Table 2.

Summary of withdrawal data in juvenile idiopathic arthritis

Publication First Author, Year, Country	Study Design	N, Total	N, Wtd	CID Criteria	N, Centers	Years of Study	JIA Category	Med	Wtd Approach	Main Wtd Outcome	Flare Definition	Follow-up	Main Results	Uveitis	Recapture	Notes
MTX
Klotsche, 2018, Germany [39]	PCo/NCC	1514	316	cJADAS10 <=1	NR1	2005-NR (after 2011)	All	MTX	Abrupt stop (62%), taper (38%)	Risk of flare	cJADAS10 >1.5 for oJIA or ≥2.5 for pJIA, or restart DMARD for any subject	Mean 3.6yr	58% flared at mean 7.4mo; 46% flared within 12mo (78% of those who flared in follow-up); flare risk higher for CID <6mo (72%) than for CID >12mo (49%)	6/7 patients with documented eye exam had active uveitis at time of flare	NR	Prospective observational study; 63% of those with flares received MTX or biologic
Foell, 2010, multiple countries [31]	RCT	364	297	Wallace2	61	2005–2008	All	MTX	Abrupt stop 6mo or 12mo after trial entry	Flare within 2yr of study entry	Loss of CID	Mean 2.8yr	Equivalent risk of flare in each arm within 2yr of study entry (56–57%); equivalent risk of flare at 12mo after stopping (40%)	NR	NR	Those assigned to 12mo of MTX had higher risk of flares before stopping
Gottlieb, 1997, USA[86]	RCo/NCC	101	25	No active synovitis, normal labs	2	1986–1996	eoJIA, pJIA, sJIA	MTX	Taper by 2.5mg/mo (92%); abrupt stop (8%)	Time to flare	NR	Mean 1.1yr after stopping	52% flare after mean 11mo	NR	90% (9/10) with follow-up data reached CID on same dose of MTX after mean 7mo	Small, retrospective study; small N
Ravelli, 1995, Italy [40]	RCo	30	17	Morning stiffness ≤15 minutes, no fatigue, no active arthritis for ≥2 months, ESR<20	1	1986–1993	eoJIA, pJIA, sJIA	MTX	NR	Risk of flare	Recurrent arthritis	Range 3–52mo	59% flared: 30% within 3–9mo, 29% within 12–52mo	NR	90% (9/10) flare restarted MTX; only 1/6 with available follow-up regained remission within median 15 months.	Small, retrospective study; single center; wtd at median 3 mo after clinical remission; small N; low MTX dose
Biologic
Minden, 2019, Germany[87]	PCo	566	NR	PhGA and cJADAS10 remission off drugs	NR (multiple, per BiKER and JuMBO registries	2005–2016	All	Mostly ETN and ADA, few TCL, ANK	NR	PhGA and cJADAS10 remission off medications at 10 years ater JIA onset	NR	Mean observation 9.1yr	cJADAS10 remission off drugs at 10 yrs of disease duration significantly higher for early bDMARD starters (<2yrs)–15.7% vs 2–5 yrs (6%, OR 0.34), or >5yrs - 3.8% (OR 0.25).	NR	NR	Early start of bDMARDs (<2yrs) -also higher functional capability, lower requirements for joint and eye surgeries
Ter Haar, 2019, The Netherlands [49]	PCo	42	25	Modified Wallace2 (PhGA <1)	1	2008–2017	sJIA	ANK7 as first line monotherapy	After 3 mo CID, Tapered to alternate day for 1 mo	% in CID off medications at 1 yr	NR	Median 5.8yrs	At 1 yr- 52% off medications, at 5yrs-72%	NR	NR
Aquilani, 2018, Italy [42]	RCo/NCC	110	110	Wallace2	1	2005–2016	oJIA, pJIA	ETN	Abrupt stop (75%) or taper (25%), dose or frequency	Risk of flare	Recurrent arthritis or uveitis	1yr	60% flared within 12mo (median time to flare 4mo); 6/7 (86%) patients with CID >2yrs before wtd flared	11% of arthritis flares also with concurrent uveitis (2 of 7 without prior uveitis)	NR	Retrospective study; did not include patients who flared while tapering; patients on ETN for ≥18mo, in CID on ETN for ≥6mo
Lovell, 2018, USA [33]	PCo/NCC3	137	106	Modified Wallace2 (PhGA<0.5)	16	2009–2014	eoJIA, pJIA	TNFi	Abrupt stop	Risk of flare	≥30% worsening in ≥3/6 JIA ACR core criteria + ≤1 improving by >30%	Median 8mo	37% flared by 8mo	75% (3/4) with prior uveitis flared with uveitis	NR	Withdrawal intervention at 6mo after study entry; 19% did not maintain CID while on TNFi within 6mo of study entry
Ruperto, 2018, multiple countries, [36]	RCT/PCo	177	44	Wallace2 or JADAS71	63	2009–2014	sJIA	Canakinumab	Halved dose, then stopped	Risk of flare	Loss of CID	Median ∼3.5yr	31% (44/144) in long-term extension study reduced drug to half dose; 59% (26/44) did not flare in median 25mo; 19% (5/26) stopped drug for ongoing remission	NR	83% (15/18) who flared with taper regained control with full dose drug	Ongoing dedicated taper trial in responders ( NCT02296424)
Simonini, 2018, Italy[44]	RCo/NCC	349	135	Modified Wallace2,4	3	2000–2016	eoJIA, ERA, oJIA, pJIA, PsJIA, sJIA	Biologics: ETN, ADA, IFX; ANK, rituximab, abatacept	NR	Time to flare	Loss of ≥ 2 Wallace criteria (not including stiffness) or Tx intensification	Median 6mo (3–109mo)	75.6% flared; 31% had sustained remission 1yr after wtd; flares more common in those with CID <2yr (60%) than those with CID >2yr (12.5%)	NR	NR	Retrospective study; 68.1% were also on MTX
Su, 2017, Taiwan[45]	RCo/NCC	30	10	Wallace2	1	2003–2015	eoJIA, pJIA, sJIA	ETN	Taper	Risk of flare	Loss of Wallace criteria for >1 visit	mean 26.4mo	44% with CR off meds5, 17% with CR off meds for ≥2yrs	NR	NR	Small, retrospective study; analysis compared those in remission and those with flare, on or off treatment
Iglesias, 2014, Spain [88]	RCo/NCC	18	18	Wallace2	1	2000–2011	ERA, oJIA, pJIA, uJIA,	ETN, ADA, IFX, +67% also on MTX	Abrupt, 6mo after MTX wtd	Risk of flare	Occurrence of new joint pain, new limited ROM, or new inflammatory signs on exam	Mean 5.1yr (SD 2.1)	82% flared after wtd of all meds, mean time to flare 3mo	1 patient with uncontrolled JIA and uveitis	NR	Small, retrospective study; did not include patients who flared while tapering; mean time to start of TNFi 18.6mo; 2/3 stopped TNFi 6mo after MTX wtd
