Biological therapies for the treatment of juvenile idiopathic arthritis: Lessons from the adult and pediatric experiences

Figures & data

Table 1 Biologics used in adult and pediatric arthritis. Adapted from Gartlehner and colleagues (2008)

Generic name	US trade name	Mechanism of action	Usual dosing	FDA-approved uses	Common JIA usage
Abatacept	Orencia^®	T-cell costimulation inhibitor	10 mg/kg (max 1000 mg) IV monthlya	RA, polyarticular JIA	None
Adalimumab	Humira^®	TNF inhibitor	24 mg/m^2 (max 40 mg) SC every other week	RA, PsA, AS, Crohn’s, JIA	Polyarticular course JIA, uveitis
Anakinra	Kineret^®	IL-1 receptor antagonist	1–2 mg/kg (max100 mg) SC daily	RA	SOJIA
Etanercept	Enbrel^®	TNF inhibitor	0.4 mg/m^2 (max 25 mg) SC twice weeklyb	RA, polyarticular JIA (age 2–17), PsA, AS, plaque psoriasis	Polyarticular course JIA
Infliximab	Remicade^®	TNF inhibitor	3–10 mg/kg IV monthlya	RA, Crohn’s, AS, PsA, plaque psoriasis, ulcerative colitis	Polyarticular course JIA, uveitis
Rituximab	Rituxan^®	B-cell depletion	1000 mg IV x two doses two weeks apart	B-cell non-Hodgkin’s lymphoma, RA refractory to TNF inhibitors	RF-positive polyarticular JIA (rarely used)
Tocilizumab	N/A	IL-6 receptor antibody	2–8 mg/kg every two weeks	None	SOJIAc

Abbreviations: AS, anklylosing spondylitis; IL, interleukin; IV, intravenous; JIA, juvenile idiopathic arthritis; N/A, not applicable; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RF, rheumatoid factor; SC, subcutaneous; SOJIA, systemic onset juvenile idiopathic arthritis; TNF, tumor necrosis factor.

Notes: ^aThe first doses are given on days 1, 15, and 29, followed by monthly;

^bCan be combined into a single weekly dose;

^cAvailable only on experimental basis in United States.

Figure 1 Mechanism of action of the TNF inhibitors. The binding of soluble TNF to its membrane-bound receptor induces cellular activation and inflammation (A) Soluble TNF receptor fused to human Ig (etanercept) serves as a decoy receptor, binding to soluble TNF and preventing the TNF from binding to its membrane-bound receptor (B) The anti-TNF monoclonal antibodies bind to membrane-bound TNF, inducing apoptosis of cells involved in the inflammatory pathway (C) Adapted from Rigby (2007).

Abbreviations: Ig, immunoglobulin; TNF, tumor necrosis factor.

