Download Supplementary File - Annals of the Rheumatic Diseases

1
Supplementary File
Methods. Tables S1 and S2 show details of the systematic literature research
presented in the main paper. Baseline characteristics of the core trials discussed in the
main paper are presented in table S3.
Description of additional studies
Apart from the strategic randomised controlled trials testing the efficacy of a treat to
target arm versus a control group, a number of studies also addressed the treat-totarget questions without using a randomised approach. In most of these trials, patients
were randomised to different treatment sequences / drugs, while the target was identical
for all arms. Although such trials cannot supply direct evidence of the value of treating to
a specific target, they still have potential to provide complementary evidence. In this
section, we will describe studies that were additionally retrieved by the search and also
considered and included in the consensus finding of the T2T project1. The scope of
studies comprises randomised controlled drug trials, as well as dose titration studies.
Randomised controlled drug trials without a routine comparator arm
(For treatment schedules and targets, see also Table S4)
A number of trials applied a targeted treatment approach, which was, however, used in
all treatment arms. Among those, the BeSt trial2, where DAS44-driven adjustment of
therapy at 3-monthly assessments was pursued comparing four different treatment
sequences. The targeted DAS44 threshold was a value of ≤2.4 reflecting low disease
activity (LDA). Applied treatment schedules encompassed traditional disease-modifying
antirheumatic drugs (DMARDs) in sequential monotherapy, step-up combination
therapy, initial DMARD combination therapy with intermediate dose glucocorticoids, and
initial combination therapy with infliximab. At the end of a one year follow-up period,
32% of all patients fulfilled the DAS44 criteria of remission (<1.6) 2. In the most recent
publication of five-year follow-up data3, overall remission rates were reported to be 48%,
while 19% of these patients were in drug-free remission.
Other trials employed a DAS28 LDA4-6, or DAS28 remission7 targeted strategy in
biologicals4;5 or in traditional DMARDs7;6: Soubrier et al.4;5 conducted a RCT comparing
methotrexate and adalimumab plus MTX, both arms aiming at LDA. Brenol et al.7
presented an open label study using a traditional DMARD step up algorithm targeting at
2
remission in 3- to 4-monthly follow up intervals. Saunders et al.6 targeted DAS28-LDA,
comparing an initial triple therapy to a step-up combination strategy of MTX,
sulfasalazine (SSZ), and hydroxychloroquine (HCQ). Open label DMARD therapy,
driven by assessment of a set of major and minor response criteria, was published by
Proudman et al.8, resulting in remission rates of 54% after 3 years. A trial design
primarily based on ACR20 response 12 weeks after starting infliximab therapy, with an
additional stratification of non-responders according to CRP-levels, was presented by
Buch et al.9. Interestingly, failure to suppress CRP at week 2 proved to already have a
negative predictive value of 86% for an ACR20 response to infliximab at week 12.
ACR20 nonresponse at week 12 stipulated a switch to etanercept only in case of
insufficient CRP reduction, whereas maintained CRP reduction led to continuation of
infliximab.
Ferraccioli10 compared 2 DMARD step up combination schedules, aiming at ACR50
response after 6 and 12 months (options comprised MTX, Cyclosporin A and SSZ). At
the end of follow-up (after 3 yrs.), the outcome was ACR remission for at least two
months. Additionally, the authors studied the fulfilling of the Magnusson criteria11 (no
steroids plus four of the following six criteria: morning stiffness < 30min, no fatigue, no
joint pain, no joint tenderness or pain on motion, no soft tissue swelling in joints or
tendon sheaths, and ESR <30mm/h (females) or <20mm/h (males)) for at least 3
months). Of notice, the trial schedule included a third arm, that is described to be
targeted at ACR50 as well, using SSZ monotherapy; however, strategies for adaption of
therapy were not provided by the authors.
Verschueren12 treated patients with either DMARD step up or step down strategy.
Treatment was adjusted according to DAS28-CRP measurements every 4 months.
