Page 93 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Epidemiology of Primary Systemic Vasculitis 69

The inflammatory cell infiltrate in aortic tissue specimens of affected patients is
composed of neutrophils, macrophages, CD4+ and CD8+ T-cells, natural killer (NK) cells
and macrophages. Infiltrating ??T-cells and NK cells appear to facilitate endothelial cell
apoptosis through production of perforin and killer cell lectin-like receptor subfamily K
(NKG2D). The latter activating C-type lectin family receptor triggers NK cells and co-
stimulates CD8+ ??? T-cell receptor+ T cells, while CD4+ Th1 cells that secrete interferon
(IF)-? promote giant cell and granulomatous lesion formation [43-46]. Peripheral T-cells,
notably Th1 and Th17, contribute to the pathophysiology of GCA and TAK [47, 48] as do
major histocompatibility complex class (MHC) I and II molecules and endothelial
intracellular adhesion molecules, expressed in tissue lesions of the aorta with TAK [49, 43].

Two GWAS conducted in TAK respectively identifying 379 United Kingdom (UK) cases
and 1985 controls [50] and 451 United States (US)/Turkish cases and 1115 controls [51],
noted strong associations with IL12B located at the 5q33.3 chromosome locus (rs6871626),
and susceptibility to the Max-like protein X (MAX) gene transcription factor-like 4 positioned
at the 17q21.2 chromosome locus (rs665268) [50], while those in the UK alone [50] exhibited
independent associations at the 6p21.32 chromosome locus in HLA-DQB1/HLA-DRB1
(rs113452171; rs189754752). HLA-DQB1 specifies the autoimmune response against insulin-
producing islet cells that leads to insulin-dependent diabetes mellitus (IDDM), while the
function of HLA-DRB1 is to present processed foreign antigens to T-cells. The US/Turkish
group reported another susceptibility locus at the Fc fragment of IgG, low affinity IIa and IIIa
receptor (FCGR2A/3A) at the 1q23.3 chromosome locus (rs10919543), leading to increased
mRNA expression of FCGR2A; and proteasome-assembling chaperone 1 (PSMG1).

With receptors present on monocytes, macrophages, neutrophils, NK cells, and T and B
lymphocytes, FCGR2A/3A play an essential role in the protection of the organism against
foreign antigens by removing antigen-antibody complexes from the circulation, and
participate in diverse functions such as phagocytosis of immune complexes and modulation of
antibody production by B cells.

Located at the 21q22.2 chromosome locus, PSMG1 is involved in the maturation of the
mammalian 20S proteasomes with a yet clear implication for TAK.

Epidemiology
The global incidence and prevalence of TAK is summarized in Table 3. Watts and

colleagues [52] employing the primary care UK General Practice Research Database
(UKGPRD) and the secondary care-based Norfolk Vasculitis Register (NORVASC) from
2000 to 2005 employing the ACR 1990 criteria for incident cases [40] and covering a
population of 445,000, identifying 16 cases with a first diagnosis of TAK with an annual
incidence of 0.8 per million calculated as the number of incident cases divided by the total
person-years, that was stable throughout the study period.

The annual prevalence of TAK was 4.7 per million, with an increase during the course of
the study period from 3.6 to 6.3 per million. Mohammad and Mandl [53] studied three
healthcare districts of southern Sweden with a total population of 983,419 as of 2011 to
identify incident cases of TAK among five hospitals in the study area and in all private
Rheumatology clinics between 1997 and 2011, noting 13 cases fulfilling the ACR 1990
criteria for TAK [40]. Among them, eight were of Swedish ancestry, one Asian, two Arabs,
one African and one northern European descent. The annual incidence rate was estimated at

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