Table 2 Summary of TNF inhibitor trials in inflammatory arthritis

Source	Disease	Study drug	Study duration (weeks)	n	Placebo		n	Study drug
					Serious infections	Hematological malignancies		Serious infections	Hematological malignancies
(Elliott et al 1994)	RA	INFL	4	24	0	0	49	1	0
(Rankin et al 1995)	RA	INFL	1–4a	12	0	0	24	0	0
(Moreland et al 1997)	RA	ETAN	12	44	0	0	136	0	0
(Maini et al 1998)	RA	INFL	26	14	0	0	87	2	0
(Moreland et al 1999)	RA	ETAN	24	80	1	0	134	0	0
(Weinblatt et al 1999)	RA	ETAN	24	30	0	0	59	1	0
(Kavanaugh et al 2000)	RA	INFL	12	7	1	0	21	≤2b	0
(Lipsky et al 2000)	RA	INFL	54	88	7	0	340	21	1
(ATTRACT)
(Lovell et al 2000)	JIA	ETAN	16	26	0	0	25	1	0
(Mease et al 2000)	PsA	ETAN	12	30	0	0	30	0	0
(Van Den Bosch et al 2002)	SpA	INFL	12	20	0	0	20	2	0
(Brandt et al 2003)	AS	ETAN	6a	17	0	0	16	0	0
(Davis et al 2003)	AS	ETAN	24	139	1	0	138	2	0
(Furst et al 2003) (STAR)	RA	ADAL	24	318	6	0	318	4	1d
(van de Putte et al 2003)	RA	ADAL	12	70	0	0	214	4	0
(Weinblatt et al 2003)	RA	ADAL	24	62	0	0	209	2	0
(ARMADA)
(Calin et al 2004)	AS	ETAN	12	39	0	0	45	0	0
(Keystone et al 2004a)	RA	ADAL	52	200	1	0	419	16c	1
(Keystone et al 2004b)	RA	ETAN	8a	53	0	0	367	5e	0
(Klareskog et al 2004)	RA	ETAN	24	228	10	0	456	20	0
(TEMPO)
(Lan et al 2004)	RA	ETAN	12	29	0	0	29	1	0
(St Clair et al 2004)	RA	INFL	54	282	6	0	722	40c	1
(Taylor et al 2004)	RA	INFL	54	12	No safety data		12	No safety data
(van de Putte et al 2004)	RA	ADAL	26	110	0	0	434	10	0
(Antoni et al 2005b)	PsA	INFL	16a	52	0	0	52	1	0
(IMPACT)
(Antoni et al 2005a)	PsA	INFL	24	100	NS	0	100	NS	0
(IMPACT II)
(Mease et al 2005) (ADEPT)	PsA	ADAL	24	162	1	0	151	1	0
(Marzo-Ortega et al 2005)	AS	INFL	30	14	0	0	28	0	0
(Quinn et al 2005)	RA	INFL	52	10	0	0	10	0	0
(van der Heijde et al 2005)	AS	INFL	24	78	0	0	201	2	0
(ASSERT)
(Abe et al 2006)	RA	INFL	14a	47	1	0	100	5	0
(Breedveld et al 2006)	RA	ADAL	104	257	7	1	542	12	1
(PREMIER)
(van der Heijde et al 2006)	AS	ADAL	24	107	1	0	208	0	0
(TEMPO)
(Westhovens et al 2006)	RA	INFL	22	363	6	0	721	24	0
(Genovese et al 2007)	PsA	ADAL	12	49	1	0	51	0	0
(Ruperto et al 2007)	JIA	INFL	52f	60	2	0	60	6	0

Abbreviations: ADAL, adalimumab; AS, ankylosing spondylitis; ETAN, etanercept; INFL, infliximab; JIA, juvenile idiopathic arthritis; NS, not specified; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SpA, spondyloarthritis.

Notes: ^aDuration of blinded, placebo-controlled phase of study;

^bUnclear which of any of these were considered serious infections;

^cStatistically significant (p < 0.05);

^dOnset of symptoms before trial;

^eEtanercept arm was treated for 16 weeks versus 8 weeks for placebo patients;

^fThe placebo-controlled duration of the trial lasted only 14 weeks, after which time all patients were treated with study drug for the duration of the 52-week study.

Figure 2 Mechanism of action of anakinra. IL-1 binds to its receptor, inducing cellular activation and inflammation (A) Exogenous IL-1 receptor antagonist (IL-1Ra; Anakinra) competes with IL-1 for binding to its receptor but does not induce cellular activation and inflammation (B).

Abbreviation: IL, interleukin.

Figure 3 Mechanism of action of abatacept. Under normal circumstances, CD80/86 on antigen-presenting cells (APC) binds to CD28 on T-cells, providing a second signal resulting in T-cell activation following peptide / MHC recognition by the T-cell receptor (A). CTLA4, another receptor on the surface of T-cells, binds to CD80/86 with increased affinity, transmitting negative signals to the T-cell (B). Soluble CTLA4-Ig (abatacept) binds to CD80/86, preventing it from binding to CD28 (C). Copright © 2007 Blackwell Publishing. Reproduced with permission from Todd DJ, Costenbader KH, Weinblatt MT. 2007. Abatacept in the treatment of rheumatoid arthritis. Int J Clin Prac, 61:494–500.

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