The FIN-RACo13 randomised patients to DMARD combination (MTX, SSZ, HCQ, and
prednisolone) or to a schedule of consecutive single DMARD therapy (initially SSZ) with
or without prednisolone. Treatment in all arms was targeted at remission (defined by the
ACR Pinals criteria14, excluding fatigue). The combination DMARD treatment arm was
expanded by adding infliximab, again targeting remission in the Neo-RACo15 schedule.
RA treatment in daily clinical practice was investigated by Kuper et al.16 who reported
outcomes of a prospective RA cohort, treated and followed up in 3 outpatient clinics. A
tight step-up DMARD scheme, always aiming at DAS28-remission, was applied, starting
with dose-increase of MTX. At week 12, SSZ was added in case of failing the DAS28
3
threshold by then, again followed by dose titration. Finally, at week 20, adalimumab was
added if the set target was missed, followed also by other TNF-inhibitors if appropriate.
Dose titration studies
Also papers applying predefined thresholds for dose titration of traditional DMARDs or
biologics17-21 were assessed (as opposed to dose ranging trials comparing groups of
patients allocated to different doses). Many of these trials evaluated adaptations of
infliximab17-19. The relative majority of strategy trials investigating dosing and frequency
escalation in infliximab as compared to other biologicals is congruent with current data
on overall dose escalation trials22. Also, for infliximab, higher serum trough
concentrations have been shown to correlate with better clinical response23;24.
Flendrie18 assessed EULAR response at week 14. Non responders had their infliximab
dose increased. Moderate responders were observed until week 22, without dose
increase. If disease activity was stable between week 14 and 22, this subgroup had
stepwise dose increases according to a DAS28 threshold of 3.2. Rahman et al.19
investigated the improvement on infliximab, and in case of lack of response, patients
were randomised to dose increase after 22 weeks.
Likewise, reducing intervals between adalimumab injections has been evaluated; in the
PREMIER trial20, adalimumab and MTX combination was compared to both substances
alone, targeting ACR20 improvement. If this response criterion was not achieved by
week 16, adalimumab (or placebo) was increased to a weekly administration. Lambert
et al.21 used a DAS28 oriented approach to escalate doses of intramuscular MTX.
DAS28 was assessed 4 and 6 weeks after switching to i.m. application, with a target
value of <3.2; those not achieving LDA were randomized to escalating doses, and the
escalation was repeated at 4-weekly assessments thereafter, if DAS was >2.5. The
authors concluded that switching to i.m. MTX resulted in minor improvement, but
increasing the dose up to 45 mg/weeks did not improve disease control.
Studies related to targeted therapy, but not included (examples)
We also encountered studies similar to the strategy trials enumerated above, that
offered an optional extension of the treatment schedule, if the response at the final
adjustment was not satisfying. Since treatment modification was not mandatory in the
protocols, we decided to exclude these papers25-27 from the review. Alike, we excluded
drug trials investigating dose titration below standard doses28-30 or drug applications off
standard use (f.e. i.v. adalimumab31).
4
Studies that investigated the best approach to avoid disease flares, where also
excluded, although tapering of drugs was in some cases similar to targeted procedure
of included trials. Finally, since they did not focus on Treatment to Target, we did not
include tapering studies in our final analyses12;32-37.
5
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6
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treatment for rheumatoid arthritis, with dose titration based on the Disease Activity Score: dose
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patients based on response patterns. Rheumatology (Oxford) 2007;46:146-9.
19 Rahman MU, Strusberg I, Geusens P, Berman A, Yocum D, Baker D, et al. Double-blinded
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20 Breedveld FC, Weisman MH, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, et al. The
PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with
adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with
early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis
Rheum 2006;54:26-37.
21 Lambert CM, Sandhu S, Lochhead A, Hurst NP, McRorie E, Dhillon V. Dose escalation of
parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional
doses of methotrexate: a randomized, controlled trial. Arthritis Rheum 2004;50:364-71.
22 Ariza-Ariza R, Navarro-Sarabia F, Hernandez-Cruz B, Rodriguez-Arboleya L, Navarro-Compan V,
Toyos J. Dose escalation of the anti-TNF-alpha agents in patients with rheumatoid arthritis. A
systematic review. Rheumatology 2007;46:529-32.
