Supplementary File by mikesanye



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-to-
target 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

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
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

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).

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.



 2 Goekoop-Ruiterman YP, De Vries-Bouwstra JK, Allaart CF, Van Zeben D, Kerstens PJ. Clinical and
   radiographic outcomes of four different treatment strategies in patients with early rheumatoid
   arthritis (the BeSt Study): A randomized, controlled trial. Arthritis Rheum 2005;52:3381-90.

 3 Klarenbeek NB, Güler-Yüksel M, van der Kooij SM, Van der Heijde DMFM, Huizinga TWJ, Kerstens
   PJSM, Peeters AJ, Ronday HK, Westedt ML, Dijkmans BAC, and Allaart CF. CLINICAL
   67 (Supp II)(187). 2008. Ref Type: Abstract

 4 Soubrier M, Puechal X, Sibilia J, Mariette X, Meyer O, Combe B, Flipo R, Mulleman D, Berenbaum
   F, Zarnitsky C, Schaeverbeke T, Fardellone P, and Dougados M. EVALUATION OF TWO
   331. 2008. Ref Type: Abstract

 5 Soubrier M, Puechal X, Sibilia J, Mariette X, Meyer O, Combe B, et al. Evaluation of two strategies
   (initial methotrexate monotherapy vs its combination with adalimumab) in management of early
   active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford) 2009.

 6 Saunders SA, Capell HA, Stirling A, Vallance R, Kincaid W, McMahon AD et al. Triple therapy in
   early active rheumatoid arthritis: A randomized, single-blind, controlled trial comparing step-up and
   parallel treatment strategies. Arthritis Rheum 2008;58:1310-7.

 7 Brenol CV, Xavier RM, da Cunha V, Bortoli R, Chakr R, Massignan A, Arlindo E, Palominos P,
   RHEUMATIC DRUGS (DMARDS). Ann Rheum Dis 67 Suppl II, 163. 2008. Ref Type: Abstract

 8 Proudman SM, Keen HI, Stamp LK, Lee AT, Goldblatt F, Ayres OC, et al. Response-driven
   combination therapy with conventional disease-modifying antirheumatic drugs can achieve high
   response rates in early rheumatoid arthritis with minimal glucocorticoid and nonsteroidal anti-
   inflammatory drug use. Semin Arthritis Rheum 2007;37:99-111.

 9 Buch MH, Seto Y, Bingham SJ, Bejarano V, Bryer D, White J, et al. C-reactive protein as a
   predictor of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of
   nonresponse and subsequent response to etanercept. Arthritis Rheum 2005;52:42-8.

10 Ferraccioli GF, Gremese E, Tomietto P, Favret G, Damato R, Di Poi E. Analysis of improvements,
   full responses, remission and toxicity in rheumatoid patients treated with step-up combination
   therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years.
   Rheumatology 2002;41:892-8.

11 Magnusson S. Treatment of rheumatoid arthritis--does it affect society's cost for the disease? Br J
   Rheumatol 1996;35:791-5.

12 Verschueren P, Esselens G, Westhovens R. Daily practice effectiveness of a step-down treatment
   in comparison with a tight step-up for early rheumatoid arthritis. Rheumatology (Oxford)

13 Möttönen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al. Comparison
   of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial.
   FIN-RACo trial group. Lancet 1999;353:1568-73.

14 Pinals RS, Masi AT, Larsen RA, the Subcommittee for Criteria of Remission in Rheumatoid Arthritis
   of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee.
   Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis & Rheumatism

15 Leirisalo-Repo M, Kautiainen H, Laasonen L, Möttönen T, Hannonen P, Korpela M, Kauppi M,
   Kaipiainen-Sepänen O, Luosujärvi R, Blafield H, Ilva K, Julkunen H, Uutela T, and Moilanen E. A
   Rheum Dis 67(Supp II), 50. 2008. Ref Type: Abstract

16 Kuper I, Hoekstra M, ten Klooster P, Vermeer M, Haagsma C, Zijlstra T, and van de Laar M.
   AFTER 25 WEEKS IN DAILY CLINICAL PRACTICE. Ann Rheum Dis 67(Suppl II), 48. 2008. Ref
   Type: Abstract

17 Sidiropoulos PI, Bertsias G, Kritikos HD, Kouroumali H, Voudouris K, Boumpas DT. Infliximab
   treatment for rheumatoid arthritis, with dose titration based on the Disease Activity Score: dose
   adjustments are common but not always sufficient to assure sustained benefit. Ann Rheum Dis

18 Flendrie M, Creemers MC, Van Riel PL. Titration of infliximab treatment in rheumatoid arthritis
   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
   infliximab dose escalation in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66:1233-8.

