Vasculitis and Its Classification

Vessel Structure and Function

Blood vessels are composed of three layers: an innermost layer—tunica intima; a middle layer—tunica media; and an outer layer—tunica adventitia. The tunica intima is formed by endothelial cells, which produce vasoregulatory substances. The characteristics of endothelial cells vary from location to location in their anatomical characteristics and expression of ligands and receptors, accounting, at least in part, for the disease-restricted distribution of affected vessels. The tunica media consists of smooth muscle and elastin fibers that regulate vasodilation and vasoconstriction under the control of the autonomic nervous system. The tunica adventitia consists of collagen fibers and nutrient blood vessels.

Classification

The vasculitides are among the most difficult of all rheumatic diseases to classify. Vasculitis syndromes have been categorized according to clinical phenotype, the predominant size of the involved vessels, or the histopathology of the involved vessel. Using this framework, in 1990 a committee of the American College of Rheumatology (ACR) provided one set of classification criteria for most types of vasculitis; disease definitions and descriptions were updated by international consensus at the International Chapel Hill Consensus Conference (CHCC) in 1994 and some additional diseases were added. A second update at the CHCC in 2012 provided revised recommendations on the names of diseases, preferred abbreviations, and disease definitions ( Table 32.1 ) but once again did not provide revised classification criteria. The CHCC 2012 retained the ACR framework for categories of vasculitis based on the size of predominantly affected blood vessels defined as follows: large-vessel vasculitis (LVV) involves the aorta and its major branches; medium-vessel vasculitis (MVV) involves the main visceral arteries and their initial branches; and small-vessel vasculitis (SVV) involves intraparenchymal arteries, arterioles, capillaries, and venules. SVV is newly subcategorized according to either the paucity of vessel wall immunoglobulin (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis [AAV]) or the prominence of vessel wall immunoglobulin:immune complex (SVV). When appropriate, immune complex vasculitis can be further subcategorized as vasculitis associated with probable etiology (e.g., drugs, cancer, or infections). Other new CHCC 2012 categories included variable-vessel vasculitis (VVV), which can involve different-sized arteries, veins, and capillaries to varying degrees and encompasses Behçet disease and Cogan syndrome and single organ vasculitis, which includes isolated central nervous system vasculitis and vasculitis associated with systemic disease (such as systemic lupus erythematosus). Since CHCC 2012, at least two monogenic conditions (deficiency of adenosine deaminase 2 [DADA2] and stimulator of interferon genes [STING]-associated vasculopathy with onset in infancy [SAVI]) have been described as having major phenotypic and sometimes histopathologic features of vasculitis. Whether or not these should also be grouped in the other “secondary vasculitis” disease categories as monogenic vasculitis or elsewhere remains to be determined (see Chapter 39 ). Subcategorization according to histopathology (e.g., granulomatous vs. nongranulomatous) has not been retained in the CHCC 2012 because of the limited consistency of histopathological findings. In the CHCC 2012, the use of eponyms has also been discontinued. Thus Wegener granulomatosis, Churg–Strauss syndrome, and Henoch–Schönlein purpura (HSP) have been replaced, respectively, with the terms granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and immunoglobulin (Ig)A vasculitis.