23 Wolbink G, Voskuyl A, Lems WF, de Groot E, Nurmohamed MT, Tak PP, et al. Relationship
between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical
response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:7047.
24 St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, et al. The
relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis:
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Rheumatism 2002;46:1451-9.
25 Weinblatt ME, Schiff MH, Ruderman EM, Clifton O, Bingham CO 3rd, Li J, et al. Efficacy and Safety
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26 Capell HA, Makhok R, Porter DR, Munro RA, McInnes IB, Hunter JA, et al. Combination therapy
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27 Porter DR, Capell HA, Hunter J. Combination therapy in rheumatoid arthritis--no benefit of addition
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28 Hamdy H, McKendry RJ, Mierins E, Liver JA. Low-dose methotrexate compared with azathioprine
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29 O'Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, et al. Treatment of early
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31 Rau R, Simianer S, Van Riel PL, Van de Putte LB, Kruger LB, Schattenkirchner M, et al. Rapid
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8
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41 Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL. The British Rheumatoid Outcome
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42 Edmonds J, Lassere M, Sharp JT, Bird P, Carlton K, the OSRA Study Group. OBJECTIVES
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ACTIVITY CONTROL IN RA. Ann Rheum Dis 2007;66:325.
43 van Tuyl LH, Lems WF, Voskuyl AE, Kerstens PJSM, Garnero P, Dijkmans BAC, et al. Tight control
and intensified COBRA combination treatment in early rheumatoid arthritis: 90% remission in a pilot
trial. Ann Rheum Dis 2008;67:1574-7.
44 Stenger AA, van Leuuwen MA, Houtman PM, Bruyn GA, Speerstra F, Barendsen BC, et al. Early
effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression. Br J
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FIN-RACo trial group. Lancet 1999;353:1568-73.
9
Supplementary Tables
Table S1. Systematic literature search: inclusion and exclusion criteria.
Inclusion Criteria:
Disease: RA
Age: adult
Time period: 1950 to 2008
Category: Human
Language: English
Trial type: strategy trial
Outcomes: Clinical: SJC, DAS, DAS28, SDAI, CDAI, ACR/EULAR response
Functional: HAQ
Radiographic: Erosion Score, Total Sharp Score, Sharp van der Heijde Score
Exclusion Criteria:
No drug intervention (surgery, physical
therapy, ergo-/physiother., exercise,
plasmapheresis, stem cell
transplantation, irradiation)
Review articles
Table S2. Search strings.
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
*Arthritis, Rheumatoid/
*Rheumatoid Arthritis/dt, dm, co, th, dr [Drug Therapy, Disease Management, Complication, Therapy, Drug Resistance]
($tnf$ OR biologic$ OR rituximab OR mabthera OR abatacept OR orencia OR tocilizumab OR actemra OR anakinra OR kineret OR infliximab OR