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;64:704-

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:
   results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis &
   Rheumatism 2002;46:1451-9.

25 Weinblatt ME, Schiff MH, Ruderman EM, Clifton O, Bingham CO 3rd, Li J, et al. Efficacy and Safety
   of Etanercept 50 mg Twice a Week in Patients With Rheumatoid Arthritis Who Had a Suboptimal
   Response to Etanercept 50 mg Once a Week - Results of a Multicenter, Randomized, Double-
   Blind, Active Drug-Controlled Study. Arthritis & Rheumatism 2008;58:1921-30.

26 Capell HA, Makhok R, Porter DR, Munro RA, McInnes IB, Hunter JA, et al. Combination therapy
   with sulfasalazine and methotrexate is more effective than either drug alone in patients with
   rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind
   placebo-controlled MASCOT study. Ann Rheum Dis 2007;66:235-41.

27 Porter DR, Capell HA, Hunter J. Combination therapy in rheumatoid arthritis--no benefit of addition
   of hydroxychloroquine to patients with a suboptimal response to intramuscular gold therapy. J
   Rheumatol 1993;20:645-9.

28 Hamdy H, McKendry RJ, Mierins E, Liver JA. Low-dose methotrexate compared with azathioprine
   in the treatment of rheumatoid arthritis. A twenty-four-week controlled clinical trial. Arthritis &
   Rheumatism 1987;30:361-8.

29 O'Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, et al. Treatment of early
   seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone.
   Arthritis Rheum 2006;54:621-7.

30 Braun J, Kästner P, Flaxenberg P, Währisch J, Hanke P, Demary W, et al. Comparison of the
   clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients
   with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind,
   controlled, phase IV trial. Arthritis Rheum 2008;58:73-81.

31 Rau R, Simianer S, Van Riel PL, Van de Putte LB, Kruger LB, Schattenkirchner M, et al. Rapid
   alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous
   administration of adalimumab in combination with methotrexate. Scand J Rheumatol 2004;33:145-

32 Clegg DO, Dietz F, Duffy J, Willkens RF, Hurd E, Germain BF, et al. Safety and efficacy of
   hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with
   methotrexate and hydroxychloroquine. J Rheumatol 1997;24:1896-902.

33 Luis M, Pacheco-Tena C, Cazarin-Barrientos J, Lino-Perez L, Goycochea MV, Vazquez-Mellado J,
   et al. Comparison of two schedules for administering oral low-dose methotrexate (weekly versus
   every-other-week) in patients with rheumatoid arthritis in remission: a twenty-four week, single
   blind, randomized study. Arthritis & Rheumatism 1999;42:2160-5.

34 Den Broeder AA, Creemers MC, Van Gestel AM, Van Riel PL. Dose titration using the Disease
   Activity Score (DAS28) in rheumatoid arthritis patients treated with anti TNF-. Rheumatology

35 van den Bemt BJ, Den Broeder AA, Snijders GF, Hekster YA, Van Riel PL, Benraad B, et al.
   Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a
   prospective dose titration study. Ann Rheum Dis 2008;67:1697-701.

36 Yamanaka H, Tanaka Y, Sekiguchi N, Inoue E, Saito K, Kameda H, et al. Retrospective clinical
   study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis
   management group in Japan (RECONFIRM). Mod Rheumatol 2007;17:28-32.

37 Teng J, Tekstra J, Breedveld FC, Lafeber F, Bijlsma JWJ, and van Laar JM. RITUXIMAB FIXED
   ARTHRITIS. Ann Rheum Dis 67 Suppl II(339). 2008. Ref Type: Abstract

38 Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment
   strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised
   controlled trial. Lancet 2004;364:263-9.

39 Verstappen SM, Jacobs JW, van der Veen MJ, Heurkens AH, Schenk Y, ter Borg EJ, et al.
   Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer
   Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann
   Rheum Dis 2007;66:1443-9.

