Current perspectives on tocilizumab for the treatment of rheumatoid arthritis: a review

Figures & data

Figure 1 Interleukin-6 activates a number of key inflammatory pathways.

Abbreviations: CRP, C-reactive protein; RBC, red blood cells; RF, rheumatoid factor; VEGF, vascular endothelial growth factor.

Figure 2 Interleukin-6 signal transduction and blockage by tocilizumab.Reprinted from Biologics, volume 2, Okuda Y, Review of tocilizumab in the treatment of rheumatoid arthritis, pages 75–82, Copyright © 2008, with permission from Dove.²⁶

Abbreviations: gp130, glycoprotein 130; mIL-6R, membrane-bound interleukin-6 receptor; sIL-6R, soluble interleukin-6 receptor.

Table 1 Key trials of tocilizumab

Trial	Year	Patients	Study duration (weeks)	Design	Population	Disease duration (years)	Prior treatment	Treatment arms
SAMURAI^Citation45	2007	306	52	X-ray reader-blind, open-label, multicenter, randomized, placebo-controlled trial	Mod severe RA	2	Failed ≥ 1 DMARD	1. TCZ 8 mg/kg monthly
							No biologic failure	2. Conventional DMARD
SATORI^Citation42	2008	125	24	Randomized, double-blind, multicenter, controlled trial	Mod severe RA	9	Inadequate response to low dose MTX	1. TCZ 8 mg/kg monthly + placebo MTX
							No biologic failure	2. MTX + placebo TCZ monthly
OPTION^Citation43	2008	623	24	Randomized, double-blind, placebo-controlled, parallel-group trial	Mod severe RA	8	Failed ≥ 1 DMARD/MTX	1. TCZ 4 mg/kg monthly + MTX
								2. TCZ 8 mg/kg monthly + MTX
							No biologic failure	3. Placebo + MTX
RADIATE^Citation44	2008	499	24	Double-blind, placebo-controlled trial	Mod severe RA	13	No prior MTX failure	1. TCZ 4 mg/kg monthly + MTX
							Biologic failure	2. TCZ 8 mg/kg monthly + MTX
								3. Placebo monthly + MTX
TOWARD^Citation10	2008	1220	24	Randomized, double-blind, placebo-controlled, multicenter study	Mod severe RA	10	No prior biologic. Can have conventional DMARD or immunosuppressive	1. TCZ 8 mg/kg monthly
								2. Placebo (DMARD)
AMBITION^Citation41	2010	673	24	Randomized, double-blind, double-dummy, parallel study	Mod severe RA	6	No previous MTX or biologic failure	1. TCZ 8 mg/kg monthly
								2. Escalating MTX
LITHE^Citation46	2011	1196	104	Randomized, double-blind, controlled trial	RA < 5 years	9	Inadequate response to MTX No previous biologic failure	1. TCZ 4 mg/kg monthly + MTX
								2. TCZ 8 mg/kg monthly + MTX
								3. Placebo monthly + MTX

Abbreviations: DMARD, disease modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis; TCZ, tocilizumab.

Table 2 Clinical efficacy in Phase III trials

Trial	Treatment group	Patient numbers	ACR20		ACR50		ACR70		DAS28 remission (< 2.6)
			Responses	Significance	Responses	Significance	Responses	Significance	Responses	Significance
SAMURAI^Citation45	TCZ 8 mg/kg monthly	158	78%	P < 0.001	64%	P < 0.001	44%	P < 0.001	59%	P < 0.001
	Conventional DMARD	148	34%		13%		6%		3%
SATORI^Citation42	TCZ 8 mg/kg monthly + placebo MTX	61	80%	P < 0.001	49%	P < 0.001	30%	P < 0.001	44%	P < 0.001
	MTX + placebo TCZ monthly	64	25%		11%		6%		2%
OPTION^Citation43	TCZ 4 mg/kg monthly + MTX	213	48%	P < 0.0001	31%	P < 0.0001	12%	P < 0.0001	13%	P = 0.0002
	TCZ 8 mg/kg monthly + MTX	205	59%	P < 0.0001	44%	P < 0.0001	22%	P < 0.0001	27%	P < 0.0001
	Placebo + MTX	204	26%		11%		2%		1%
RADIATE^Citation44	TCZ 4 mg/kg monthly + MTX	161	30%	P < 0.001	17%	P < 0.001	5%	P = 0.1	8%	P = 0.053
	TCZ 8 mg/kg monthly + MTX	170	50%	P < 0.001	29%	P < 0.001	12%	P < 0.01	30%	P = 0.053
	Placebo monthly + MTX	158	10%		4%		1%		2%
TOWARD^Citation10	TCZ 8 mg/kg monthly	803	61%	P < 0.001	38%	P < 0.0001	21%	P < 0.0001	30%	P < 0.0001
	Placebo (DMARD)	415	25%		9%		3%		3%
AMBITION^Citation41	TCZ 8 mg/kg monthly	288	70%	P < 0.001	44%	P = 0.002	28%	P < 0.001	34%	Not stated
	Escalating MTX	284	53%		34%		15%		12%
LITHE^Citation46	TCZ 4 mg/kg monthly + MTX	399	51%	P < 0.0001	25%	Not stated	1 1%	P < 0.0001	30%	P < 0.05
	TCZ 8 mg/kg monthly + MTX	298	56%	P < 0.0001	32%	P < 0.0001	13%	P < 0.0001	47%	P < 0.0001
	Placebo monthly + MTX	393	27%		10%		2%		8%