remicade OR adalimumab OR humira OR etanercept OR enbrel OR cimzia OR certolizumab OR golimumab OR IDEC-C2B8 OR CTLA4Ig OR rmetHuIL-1ra OR cA2 OR D2E7 OR TNRF:Fc OR CDP870 OR CNTO 148 ).ti [Title]
*Biological Therapy/
*"Biologic Factors and Agents Acting on the Immune System"/cm, cb, dt, pr, ct, do [Drug Comparison, Drug Combination, Drug Therapy,
Pharmaceutics, Clinical Trial, Drug Dose]
(leflunomide OR arava OR HWA 486 ).ti
*Methotrexate/ OR *Sulfasalazine/ OR *Hydroxychloroquine/ OR MTX OR methotrexate OR ebetrexat OR SPZ OR sulfasala$ OR sulphasala$ OR
salazopyr$ OR HCQ OR hydroxychloro$ OR resochin$ OR DMARD$ OR (disease and modif$ and antirheumatic$).ti
*Remission Induction/ OR (strateg$.ti OR aim$.ti OR goal$.ti OR target$.ti OR tight$.ti OR aggressiv$.ti OR intens$.ti OR control$.ti) OR
((strateg$.mp OR aim$.mp OR goal$.mp OR target$.mp OR tight$.mp OR aggressiv$ OR control$.mp) adj2 (treat$.mp OR therap$.mp)) OR
optim$.ti OR adapt$.mp OR switch$.ti OR add$.ti OR chang$.ti OR expand$.ti OR step$.ti OR combin$.ti OR intensif$.ti OR escalat$.ti OR
titrat$.mp OR adjust$.mp OR response-based.mp OR control$.ti AND *Disease Progression/ OR *Disease Management/ OR *Disease Outbreaks/
OR Disease/ OR ((strateg$ OR proced$ OR consequ$ OR therap$ OR halt$ OR stop$ OR revers$ OR dela$ OR arrest$ OR detain$ OR slow$ OR
preven$ OR retard$ OR avoid$) adj3 (structural OR functional OR erosi$ OR progre$ OR disabilit$ OR invalidity OR impediment OR disablement
OR radiograph$ OR radiolog$)).mp. OR (remission OR ((low$ OR moderate OR medium OR high) AND activity)) adj3 (strateg$ OR optimi$ OR
adapt$ OR control$ OR frequency OR dose$ OR dosing)
randomized controlled trial.pt. OR clinical trial.pt. OR Double-Blind Method/ OR "double blind:".mp. OR Placebos/ OR placebo:.mp. OR
random:.mp. OR single-blind method/ OR exp Clinical Trials/ OR clinical trial$.mp. OR ((singl$ or doubl$ or trebl$) adj2 (blind$ or mask$)).mp. OR
placebo$.mp. OR exp Research Design/ OR comparative study.pt. OR exp Evaluation Studies/ OR follow-up studies/ or prospective studies/ OR
(control$ or prospectiv$ or volunteer$).mp. OR controlled clinical trial.pt. OR clinical trial, phase i.pt. OR clinical trial, phase ii.pt. OR clinical trial,
phase iii.pt. OR clinical trial, phase iv.pt. OR (clinical: adj2 trial:).mp. OR meta-analysis.pt. OR meta-analy:.mp. OR meta analy:.mp. OR
metaanaly:.mp. OR metanaly:.mp.
Strings in italic apply to Embase search only
Table S3. Baseline characteristics of the core trials (main paper; targeted groups).
Author
SJC applied
HAQ
DAS
APR
CRP [mg/L]
ESR [mm/h]
Grigor38
SJC44
12±4§
2.0±0.8§
DAS
4.9±0.9§
CRP 44±53§
ESR 45±31§
Verstappen39
SJC38
14±6§
1.2±0.7§
Fransen40
n.r.
n.r.
DAS28
4.6±1.2§
ESR 20 (10-32)$
Symmons41
3 (1,5.5)$$
1.25
(0.88,1.88)$$
n.r.
CRP 8 (3,19)$$
ESR 21
(10,32)$$
Edmonds42
3 groups:
12±5§ 11.6±5§
11.84±5§
n.r.
Van Tuyl43
SJC28
10±6§
0.93±0.74§
Stenger44
14 (2-36)$
n.r.
ESR 36±27§
DAS28
5.1±1.2
4.9±1.3
5.07±1.5
DAS28
5.37±0.98§
CRP
12±11§
20.7±28§
17.7±25§
n.r.
CRP 53 (8-186)$
§ mean±SD, $ median (range), $$ medium (IQR)
ESR 36±29§
Radiogr.
Status:
Score
employed
Follow-up
TSS 28±23§
18 mo
Radiographic
damage score:
1.6±4.2§
Joint damage
65%
Larsen 67
(39,97)$$
Eroded joint
count 11 (5,19)$$
n.r.