40 Fransen J, Bernelot Moens H, Speyer I, Van Riel PL. Effectiveness of systematic monitoring of
   rheumatoid arthritis disease activity in daily practice: a multicentre, cluster randomised control trial.
   Ann Rheum Dis 2005;64:1294-8.

41 Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL. The British Rheumatoid Outcome
   Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-
   effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis. Health
   Technol Assess 2005;9:1-78.

42 Edmonds J, Lassere M, Sharp JT, Bird P, Carlton K, the OSRA Study Group. OBJECTIVES
   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
   Rheumatol 1998;37:1157-63.

45 Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, Van Riel PL. When a DMARD fails, should
   patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide? Ann Rheum Dis

46 Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al. Comparison
   of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial.
   FIN-RACo trial group. Lancet 1999;353:1568-73.

Supplementary Tables
Table S1. Systematic literature search: inclusion and exclusion criteria.
 Inclusion Criteria:                                                                                 Exclusion Criteria:
 Disease: RA                                                                                         No drug intervention (surgery, physical
 Age: adult                                                                                                therapy, ergo-/physiother., exercise,
 Time period: 1950 to 2008                                                                                 plasmapheresis, stem cell
 Category: Human                                                                                           transplantation, irradiation)
 Language: English                                                                                   Review articles
 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

Table S2. Search strings.
 (1)           *Arthritis, Rheumatoid/
 (2)           *Rheumatoid Arthritis/dt, dm, co, th, dr [Drug Therapy, Disease Management, Complication, Therapy, Drug Resistance]
 (3)           ($tnf$ 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 r-
               metHuIL-1ra OR cA2 OR D2E7 OR TNRF:Fc OR CDP870 OR CNTO 148 ).ti [Title]
 (4)           *Biological Therapy/
 (5)           *"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]
 (6)           (leflunomide OR arava OR HWA 486 ).ti
 (7)           *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$).ti
 (8)           *Remission Induction/ OR (strateg$.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$.mp OR OR control$.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)
 (9)           randomized controlled OR clinical OR Double-Blind Method/ OR "double blind:".mp. OR Placebos/ OR OR
      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 OR exp Evaluation Studies/ OR follow-up studies/ or prospective studies/ OR
               (control$ or prospectiv$ or volunteer$).mp. OR controlled clinical OR clinical trial, phase OR clinical trial, phase OR clinical trial,
               phase OR clinical trial, phase OR (clinical: adj2 trial:).mp. OR OR OR meta OR
Strings in italic apply to Embase search only

