Lumpers and splitters: ongoing issues in the classification of large vessel vasculitis.

Large vessel vasculitis (LVV) is defined as inflammation that affects the aorta and its major branches. Takayasu arteritis (TAK) and giant cell arteritis (GCA) are the 2 main forms of LVV1. Historically, GCA is considered a disease of the elderly that targets the extracranial arteries (e.g., carotid and temporal arteries). In contrast, TAK typically affects younger patients and targets the aorta and its primary branches (e.g., subclavian and renal arteries). However, increasing evidence, primarily based on radiographic studies, demonstrates that vasculitic involvement of the aorta and primary branches can occur in GCA in addition to the more widely recognized cranial features of the disease2. Current estimates about the prevalence of involvement of the aorta and primary branches in GCA vary widely across different cohorts, but large vessel pathology is apparent by angiography in about 20%–30% of patients with GCA3,4. There are no existing guidelines regarding screening for large artery involvement in GCA, so the incidence of large vessel disease in GCA may be underestimated. An older necropsy study of 4 patients with GCA and known temporal arteritis, in which there was no clinical suspicion for vasculitis in the aorta and branch vessels, demonstrated widespread vasculitic lesions throughout the large arteries in every patient5. Cumulative incidence rates of large vessel involvement in GCA have increased dramatically over the last 2 decades in parallel with increased awareness about this feature of GCA6. Recognition of involvement of vessels beyond the extracranial arteries as a feature of GCA has created new challenges in the disease classification of LVV. The 1990 American College of Rheumatology (ACR) Classification Criteria for GCA were developed in a time when involvement of the aorta and primary branches was not a well-recognized feature of GCA and are focused on the cranial aspects of the disease7. In contrast, the 1990 ACR Classification Criteria for TAK focus on clinical features of arterial damage related to the aorta and primary branches (e.g., limb claudication)7. About two-thirds of patients with GCA and large vessel disease have involvement of the aorta or primary branches in the absence of cranial features of disease (e.g., headache, jaw claudication, ocular disease, positive temporal artery biopsy)8,9. Differentiating the subset of patients with GCA who do not have cranial features of disease from patients with TAK is difficult. Age is incorporated into existing criteria for both GCA and TAK; consequently, age is often arbitrarily applied as the primary determinant of disease classification in a patient with large vessel vasculitis. Involvement of the aorta and primary branches with disease onset at < 40 years is classified as TAK, and large vessel involvement with disease onset at > 50 years is often classified as GCA. Based upon observed similarities between TAK and GCA, there are suggestions that these 2 conditions may exist on a spectrum within the same disease10. The histopathology of vasculitic lesions is indistinguishable between the 2 diseases5. Common genetic variants (e.g., FCGR2A/FCGR3A) have been identified11. There is overlap in the signs and symptoms at presentation10. An ongoing therapeutic trial in large vessel vasculitis is studying treatment effect in a combined cohort of patients with TAK or GCA (NCT00556439). Our group recently reported on the distribution of arterial lesions in patients with TAK or GCA and found striking similarities between the 2 diseases8. Lesions tended to be contiguous in the aorta and symmetric in branch vessels in both diseases. The distribution of affected vessels was similar with few exceptions. There was notably increased axillary artery involvement in GCA, and a high prevalence of left subclavian artery involvement was seen in TAK. Using latent class analysis, a statistical technique to identify potentially unobservable subgroups within a population, there was little differentiation between the 2 diseases on the basis of patterns of arterial involvement. We suggested that TAK and GCA might exist on the same spectrum of disease with subtle skewing of disease phenotypes influenced by immunosenescence. In the current issue of The Journal, Furuta, et al report upon findings in a cohort of patients with LVV12. Unlike our previous work, which focused only upon angiographic data, the authors expand the scope of comparison between TAK and GCA to include clinical and laboratory data. Only