TSS 6.8±11.8§
Erosions: 56%
Radiogr. score:
4(0-28)$
Dis. duration
defined per
incl.-criteria*;
and at
baseline**
<5 yrs*
19±16 mo§**
1 yr / 2yrs
<1yr*
24 we
6 (3-14) yrs$$**
3 yrs
>5 yrs*
12.5±6.8 yrs§**
2 yrs
7.2±6.6 yrs§**
40 we
2±2 mo§**
2 yrs
6.5±3.2 yrs§**
10
Table S4. Treat and target of traditional RCT drug trials and dose titration trials; clinical, functional and radiographic outcomes
Trial
(1)
Treatment decision driving target: DAS44<2.4 LDA every 3 months
508
CLINICAL: outcomes at 1 yr$ and 2 yrs$$
32% of all patients in DAS44 remission$
5 yr. follow-up, remission rates 48% (19% of these patients in drug-free remission)$$
FUNCTIONAL: mean HAQ 0.7 and 0.5; p=0.009$
RADIOGRAPHIC: median increases in Sharp vdHeijde score 2.0, 2.5, 1.0, 0.5; p<0.001$
65
CLINICAL: LDA at 12 weeks: 25% (step-up) and 64% (initial combination; p=0.001)
65% and 64%, at week 52 (p=0.98).
FUNCTIONAL: mean decrease in HAQ after 52 weeks: -0.93 (95% CI -0.69; -1.17) and -1.02 (-0.81; -1.24); p=n.s. between groups
RADIOGRAPHIC: mean increase in mTSS after 1 yr: 1.8±4.7 and 1.9±4; p=n.s. between groups
14 months
241
CLINICAL:
DAS28-remission: 12.6 vs. 20.4%; p<0.001
DAS28-LDA 7.9 vs. 13.1%; p<0.001
FUNCTIONAL: n.r.
RADIOGRAPHIC: n.r.
48 weeks
968
CLINICAL: EULAR response: 20% plac+SSZ and 30% LEF+SSZ (p=0.081); ACR50 8.9% LEF+SSZ and 0% in plac+SSZ group; p=0.038
FUNCTIONAL: change in HAQ -0.09±0.32 LEF+SSZ and -0.02±0.36 plac+SSZ
RADIOGRAPHIC: n.r.
96
CLINICAL: mean decrease in DAS28 (primary outcome): -4.0 (step-up) vs. -3.3 (triple); p=0.163; DAS28 remission 45% vs. 33%; p=n.s.; ACR20
77% vs. 76%, ACR50 60% vs. 51%, ACR70 30% vs. 20%; p=n.s.
FUNCTIONAL: HAQ score changes:-0.9±0.7 (step up) and -0.8±0.7 (triple)
RADIOGRAPHIC: TSS changes: 6.0±5.3 (step up) and 6.6±7.0 (triple)
1yr2
5yrs (AB)3
Soubrier 2008 Guepard4;5
Treat: add / intensify ADA
Treatment decision driving target: DAS28ESR<3.2 LDA every 3 months
(3)
1 yr.
Brenol 20087 (abstract)
Treat: DMARD step up (MTX, SSZ)
Treatment decision driving target: DAS28 and CDAI remission / LDA (2.6
and 2.8 / 3.2 and 10) at 3 to 4 months assessments
(4)
Dougados 2005 RELIEF45
Treat: LEF open-label, then randomisation: switch or add SSZ
Treatment decision driving target: DAS28 (EULAR) good or moderate
response at 24 weeks
(5)
Saunders 20086
Treat: intitial triple parallel DMARD, dose adjustment vs. step-up SSZ, MTX,
HCQ; TNFi
Treatment decision driving target: DAS28 <3.2 LDA; DAS28>5.1 HDA at
3 months assessment: (HDATNFi)
(6)
12 months
Proudman 20078
Treat: triple DMARD therapy (MTX, SSZ, HCQ); dose adjustments. (at 6
months add TNFi or CyA, at 9 months add AZA)
Treatment decision driving target: major criteria for non-response:
SJC>1, ESR or CRP elevated
minor criteria for non-response: TJC>1, MST>30min, pain>30, fatigue>30
2 major or 1 major and 2 minor criteria required
(7)
3 yrs.