Table S3. Baseline characteristics of the core trials (main paper; targeted groups).
                                                                                                                                                         Dis. duration
                                                                                      APR                                                                defined per
  Author           SJC applied           HAQ                    DAS                   CRP [mg/L]                                   Follow-up             incl.-criteria*;
                                                                                      ESR [mm/h]                                                         and at
                   SJC44                                        DAS                   CRP 44±53§                                                         <5 yrs*
  Grigor38                               2.0±0.8§                                                            TSS 28±23§            18 mo
                   12±4§                                        4.9±0.9§              ESR 45±31§                                                         19±16 mo§**
  Verstappen39                           1.2±0.7§                                     ESR 36±27§             damage score:         1 yr / 2yrs           <1yr*
                                                                DAS28                                        Joint damage
  Fransen40        n.r.                  n.r.                                         ESR 20 (10-32)$                              24 we                 6 (3-14) yrs$$**
                                                                4.6±1.2§                                     65%
                                                                                                             Larsen 67
                                                                                      CRP 8 (3,19)$$
                                         1.25                                                                (39,97)$$                                   >5 yrs*
  Symmons41        3 (1,5.5)$$                                  n.r.                  ESR 21                                       3 yrs
                                         (0.88,1.88)$$                                                       Eroded joint                                12.5±6.8 yrs§**
                                                                                                             count 11 (5,19)$$
                                                                DAS28                 CRP
                   3 groups:
                                                                5.1±1.2               12±11§
  Edmonds42        12±5§ 11.6±5§         n.r.                                                                n.r.                  2 yrs                 7.2±6.6 yrs§**
                                                                4.9±1.3               20.7±28§
                                                                5.07±1.5              17.7±25§
                   SJC28                                        DAS28                                        TSS 6.8±11.8§
  Van Tuyl43                             0.93±0.74§                                   ESR 36±29§                                   40 we                 2±2 mo§**
                   10±6§                                        5.37±0.98§                                   Erosions: 56%
                                                                                                             Radiogr. score:
  Stenger44        14 (2-36)$            n.r.                   n.r.                  CRP 53 (8-186)$                              2 yrs                 6.5±3.2 yrs§**
§ mean±SD, $ median (range), $$ medium (IQR)
  Table S4. Treat and target of traditional RCT drug trials and dose titration trials; clinical, functional and radiographic outcomes
                                                                               Follow                                                                            Outcome$
      Trial                                                                                 N
      (1)   Goekoop-Ruiterman 2005 BeSt2
Treat: sequential DMARD mono vs. step-up vs. initial combi incl. steroid vs.                      CLINICAL: outcomes at 1 yr$ and 2 yrs$$
initial combi incl. IFX                                                                           32% of all patients in DAS44 remission$
                                                                                            508   5 yr. follow-up, remission rates 48% (19% of these patients in drug-free remission)$$
                                                                               5yrs (AB)3
Treatment decision driving target: DAS44<2.4 LDA every 3 months                                   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$
      (2)   Soubrier 2008 Guepard4;5
Treat: add / intensify ADA                                                                        CLINICAL: LDA at 12 weeks: 25% (step-up) and 64% (initial combination; p=0.001)
                                                                                                  65% and 64%, at week 52 (p=0.98).
                                                                                 1 yr.      65
Treatment decision driving target: DAS28ESR<3.2 LDA every 3 months                                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
      (3)   Brenol 20087 (abstract)
Treat: DMARD step up (MTX, SSZ)                                                                   CLINICAL:
                                                                                                  DAS28-remission: 12.6 vs. 20.4%; p<0.001
Treatment decision driving target: DAS28 and CDAI remission / LDA (2.6         14 months    241   DAS28-LDA 7.9 vs. 13.1%; p<0.001
and 2.8 / 3.2 and 10) at 3 to 4 months assessments                                                FUNCTIONAL: n.r.
                                                                                                  RADIOGRAPHIC: n.r.
      (4)   Dougados 2005 RELIEF45
Treat: LEF open-label, then randomisation: switch or add SSZ                                      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
Treatment decision driving target: DAS28 (EULAR) good or moderate              48 weeks     968   FUNCTIONAL: change in HAQ -0.09±0.32 LEF+SSZ and -0.02±0.36 plac+SSZ
response at 24 weeks                                                                              RADIOGRAPHIC: n.r.
      (5)   Saunders 20086
Treat: intitial triple parallel DMARD, dose adjustment vs. step-up SSZ, MTX,                      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
HCQ; TNFi                                                                                         77% vs. 76%, ACR50 60% vs. 51%, ACR70 30% vs. 20%; p=n.s.
                                                                               12 months    96    FUNCTIONAL: HAQ score changes:-0.9±0.7 (step up) and -0.8±0.7 (triple)
Treatment decision driving target: DAS28 <3.2 LDA; DAS28>5.1 HDA at
