IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review

Figures & data

Figure 1 The pathogenic role of IL-6 in RA synovitis. There are the two main cellular components in the synovium. Type A synoviocytes are bone marrow derived macrophage-like cells. Type B synoviocytes are residential fibroblast like cells also known as FLS. In the rheumatoid synovium, FLS mainly contributes to arthritis by producing IL-6, RANKL, MMP3, GM-CSF, IFN-γ, and VEGF. TNF and IL-6 stimulate FLS autocrinally and induce tumor-like proliferation of FLS. Local arthritic symptoms are generated by the collaboration of IL-6 with TNF- and FLS-derived cytokines. Systemic symptoms are caused by IL-6. IL-6 also contributes to immune activation and leads to synovitis, resulting in a vicious circle.

Table 1. The efficacy of TCZ in clinical study.

Study	Population	Evaluation	Treatment arms	n	ACr20 (%)	Remission (%)	Ref
AMBITION	MTX naïve	24 W	TCZ-IV (8 mg/kg)	286	70	34	37
			MTX	284	53	12
SAMURAI	DMARDs-IR	52 W	TCZ-IV (8 mg/kg)	157	78	59	38
			DMARDs	145	34	3
SATORI	MTX-IR	24 W	TCZ-IV (8 mg/kg)	61	80	43	39
			MTX	64	25	2
TOWARD	DMARDs-IR	24 W	TCZ-IV (8 mg/kg) + DMARDs	803	61	30	40
			DMARDs	413	25	3
RADIATE	TNFi-IR	24 W	TCZ = IV (4 mg/kg) + MTX	161	30	8	41
			TCZ-IV (8 mg/kg) + MTX	170	50	30
			MTX	158	10	2
OPTION	MTX-IR	24 W	TCZ-IV (4 mg/kg) + MTX	186	48	13	42
			TCZ-IV (8 mg/kg) + MTX	191	59	27
			MTX	189	47	1
LITHE	MTX-IR	52 W	TCZ-IV (4 mg/kg) + MTX	394	47	30	43
			TCZ-IV (8 mg/kg) + MTX	398	56	47
			PBO	393	26	8
MUSASHI	All DMARDs-IR	24 W	TCZ-SC (152mg q2w)	159	79	50	44
			TCZ-IV (8 mg/kg)	156	89	62
SUMAACTA	All DMARDs-IR	24 W	TCZ-SC (162 mg qw) + DMARDs	572	69	37	45
			TCZ-IV (8 mg/kg) + MTX	564	74	38
BREVACTA	All DMARDs-IR	24 W	TCZ-SC (162 mg q2w) + DMARDs	437	61	32	46
			PBO + DMARDs
SHIOBI	TCZ-SC q2w-IR	12 W	TCZ-SC (162 mg qw)	21	52	19	47
			TCZ-SC (162 mg q2w)	20	20	10

TCZ: tocilizumab; TCZ-IV: intravenous TCZ; TCZ-SC: subcutaneous TCZ; qw: every week; q2w: every other week; q4w: every 4 week; IR: inadequate response; MTX: methotrexate; DMARDs: disease modifying anti rheumatic drugs; ACR20: American college of rheumatology.

Table 2. AEs of TCZ.

Rate/100 PY		Observation	Phase	Total AE	Serious AE	Serious infection	Refs.
TCZ-IV q4w combo	Pooled RCT	8,580 PY	III	278.2	14.4	4.7	65
TCZ-IV q4w mono	Pooled	2,188 PY	IV	465.1	–	6.2	66
TCZ-IV q4w mix	Japan (2008–2010)	3,831.8 PY	PMS	168.6	27.4	4.3	16
TCZ mix	Global (2008–2015)	22,394 PY	PMS	–	14.2	4.3	67
TCZ-IV q4w combo	ACT-SURE	767.7 PY	IIIb	593.0	7.8	5.1	68
TCZ-IV q4w combo	ACT-RAY (24 w)	118.32 PY	IV	491	21	6	48
TCZ-IV q4w mono	ACT-RAY (24 w)	116.4 PY	IV	467	14.4	4.7	48
TCZ-SC q2w mono	MUSASHI	561.71 PY	III	498.3	16.9	5.3	35
TCZ-SC q2w combo	BREBACTA	615.95 PY	III	332.8	11.2	3.3	69
TCZ-SC qw combo	SUMMACTA	298.82 PY	III	602.8	11.7	3.1	45
TCZ-SC combo	TOZURA	943.3 PY	IV	622.4	14.6	3.6	70
TCZ-SC q2w mix	Japan (2013–2016)	N = 1,003	PMS	94.4	13.9	4.5	71

TCZ: tocilizumab; TCZ-IV: intravenous TCZ; TCZ-SC: subcutaneous TCZ; AE: adverse events; combo, combination with DMARDs; RCT: randomized controlled trials; PY: patient years.

Figure 2 Differential inhibitory function of IL-6 signaling pathways by IL-6 and IL-6R antibody; a possible mechanism of action. Complexes of IL-6/IL-6R, IL-30/IL-6R, and IL-6/EBI3 can activate gp130, a cell surface signal transduction molecule. IL-6R antibody inhibit IL-6/IL-6R and IL-30/IL-6R but not IL-6/EBI3 dependent signal, whereas IL-6 antibody inhibits IL-6/IL-6R and IL-6/EBI3 but not IL-30/IL-6R dependent signal. IL-6: Interlukin-6; IL-6R: interleukin-6 receptor; IL-30: Interleukin-30; EBI3: Epstein-Barr virus-induced 3; WSX-1: interleukin-27 receptor α.