Cai, 2013 China [32]	PCo/NCC3	31	31	Wallace2	1	2008–2012	eoJIA, ERA, pJIA	ETN	Dose decrease by 50%: 0.4 mg/kg per wk x12mo, then 0.4 mg/kg per mo	Risk of flare	Recurrent arthritis, systemic symptoms, or disease progression on MRI	Mean 5.1yr (SD 2.1)	12.9% flared within 12mo, none during subsequent 12 mo; no disease progression on MRI in those who stayed in CR	NR	NR	Small, prospective observational study; single center; MRI performed at study entry, 1yr, or time of flare
Postepski, 2013, Poland [89]	RCo/NCC	39	39	Wallace	2	NR	ERA, oJIA, pJIA, PsJIA, sJIA	ETN	Abrupt	Duration of CID after ETN wtd	NR	Mean 25.4mo	38.5% flared at 6mo; 30.8% remained in long-term CR off meds for mean 25.4 ± 12mo; mean duration of remission after ETN wtd 14.2mo	NR	12/30 (40%) patients who started csDMARD for flare needed ETN, all of whom “responded satisfactorily”	Small, retrospective study; mean duration of remission on medication - 21.3mo (4–42mo)
Baszis, 2011, USA [90]	RCo/NCC	171	136	Wallace2	1	1998–2009	All	ETN, ADA, IFX	Abrupt; those on csDMARD-TNFi combo stopped TNFi first	CR after stopping TNFi	NR	Mean 3.8yr after TNFi started	33% with CR at 12mo; median CR duration 3.9mo; 40% of post-wtd flares while on MTX	Present in 16%, no other reported data	NR	Retrospective, single-center study; median duration TNFi Tx with CID 6mo (range 0–67.9mo)
Otten, 2011, Netherlands [37]	PCo/NCC	262	39	Modified Wallace2 (PhGA<1)	NR1,6	1999–2011	All	ETN	NR	NR	NR	Median after ETN wtd 13.4mo (IQR 5.3–27.4mo)	38% flared; compared to those with sustained CR off meds, those who flared had shorter prior ETN Tx (mean 29mo vs. 45mo)	NR	NR	Observational prospective study; performed within Dutch registry
Pratsidou-Gertsi, 2010, Greece [47]	RCo/NCC	36	11	Wallace2	1	2004–2008	oJIA, pJIA	ETN	Abrupt stop (82%), taper by interval in ≤3mo (18%)	Risk of flare	NR	Median 3mo (1–15mo)	100% flared (median time to flare 3mo); longer time to flare in those who also had stopped MTX prior to ETN	1 uveitis flare	Milder disease activity with flare, controlled with MTX/CSA in 10/11 and ADA+MTX in 1 (also had uveitis)	Small retrospective study; ETN withdrawn after ≥12mo of CID
Remesal, 2010, Spain [46]	RCo/NCC	26	24	Wallace2	1	2004–2009	ERA, pJIA, PsJIA, oJIA, sJIA	ETN	Abrupt (54%), Gradual (46%) by dose or frequency	Risk of flare and response to re-treatment	Active arthritis on physical exam	Mean 17+/−13mo	69% relapsed after mean 5.8mo (0.6–15.9); in all 12 patients with taper, flare happened after complete wtd.	NR	18 restarted ETN for flare and “responded satisfactorily”; 6/18 received IA or systemic GCs	Small retrospective study; ETN was weaned after 1–36mo (mean 14.7mo) in CID
Prince, 2009, Netherlands [43]	RCo/NCC	19	19	Modified Wallace2 (PhGA <1)	NR1	1999–2008	eoJIA, ERA, pJIA, sJIA	ETN	Abrupt (26%), taper (74%)	Risk of flare, time to flare	NR	Median 0.8yr (IQR 0.5–2.8yr)	47% flared; higher rates of flare in those with shorter time on ETN (2.1 vs. 3.5yr, p=0.21), shorter time in CID (0 vs. 1.5 yr, p<0.01), and who abruptly stopped ETN (80% vs. 36%, p=?)	NR	8/9 resumed ETN and “reacted promptly to treatment”	Small, retrospective study; did not include patients who flared while tapering; performed within Dutch registry
Combination treatment
Hissink Muller, 2018, Netherlands [34]	RCT/PCo	94	54	Modified Wallace2 (PhGA<1)	1	2009–2014	oJIA, pJIA, PsJIA	Arm 1: MTX or SSZ Arm 2: MTX + Pred Arm 3: MTX + ETN	Taper in 1–2mo	Time to flare	Recurrence of arthritis	Mean 2yr	Median time to flare 3mo (3.0–6.8mo); after 2y, CID off meds in 31–45% across arms	Excluded	26% (14/54) restarted treatment; 71% (10/14) regained CID within 3mo	Single-center treatment strategy RCT; taper for ≥3mo CID for oJIA and 6 mo for pJIA
Guzman, 2016, Canada [38]	PCo/NCC	1497	1146	Modified Wallace2 (0 enthesitis, PhGA<1)	16	2005–2012	All	MTX ± biologics (TNFi and ANK for sJIA)	NR	Risk of flare	Recurrent disease activity or PhGA≥1	Mean 2yr	32% flared within 12mo of Tx wtd; 25% required treatment escalation	NR	NR	Prospective, observational study within national inception cohort; few RF+ pJIA and eoJIA stopped treatment
Chang, 2015 USA [41]	RCo/NCC	455	335	Wallace2	1	2000–2011	ERA, pJIA	MTX and/or TNFi	MTX+ TNFi: abrupt stop (64%) or taper (36%) of first drug; NR for MTX or TNFi monotherapy	Risk of flare, time to flare	Loss of CID	Mean 3.8yr	63% flared within 12mo; among those on TNFi+MTX, those stopping TNFi first had higher risk of flare within 12mo (78%) than those stopping MTX first (19%) (higher risk of flare in those with ERA); among those on TNFi±MTX, 83% flared within 12mo of stopping all medicines; among those on MTX monotherapy, 50% flared within 12 months	NR	49% regained CID within 12mo	Retrospective, single-center study
Wallace, 2014, USA[35]	RCT/PCo	48	NR	Wallace2	12	2010–2012	pJIA	MTX ± ETN and Pred	NR	Duration of CID	Loss of CID	Mean 1.8yr	15% achieved CID without meds, 2 of 7 for ≥12mo	NR	NR	Performed with RCT extension study; subjects with highly active disease at trial entry; 65% of subjects with CID did not remain in CID (75% because of tapering)

