Association between rapid and sustained remission and clinician-and patient-reported outcomes in patients with rheumatoid arthritis: post hoc analysis of data from the SELECT-COMPARE study
Running title: Value of rapid and sustained remission in rheumatoid arthritis

Laure Gossec, Jayesh Patel, Aditi Kadakia, Siran Fang, Yi Peng, Sander

Strengholt, Peter Taylor, Andrew Östör

► To cite this version:

Laure Gossec, Jayesh Patel, Aditi Kadakia, Siran Fang, Yi Peng, et al.. Association between rapid and sustained remission and clinician-and patient-reported outcomes in patients with rheumatoid arthritis: post hoc analysis of data from the SELECT-COMPARE study Running title: Value of rapid and sustained remission in rheumatoid arthritis. Arthritis Research & Therapy, 2025, 27 (1), pp.123. 10.1186/s13075-025-03580-1 . hal-05441179

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1 Association between rapid and sustained remission and clinician- and patient-reported

2 outcomes in patients with rheumatoid arthritis: post hoc analysis of data from the

3 SELECT-COMPARE study

4 Running title: Value of rapid and sustained remission in rheumatoid arthritis

5 Authors: Laure Gossec¹,², Jayesh Patel³, Aditi Kadakia³, Siran Fang³, Yi Peng³, Sander

6 Strengholt³, Peter C. Taylor⁴ and Andrew Östör⁵

7 Affiliations: ¹Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique,

8 Paris, France; ²AP-HP, Pitié Salpêtrière Hospital, Paris, France; ³AbbVie Inc, North Chicago, IL,

9 USA; ⁴Botnar Research Centre, University of Oxford, Oxford, UK, ⁵Monash University and

10 Emeritus Research Melbourne & ANU Canberra, Australia.

11 Corresponding Author: Aditi Kadakia

12 Dept GMH1, Blg ABV1-4SE-108-01

13 26525 North Riverwoods Blvd.

14 Mettawa, IL 60045

15 Phone: 781-759-3799

16 Email: aditi.kadakia@abbvie.com

17 Target Journal: *Arthritis Research and Therapy*

18 Figure/Table count: 2 tables, 3 figures (no limit)

19 Word Count: 2545 (no limit)

20

21 Abstract **350/350 WORDS**

22 **Background:** Rapid remission has been shown to be beneficial in patients with early
23 rheumatoid arthritis (RA). This study assessed the association of rapid and sustained remission
24 with long-term clinician- and patient-reported outcomes (CRO/PROs) in patients treated with
25 b/tsDMARDs.

26 **Methods:** This post hoc analysis used pooled data on patients with moderately-to-severely
27 active RA receiving upadacitinib or adalimumab from the SELECT-COMPARE trial
28 (NCT02629159) and its open-label long-term extension (up to 5 years). This study assessed the
29 effect of achieving rapid remission, time to remission, and time in sustained remission on
30 CRO/PROs. Rapid remission was defined as a Disease Activity Score 28 with C-reactive protein
31 (DAS28-CRP) <2.6 after 12 weeks' treatment. The outcomes of interest included a variety of
32 PROs, such as pain, fatigue, quality of life, and CROs (28 swollen/tender joint counts). Where
33 available, outcomes were assessed for up to 5 years; mean change in outcomes, as well as
34 adjusted odds ratios (aOR) of achieving minimal clinically important differences (MCIDs) or
35 normative values. Multivariate regression analyses were conducted adjusting for baseline
36 covariates.

37 **Results:** In total, 28% of patients (n/N=247/865; mean disease duration: 8.2±7.8 years)

38 achieved rapid remission. Rapid remission was associated with significantly greater

39 improvements from baseline in all outcomes at Week 26 and significantly greater odds of

40 achieving MCIDs (aOR range: 2.2–5.6) or normative values (aOR range: 1.6–9.8) in most
41 PROs, including pain, fatigue, and physical functioning, over the variable 5-year follow-up;
42 significantly lower swollen/tender joint counts were also observed. Time to achieve remission
43 was associated with better outcomes: for every month delay in achieving remission, likelihood of
44 achieving MCIDs or normative values decreased, on average, by 13%. Increasing time spent in
45 sustained remission was associated with long-term improvement in CRO/PROs.

46 **Conclusions:** Remission is a key outcome in RA; this study showed that achieving rapid
47 remission, as well as reducing time to achieving remission, was associated with less pain and
48 fatigue, and better physical functioning and quality of life over 5 years. Similarly, increasing time
49 spent in sustained remission correlated with sustained improvement in CRO/PROs. Striving for
50 rapid, sustained remission leads to long-term benefits.

51 **Keywords:** rheumatoid arthritis, upadacitinib, adalimumab, patient-reported outcomes,
52 remission

54 **Introduction**

55 Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory arthritis and is the most
56 common form of inflammatory polyarthritis, estimated to affect approximately 18 million people
57 worldwide [1]. RA has been shown to have a negative impact on daily activities and is
58 associated with high disease burden and impaired health-related quality of life (HRQoL) [2, 3].
59 Moreover, RA is associated with significant economic burden, especially among patients who do
60 not achieve disease control on treatment [4].

