysms when a PAN is suspected), but without providing a list of these. It should be noted that the proposed definitions were developed based on the opinion and clinical experience of the experts gathered at the conference and not on an objective data analysis, and that they were not intended to be diagnostic or classification criteria. It is also important to say that, although the relationship between ANCA and vasculitis was well known by the experts at the time of CCCH publication, these was not included in the definition of ANCA-associated vasculitis (AAV).</p><p id="par0030" class="elsevierStylePara elsevierViewall">The lack of concordance between ACR criteria and CCCH definitions,<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,16</span></a> as well as the absence of classification criteria for MAP, prompted the proposal and validation of a classification algorithm for AAV and PAN in 2007.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In this, with well-defined vasculitis inclusion criteria and surrogate markers, an algorithm was applied to a patient with clinical suspicion of AAV or PAN, in whom the presence or absence of ANCA is assessed, as well as clinical or classification criteria for EGPA, GPA, MPA and PAN, sequentially. The purpose of the algorithm was to obtain the minimum possible number of unclassifiable forms of vasculitis, especially for epidemiological and clinical trial inclusion purposes.</p><p id="par0035" class="elsevierStylePara elsevierViewall">A new CCCH took place in 2012 with the intention of incorporating the advances in knowledge acquired in previous years.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In it some of the eponyms were changed by pathophysiological descriptions (for example, Churg-Strauss syndrome was renamed eosinophilic granulomatosis with polyangiitis) and substantial changes were introduced in the definition of the diseases already included in the first conference. One of the most relevant was the recognition of AAV as a well differentiated subgroup, with the ANCAs within the definition of the latter or as a useful marker in the exclusion of other entities (for example, PAN). In addition, some of the entities were reclassified, with CV (its idiopathic or essential form) and IgAV being included in the group of immunocomplex-mediated small vessel vasculitis, adding to this group also hypocomplementemic vasculitis and anti-glomerular basement membrane disease, with their respective definitions. Also included were single-organ vasculitis (central nervous system, breast, skin, etc.) and vasculitis of varying vessel size (Behçet's disease and Cogan's syndrome), as well as forms secondary to neoplasms, drugs, infections (typically to hepatitis <span class="elsevierStyleHsp" style=""></span>B and<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">C</span> virus) or those associated with other pathologies (for example, rheumatoid arthritis or systemic lupus erythematosus).</p><p id="par0040" class="elsevierStylePara elsevierViewall">As we have already mentioned, the ACR criteria do not include MPA and have important deficiencies, so they are now clearly obsolete. In addition, in the absence of diagnostic criteria they are often used for that purpose, even though they were not designed for that objective. For this reason, an international project launched by the <span class="elsevierStyleItalic">European League Against Rheumatism</span> (EULAR) in 2011, the ACR and the <span class="elsevierStyleItalic">Vasculitis Foundation</span> for the development of diagnostic criteria and new classification criteria for vasculitis, called DCVAS <span class="elsevierStyleItalic">(Diagnostic and Classification Criteria in Vasculitis).</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Upon completion of the recruitment phase in December 2017, 6991 patients (4994 with vasculitis and 1997 with other diagnoses used as a comparison group) have been included in 136 centres in 32 different countries. The specific data of the origin and the number of patients included in each of the types of vasculitis can be found on the project's website.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The effort carried out in this project has already begun to bear fruit. Although, to date, they have only been communicated in conferences, there are already provisional classification criteria for GPA, GCA and TA.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> One of the features we can highlight of the new proposed criteria compared to those of the ACR is the fact that each item included has a certain score, which is added to obtain a final score, having to reach a minimum of points for the correct classification. In addition, as expected, ANCAs are included in the GPA criteria (with the highest score among the 9 items proposed), and imaging techniques play a very important role in large vessel vasculitis (for example, the finding of the "halo sign" in the temporal artery with Doppler ultrasound scores the same as a pathological temporal artery biopsy).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Perhaps it is too early to talk about limitations of the DCVAS project, but it should be noted that the diagnosis of patients included was based on the clinical criteria of the participating physician (<span class="elsevierStyleItalic">gold standard</span>) and that the follow-up of these does not go beyond 6<span class="elsevierStyleHsp" style=""></span>months after diagnosis, which makes it difficult to detect possible diagnostic or reclassification errors for vasculitis, a situation quite common in patients with this diagnosis.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In summary, the current classification criteria for vasculitis are almost three decades old and have significant deficiencies, but thanks to the international effort and the incorporation of clinical markers such as ANCA and imaging technique findings, we could soon be witnessing their renovation and the probable development of the long-awaited diagnostic criteria.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0055" class="elsevierStylePara elsevierViewall">Subsidized by Marató TV3 2104/201507 and the Ministry of Economy, Industry and Competitiveness (SAF 2017-88275-R).</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interests</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interests" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Marco-Hernández J, Prieto-González S. 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