ADA adalimumab, ANK anakinra, CID clinical inactive disease, cJADAS10 clinical juvenile arthritis disease activity score 10 joints, CR clinical remission, csDMARD conventional synthetic disease-modifying antirheumatic drug, Dx diagnosis, eoJIA extended oligoarticular JIA, ERA enthesitis-related arthritis, ESR erythrocyte sedimentation rate, ETN etanercept, GC glucocorticoid, IA intra-articular, IFX infliximab, IQR interquartile range, JIA juvenile idiopathic arthritis, JADAS71 juvenile arthritis disease activity score 71 joints, Med medication, mo month, MTX methotrexate, NCC nested case-control, NR not reported, oJIA oligoarticular JIA, PaGA patient/parent global assessment, PCo prospective cohort PhGA physician global assessment, pJIA polyarticular JIA, Pred Prednisone, PsJIA juvenile psoriatic arthritis, RCT randomized controlled trial, RCo retrospective cohort, sJIA systemic JIA, SSZ sulfasalazine, TNFi tumor necrosis factor inhibitor, TCL tocilizumab, Tx treatment, uJIA undifferentiated JIA, wk week, wtd withdrawal, yr year

¹Multiple participating centers within the country

²Wallace criteria: no joints with active arthritis; no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA; No active uveitis; best possible physician’s global assessment of disease activity score (or as modified); normal ESR and/or CRP; if elevated, not attributable to JIA; duration of morning stiffness ≤15 minutes [12]

³Protocolized, single-arm withdrawal interventional study

⁴Wallace criteria as defined above except including no enthesitis and not including stiffness criterion

⁵Clinical remission defined as CID on medication for ≥6 months or CID off medication for ≥12 months

⁶All Dutch patients with JIA who used ETN since 1999