61
CLINICAL: EULAR remission: 54%
FUNCTIONAL: significant HAQ decline, mean endpoint HAQ 0.3±0.4
RADIOGRAPHIC: erosions in 62%.; median (IQR) chance in mTSS/year: 1(0-3)§
Buch 20059
Treat: switching of biologicals (IFXETA)
Treatment decision driving target: ACR20 at 12 weeks  responders /
non-responders  CRP at weeks 2, 6, 12
(8)
Outcome$
N
Goekoop-Ruiterman 2005 BeSt2
Treat: sequential DMARD mono vs. step-up vs. initial combi incl. steroid vs.
initial combi incl. IFX
(2)
Follow
up
24 weeks
207
3 yrs.
126
Ferraccioli 200210
Treat: DMARD step up combination (MTX, CsA, SSZ vs. mono SSZ)
CLINICAL: ACR20 at week 24: after switching to ETA (succeeding primary non-response to IFX): 66% (succeeding ACR and CRP non-response)
vs. 71% (succeding ACR non-response and partial CRP non-response); vs. 59% (succeeding week 12-ACR-non-response, but CRP response, and
continued IFX)
FUNCTIONAL: significant reduction of HAQ– numbers not specified
RADIOGRAPHIC: n.r.
11
CLINICAL: ACR remission at 3 yrs: remission in the step-up groups 9%, vs. 7% in the control group
full Magnusson response criteria: 40% in step-up groups, vs. 21% in the SSZ mono group, (p=0.009),
FUNCTIONAL: n.r.
RADIOGRAPHIC: n.r.
Treatment decision driving target: ACR50 after 6 months (add MTX /
CsA) and after 12 months (add SSZ)
(9)
Verschueren 200812
Treat: tight step up vs. step down; (step down: modified COBRA: SSZ,
MTX, steroids, tapered; randomization at week 40 to SSZ or MTX, if DAS
„acceptably low“ vs. step up therapy)
2 yrs.
19+52
CLINICAL: DAS28 remission after 4 months: 63.2% step down vs. 36.4% (p=0.049), 2yrs: numbers not specified
FUNCTIONAL: HAQ=0 at 12 months: 61.1% (step down group) vs. 31.8% (p=0.033); 2yrs: numbers not specified
RADIOGRAPHIC: n.r.
Treatment decision driving target: aiming at DAS28CRP remission <2.6,
“or at least” DAS28CRP LDA <3.2 at 4-6 weeks, then every 4 months
(10) Möttönen 199946
Treat: randomised to DMARD combination (MTX, SSZ, HCQ and
prednisolone) vs. a schedule of consecutive single DMARD therapy (initially
SSZ) with or without prednisolone
195
CLINICAL: remission at 2yrs: 37% combi and 18% single; p=0·003
ACR50 after 1 year 75% combi vs. 60%) mono (p=0.028), after 2 yrs. (71% vs 58%, p=0.058)
FUNCTIONAL: mean (95%CI) change of HAQ in 2 years: -0.6 (-0.7 to -0.4) combination vs. -0.6 (-0.8 to -0.5) single
RADIOGRAPHIC: median (IQR) Larsen score increase at 2yrs: 2 (0–4) to 4 (0–14) combi; and 2 (0–8) to 12 (4–20) single; (increase was greater in
the single-treatment group (p=0·002).
2 yrs.
100
CLINICAL: 2yr-remission rate: 53% (95%CI 38-67) in FINRaCo+plac. vs. 70% (95%CI: 55-82) in FINRaCo+IFX (p=0.08)
Sustained remission: 31% (95%CI 18-45) in FINRaCo+plac vs. 40% (95%CI 26-55) FINRaCo+IFX; p=0.40
FUNCTIONAL: n.r.
RADIOGRAPHIC: 2yr-Median total SHS still 0 (baseline): 41% in plac. and 54% in IFX;
mean (95% CI) change of SHS from 0 to 24 months: 1.4 (0.8-2.2) in FINRaCo+plac. and -0.2 (-1.1-0.4) in FINRaCo+IFX; p=0.005
~2 yrs.