Notes: P-values are all compared to controls. ACR20, ACR50, and ACR70 are defined by a 20%, 50%, or 70% clinical improvement from baseline after treatment, respectively.

Abbreviations: ACR, American College of Rheumatology; DAS28, Disease Activity Score of 28 joints; DMARD, disease modifying antirheumatic drug; MTX, methotrexate; TCZ, tocilizumab.

Table 3 Changes in fatigue, pain and disability in key trials

Trial	Outcome	Placebo/control	Tocilizumab 4 mg/kg	Tocilizumab 8 mg/kg
SAMURAI^Citation45	Modified HAQ	−0.13 (40%)	–	−0.50 (68%, P < 0.001)
SATORI^Citation42	Modified HAQ	−0.18 (34%)	–	−0.4 (67%, P < 0.01)
OPTION^Citation43	Modified HAQDI	−0.34	−0.52 (P < 0.005)	−0.55 (P = 0.0082)
	FACIT – fatigue	4.0	7.3 (P = 0.0063)	8.6 (P < 0.0001)
	SF36 mental	9.7	5.7 (P = 0.0394)	7.3 (P = 0.0012)
	SF36 physical	5.0	9.7 (P < 0.0001)	9.5 (P < 0.0001)
RADIATE^Citation44	HAQ	−0.05	−0.31 (P = 0.003)	−0.39 (P < 0.001)
TOWARD^Citation10	HAQ-DI	−0.2	–	−0.5 (P < 0.0001)
	FACIT	3.6		8.0 (P < 0.0001)
	SF36 mental	2.3		8.9
	SF36 physical	4.1		5.3
AMBITION^Citation41	HAQ-DI	−0.5	–	−0.7
LITHE^Citation46	HAQ-DI	52.7%	59.6% (P < 0.0001)	62.7% (P < 0.0001)

Note: P-values are all compared to controls.

Abbreviations: FACIT, functional assessment of chronic illness therapy; HAQ-DI, Health Assessment Questionnaire Disability Index; SF36, Short Form (36) Health Survey; HAQ, Health Assessment Questionnaire.

Table 4 Adverse events in Phase III trials

	SAMURAI^Citation45		SATORI^Citation42		OPTION^Citation43			RADIATE^Citation43			TOWARD^Citation10		AMBITION^Citation39		LITHE^Citation46,*
	TCZ 8 mg/kg	Placebo	TCZ 8 mg/kg	Placebo	TCZ 4 mg/kg	TCZ 8 mg/kg	Placebo	TCZ 4 mg/kg	TCZ 8 mg/kg	Placebo	TCZ 8 mg/kg	Placebo	TCZ 8 mg/kg	Placebo	TCZ 4 mg/kg	TCZ 8 mg/kg	Placebo
Any AEs	89%	82%	92%	72%	71%	69%	63%	87%	84%	81%	73%	61%	80%	78%	324	325	280
Serious AEs	18%	13%	7%	5%	6%	6%	6%	2%	5%	3%	8%	4%	4%	3%	13	12	10
AEs leading to death	0	0	0	0	0	0	0	0	0	0	0.3%	0.5%	1.0%	0.4%	–	–	–
AEs leading to withdrawal	0	0	0	0	–	–	–	6%	6%	5%	4%	2%	4%	5%	–	–	–
Serious infections	5%	4%	2%	2%	1%	3%	1%	2%	5%	3%	3%	2%	–	–	4	4	2
TB infection	0	0	0	0	–	–	–	–	–	–	0	0	0	0	–	–	–

Notes:SAMURAI, SATORI and OPTION were studies with tocilizumab monotherapy. RADIATE, TOWARD, AMBITION and LITHE were tocilizumab plus methotrexate.

* LITHE reported per 100 patient years.

Abbreviations: AEs, adverse events; TB, tuberculosis; TCZ, tocilizumab.

Figure 3 Radiological efficacy.

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