Pathophysiology of large vessel vasculitis and utility of interleukin-6 inhibition therapy

Figures & data

Figure 1 Progression of large arterial lesions in TAK and GCA.

Figure 2 Histopathology of large arterial lesions in TAK and GCA.

Figure 3 Histopathology of medium-sized arterial lesions in GCA.

Table 1. Characteristics of TAK and GCA.

	TAK	GCA	References
Onset age	Usually ≤40	Usually ≥50	[9,18]
Associated HLA	HLA-B*52 (class I)	HLA-DRB1*04 (class II)	[10,19]
Geoepidemiology	Asia, South America	Europe, North America	[11,57]
Comorbidity	Ulcerative colitis	Polymyalgia rheumatica	[12,13,21]
Dominantly affected arteries	Mesenteric artery, carotid artery	Cranial arteries, axillary artery	[57–60]
Common ophthalmopathy	Ischemic retinopathy	Ischemic optic neuropathy	[15,23,28]
Main histopathological locus of aortic lesion	Outer layer of the media, adventitia	Middle or inner layer of the media	[27,28]
Form of aortic lesion	Aneurysm, stenosis	Aneurysm	[57,60]
Aortic dissection	Rare	Occasional	[26,30]
Regions of associated SNPs	IL12B, FCGR2A/FCGR3A, MLX, IL6, RSP9/LILRB3	REL, PTPN22, LRRC32 (below significant level)	[31–34]
Th1 and Th17 cytokines	Both Th1 and Th17 prominent	Relatively less enhanced (except high IL-23)	[45]
Response to TNF inhibitors	Yes (without RCT)	No	[37–42]
Response to abatacept	No	Yes	[35,36]

HLA: human leukocyte antigen; RCT: randomized controlled trial; SNP: single-nucleotide polymorphism; TNF: tumor necrosis factor.

Figure 4 (a) IL-12 and IL-23 share p40, which is encoded by IL12B, a candidate susceptibility gene in two genome-wide association studies of TAK [31,32]. (b) Roles of Th1 and Th17 in TAK and GCA. IL-6 and Th17 form a vicious cycle.

Table 2. Trials and case series using TCZ for TAK and GCA.

Disease	Author, year	Design	Case No.	Dosage	Route	Main outcomes	p-Value
TAK	Nakaoka et al., 2013 [47]	Single arm	4	8 mg/kg/4 wks.	div.	Regression of inflamed arteries, reduction of GC dose	–
TAK	Mekinian et al., 2018 [48]	Retrospective	46	8 mg/kg/mo.	div.	Higher relapse-free survival rate than in the DMARD group	.02
TAK	Nakaoka et al., 2018 [8]	RCT	36	162 mg/wk.	s.c.	Higher relapse-free survival rate than in the placebo group	.0596
GCA	Seitz et al., 2011 [49]	Single arm	7	8 mg/kg/2–4 wks.	div.	Improvement of symptoms, reduction of GC dose	–
GCA	Loricera et al., 2015 [50]	Single arm	22	8 mg/kg/mo.	div.	Improvement of symptoms, reduction of GC dose	–
GCA	Villiger et al., 2016 [6]	RCT	30	8 mg/kg/4 wks.	div.	Higher relapse-free survival rate than in the placebo group	.0005
GCA	Stone et al., 2017 [7]	RCT	250	162 mg/wk.	s.c.	Higher relapse-free survival rate than in the placebo group	<.001

div.: intravenous drip; DMARD: disease-modifying antirheumatic drug; GC: glucocorticoid; RCT: randomized controlled trial; s.c.: subcutaneous.

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