190
CLINICAL: median time to first remission: 25.0 (21.7-28.3) weeks. time to first LDA: 20.0 (16.2-23.8) weeks. remission: 15.5% at week 8, 22.2% at
week 12, 30.7% at week 20, 38.8% at week 24, 52.1% at week 36 and 51.0% at week 48-52
FUNCTIONAL: n.r.
RADIOGRAPHIC: n.r.
68
CLINICAL: EULAR good response: at 12th infusion: 22.9%, EULAR moderate response: 43.8%
Intensification of (MTX or IFX) treatment in non responders (79%) led to sign. decrease in mean DAS44: (5.27 to 4.54; p<0.002)
FUNCTIONAL: n.r.
RADIOGRAPHIC: n.r.
~37 weeks
76
CLINICAL: interval reduction after moderate response  mean DAS28 at endpoint: 3.6±0.8; sign decresase; p=0.005
dose incease after moderate response mean DAS28 at endpoint 3.6±1.0; sign decresase; p=0.04
dose adjustment after non-response: mean DAS28 at endpoint:: 5.0±1.3; modest or no improvement
FUNCTIONAL: n.r.
RADIOGRAPHIC: n.r.
1 yr.
329
CLINICAL: 77% primary non-responders responded to dose escalation; 83% of the secondary non-responders responded to dose escalation
FUNCTIONAL: n.r.
RADIOGRAPHIC: n.r.
2 yrs.
799
CLINICAL: outcomes at 1 year$ and 2 years$$
DAS28 remission: combination group: 43% vs. 23% ADA monotherapy and 21% MTX mono; both p<0.001$
2 yrs.
Treatment decision driving target: remission defined by ACR criteria
(Pinals14, excluding fatigue)
(11) Leirisalo-Repo 200815 (abstract)
Treat: FINRaCo combination treatment arm augmented with IFX
Treatment decision driving target: remission defined by ACR criteria
(Pinals14, excluding fatigue)
(12) Kuper 200816 (abstract)
Treat: tight step-up DMARD scheme, starting with dose-increasing of MTX,
SSZ add at week 12, ADA add at week 20
Treatment decision driving target: remission DAS28<2.6
(13) Sidiropoulos 200417
Treat: Dose titration IFX
Treatment decision driving target: DAS44<2.4
72-96
weeks
(14) Flendrie 200718
Treat: Dose titration IFX
Treatment decision driving target: EULAR response at week 14
(15) Rahman 200719
Treat: Dose titration IFX
Treatment decision driving target: 20% improvement of SJC, TJC
(16) Breedveld 200620
Treat: ADA tightening intervals
Treatment decision driving target: ACR20 after week 16
12
DAS28 remission: combination group: 49% vs. 25% in both mono arms; both p<0.001$$
ADA dose escalation in non-responders had minimal effect on ACR response or DAS28 remission
FUNCTIONAL: improvement in HAQ of ≥0.22 units: 72% combi vs. 58% ADA and 63% MTX.; p<0.05$$
RADIOGRAPHIC: Mean change in Sharp units (co-primary outcome): 1.9 combi vs. 5.5 ADA vs. 10.4 MTX; p=0.002 both$$
(17) Lambert 200421
Treat: escalate doses of intramuscular MTX
Treatment decision driving target: DAS28>3.2 after 4 and 6 weeks,
DAS28>2.5 every 4 weeks
22 weeks
64
CLINICAL: outcome at week 22
DAS28<3.2: (primary outcome):1 patient (3.7%) in each group
improvement of >1.2 in the DAS28: 18.5% in each group
ACR20: 1 patient (3.7%) in each group , none achieved EULAR good response
DAS28 percent change: -9 (MTX esc.) vs. -13 (controls)
FUNCTIONAL: HAQ percent change: -4 (MTX escalation) vs. 12 (controls; Plac. escalation)
RADIOGRAPHIC: n.r.
AB=abstract only; n.s.=not significant; n.r.=not reported; n.a.=not applicable; §mean(IQR); $outcome at end of follow-up if not otherwise specified; (m)TSS=(modified) total Sharp Score; SHS=Sharp
van der Heijde Score
13