3 months assessment: (HDATNFi)                                                                   RADIOGRAPHIC: TSS changes: 6.0±5.3 (step up) and 6.6±7.0 (triple)
      (6)   Proudman 20078
Treat: triple DMARD therapy (MTX, SSZ, HCQ); dose adjustments. (at 6                              CLINICAL: EULAR remission: 54%
months add TNFi or CyA, at 9 months add AZA)                                                      FUNCTIONAL: significant HAQ decline, mean endpoint HAQ 0.3±0.4
Treatment decision driving target: major criteria for non-response:                               RADIOGRAPHIC: erosions in 62%.; median (IQR) chance in mTSS/year: 1(0-3)§
                                                                                 3 yrs.     61
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)   Buch 20059
Treat: switching of biologicals (IFXETA)                                                         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
Treatment decision driving target: ACR20 at 12 weeks  responders /            24 weeks     207   continued IFX)
non-responders  CRP at weeks 2, 6, 12                                                            FUNCTIONAL: significant reduction of HAQ– numbers not specified
                                                                                                  RADIOGRAPHIC: n.r.
      (8)   Ferraccioli 200210
Treat: DMARD step up combination (MTX, CsA, SSZ vs. mono SSZ)                    3 yrs.     126
                                                                                                  CLINICAL: ACR remission at 3 yrs: remission in the step-up groups 9%, vs. 7% in the control group
Treatment decision driving target: ACR50 after 6 months (add MTX /                                full Magnusson response criteria: 40% in step-up groups, vs. 21% in the SSZ mono group, (p=0.009),
CsA) and after 12 months (add SSZ)                                                                FUNCTIONAL: n.r.
                                                                                                  RADIOGRAPHIC: n.r.
      (9)   Verschueren 200812
Treat: tight step up vs. step down; (step down: modified COBRA: SSZ,                              CLINICAL: DAS28 remission after 4 months: 63.2% step down vs. 36.4% (p=0.049), 2yrs: numbers not specified
MTX, steroids, tapered; randomization at week 40 to SSZ or MTX, if DAS                            FUNCTIONAL: HAQ=0 at 12 months: 61.1% (step down group) vs. 31.8% (p=0.033); 2yrs: numbers not specified
„acceptably low“ vs. step up therapy)                                           2 yrs.    19+52   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                                         CLINICAL: remission at 2yrs: 37% combi and 18% single; p=0·003
prednisolone) vs. a schedule of consecutive single DMARD therapy (initially                       ACR50 after 1 year 75% combi vs. 60%) mono (p=0.028), after 2 yrs. (71% vs 58%, p=0.058)
SSZ) with or without prednisolone                                               2 yrs.     195    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
Treatment decision driving target: remission defined by ACR criteria                              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
(Pinals14, excluding fatigue)                                                                     the single-treatment group (p=0·002).
      (11) Leirisalo-Repo 200815 (abstract)
Treat: FINRaCo combination treatment arm augmented with IFX                                       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
Treatment decision driving target: remission defined by ACR criteria            2 yrs.     100    FUNCTIONAL: n.r.
(Pinals14, excluding fatigue)                                                                     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
      (12) Kuper 200816 (abstract)
Treat: tight step-up DMARD scheme, starting with dose-increasing of MTX,                          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
SSZ add at week 12, ADA add at week 20                                                            week 12, 30.7% at week 20, 38.8% at week 24, 52.1% at week 36 and 51.0% at week 48-52
                                                                               ~2 yrs.     190
                                                                                                  FUNCTIONAL: n.r.
Treatment decision driving target: remission DAS28<2.6                                            RADIOGRAPHIC: n.r.
      (13) Sidiropoulos 200417
Treat: Dose titration IFX                                                                         CLINICAL: EULAR good response: at 12th infusion: 22.9%, EULAR moderate response: 43.8%
                                                                               72-96              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)
Treatment decision driving target: DAS44<2.4                                   weeks              FUNCTIONAL: n.r.
                                                                                                  RADIOGRAPHIC: n.r.
      (14) Flendrie 200718
Treat: Dose titration IFX                                                                         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
                                                                              ~37 weeks    76     dose adjustment after non-response: mean DAS28 at endpoint:: 5.0±1.3; modest or no improvement
Treatment decision driving target: EULAR response at week 14                                      FUNCTIONAL: n.r.
                                                                                                  RADIOGRAPHIC: n.r.
      (15) Rahman 200719
Treat: Dose titration IFX                                                                         CLINICAL: 77% primary non-responders responded to dose escalation; 83% of the secondary non-responders responded to dose escalation
                                                                                1 yr.      329    FUNCTIONAL: n.r.
Treatment decision driving target: 20% improvement of SJC, TJC                                    RADIOGRAPHIC: n.r.
      (16) Breedveld 200620
Treat: ADA tightening intervals                                                                   CLINICAL: outcomes at 1 year$ and 2 years$$
                                                                                2 yrs.     799    DAS28 remission: combination group: 43% vs. 23% ADA monotherapy and 21% MTX mono; both p<0.001$
Treatment decision driving target: ACR20 after week 16
                                                                                    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                                          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
Treatment decision driving target: DAS28>3.2 after 4 and 6 weeks,   22 weeks   64   ACR20: 1 patient (3.7%) in each group , none achieved EULAR good response
DAS28>2.5 every 4 weeks                                                             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

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