The CHCC 2012 nomenclature and the definitions do not provide diagnostic or classification criteria. Therefore the 1990 ACR criteria, derived primarily from adult-patient data, remain the most widely used system for classifying patients with vasculitis. These ACR classification criteria have limited usefulness when applied to children with chronic vasculitis and result in a significant proportion of pediatric and adolescent patients with vasculitis being described as unclassifiable. A pediatric adaptation of the ACR criteria, taking into account common pediatric clinical manifestations and the presence of ANCA, was developed by consensus by a group of pediatric experts and reported in 2006 ( Box 32.1 ). Subcategorization according to histopathology and some old terminology/eponyms are retained as these proposals predated the CHCC 2012. Proposed criteria for four diseases (GPA, Takayasu arteritis [TAK], polyarteritis nodosa [PAN], and HSP) were subsequently tested and improved upon using a cohort of pediatric patients. The final validated Ankara 2006 criteria had improved sensitivity compared with the ACR criteria and were published in 2010, after having been endorsed by the European League Against Rheumatism (EULAR), the Pediatric Rheumatology International Trials Organization (PRINTO), and the Pediatric Rheumatology European Society (PReS). ^, The Ankara criteria proposed for these diseases will be presented in relevant chapters. Unfortunately, these criteria retain some inherent limitations of the ACR criteria that have also been recognized in the adult literature. Specifically, the lack of any criteria for microscopic polyangiitis (MPA) has led to difficulties in discriminating GPA patients from MPA patients (see Chapter 36 ). On the one hand, this conundrum has led to the convenient grouping of GPA and MPA in adult clinical trials under the rubric of AAV. On the other hand, complex algorithms have been proposed to differentiate patients with the various types of AAV and PAN for study. Because of this and other classification inadequacies, the whole system for classifying vasculitis currently remains under scrutiny. The Diagnostic and Classification of Vasculitis (DCVAS) prospective study is an international initiative launched in 2010 aiming to develop both revised classification criteria and a validated set of diagnostic criteria for systemic vasculitis in adult patients. This will have implications for the diagnosis and classification of pediatric patients that will be evaluated in an integrated Pediatric Vasculitis Initiative (PedVas) ( https://clinicaltrials.gov/ct2/show/NCT02006134 ).

In practice, the classification of vasculitis is very much dependent on the clinical presentation. The classification used in this book references the new nomenclature described in the CHCC 2012, pediatric-specific classification criteria that have been validated, and ACR classification criteria used in the absence of validated pediatric criteria.

Evaluation of Vasculitis

Ideally, accurate disease classification in a given patient at disease onset should also assist in determining the disease course (trajectory), prognosis (predicted outcome), and optimal treatment choices. In addition, treatment choices at disease onset and during the disease course (when to start, stop, increase, or decrease therapy) are determined after assessing disease activity and severity. Disease severity and activity plus disease damage assessments are used to measure disease outcome and/or effectiveness of treatment. Clinical assessment tools in adults have enabled a more systematic and formal approach to staging levels of disease activity and damage in vasculitis. The Birmingham Vasculitis Activity Score (BVAS) and the Vasculitis Damage Index (VDI) are widely used for evaluation of adult AAV and accepted by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) initiative. These tools are not fully applicable to childhood vasculitis, but a pediatric adaption of the BVAS, known as the pediatric vasculitis activity score (PVAS), and initiatives to establish a pediatric adaption of the VDI are discussed in Chapter 36 .

Epidemiology

The incidence and prevalence of vasculitis in children are unknown. In the pediatric population, the most common vasculitides are IgA vasculitis (IgAV)/HSP and Kawasaki disease (KD). All others are very uncommon or rare. There are striking geographical differences in relative disease frequency. KD and TAK are most prevalent in Japan. KD and IgAV/HSP are the most common vasculitides in North America and Europe. Comprehensive studies of the frequencies of the vasculitides in other parts of Asia are not available, but it is probable that KD and TAK constitute a larger proportion of vasculitis in that area of the world. PAN and cutaneous polyarteritis may also be more common in Japan and Turkey. In a multicenter survey in Turkey, Ozen et al. noted that IgAV/HSP was much more common than KD; that PAN was possibly increased relative to other vasculitides; and that GPA, which appears to be more common in Western Europe and North America, is less frequent in the Turkish population. Isolated vasculitis of the central nervous system has been recognized in childhood, and its classification and relative frequency have yet to be established. Studies in African populations have not been reported.

In national registries, the various forms of chronic vasculitis account for 1% to 6% of pediatric rheumatic diseases. ^{, ,} The proportions of children from three registries that identified specific vasculitides are shown in Table 32.2 . The wide differences in frequencies may just as likely reflect referral patterns as determinable geographical differences.

Although childhood vasculitis is uncommon, it is an important component of referrals to pediatric rheumatology clinics, and children with vasculitis often require disproportionately large amounts of time and expertise. Diagnosis can be difficult and challenging, monitoring disease activity is problematic, and the outcome for some of the vasculitides may be serious or fatal.