61 Treatment guidelines for RA recommend a treatment target of sustained remission or low
62 disease activity in every patient [5]. Achieving remission has been associated with significant
63 impacts on patient outcomes, including improved long-term clinical outcomes, better HRQoL,
64 and increased productivity [4] Altogether, these benefits are likely to translate to reduced
65 economic burden due to lower healthcare resource utilization, reduced healthcare costs, and
66 increased work and activity abilities [4].

67 Currently, there is evidence indicating that achieving rapid remission is associated with clinical
68 and functional benefits earlier in the disease course for RA patients using conventional synthetic
69 (cs) disease-modifying antirheumatic drugs (DMARD) [6, 7]. Methotrexate (MTX), as csDMARD,
70 is recommended as a first-line treatment, but rates of remission with MTX monotherapy are
71 relatively low (and even if achieved, often not sustained), especially for patients with a longer
72 disease duration [5]. However, there is some evidence that suggests that early, intensive
73 treatment with a combination of MTX and a biologic or targeted synthetic (b/ts)DMARD may
74 help patients achieve low disease activity or remission earlier [6].

75 The current study aims to further add to the evidence that rapid response to conventional [6, 7]
76 and targeted therapy [8, 9] in patients in the established phase of disease is an indicator of
77 better long-term outcomes, with respect to both disease activity measures and patient-reported
78 outcomes (PROs). Most importantly, this study sought to evaluate the impact of the time to
79 achieving remission, and the time spent in remission (herein referred to as sustained remission),
80 on long-term PROs and clinician-reported outcomes (CROs). This is important because it has
81 been shown that those patients who do not achieve rapid remission on advanced therapies are
82 unlikely to achieve sustained remission later [7]. The three main objectives of this analysis were
83 to: 1) to assess the association of achieving rapid remission with long-term CRO/PROs in
84 patients with RA receiving advanced therapies, 2) to evaluate the association of time to
85 achieving remission with CRO/PROs, and 3) to assess the association of time in sustained
86 remission with CRO/PROs.
87

## 88 Materials and methods

## 89 Study design and participants

90 Data from SELECT-COMPARE (NCT02629159), a phase 3 randomized clinical trial evaluating upadacitinib (UPA) versus adalimumab (ADA) or placebo in patients with moderately-to-severely active RA who were on stable background MTX (≥3 months with stable dosage), were used in this post hoc analysis [10, 11].

94 Patient eligibility criteria have been published elsewhere [10, 11]. Briefly, eligible patients were aged ≥18 years, diagnosed with RA for ≥3 months, and were receiving MTX for ≥3 months, with a stable dose for ≥4 weeks prior to the study start. Patients also had to have a swollen joint count (SJC) and tender joint count (TJC) ≥6 at screening and baseline and no prior exposure to a Janus kinase (JAK) inhibitor or ADA. Patients with prior exposure to a bDMARD could be included if they had ≤3 months' exposure and/or discontinued the bDMARD due to intolerance; patients with an inadequate response to a bDMARD were excluded.

101 Data from patients receiving UPA or ADA for up to 5 years were pooled for the analysis; patients receiving placebo were excluded. Patients included in this analysis were classified as having achieved rapid remission if they achieved a Disease Activity Score 28 with C-reactive protein (DAS28-CRP) <2.6 at Week 12.

## 105 Outcomes

106 This analysis assessed the association between: 1) achievement of rapid remission (DAS28-CRP <2.6 at Week 12); 2) time to achieving remission; and 3) time spent in sustained remission with the mean difference from baseline in a variety of PROs, the odds of achieving minimal clinically important differences (MCIDs) in PROs, and the odds of achieving normative values for CRO/PROs.

111 The PROs evaluated were: pain measured by 100 mm visual analog scale (VAS), physical function (measured using Health Assessment Questionnaire – Disability Index [HAQ-DI]), quality of life (measured using the Short Form-36 Physical and Mental Component Summary scores [SF-36 PCS and MCS, respectively]), fatigue (measured using Functional Assessment of Chronic Illnesses Therapy-Fatigue [FACIT-Fatigue]), and Patient's Global Assessment (PGA). CROs included the Physician's Global Assessment (PhGA), SJC28, and TJC28. MCIDs and normative values for each outcome are listed in **Supplementary Table 1**.

## 118 Statistical analysis of data

119 Baseline demographics are reported descriptively. Data are reported as mean change difference with standard deviation at Weeks 26, 48, 256, and 252. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) at Weeks 26, 28, 156, and 252 were reported for the association between achievement of rapid remission and CROs/PROs; for the association between time to achieving remission and time in sustained remission with CROs/PROs, aORs are reported at Week 48. Mean change differences and aORs were calculated using multivariable linear/logistic regression adjusting for age, sex, RA diagnosis duration group, baseline MTX dose group, baseline oral glucocorticoid dose group, baseline DAS28-CRP status, and baseline CRO/PRO score for each outcome evaluated.

128 For objective 1, outcomes for patients who achieved rapid remission versus those who did not were compared at Weeks 26, 48, 156, and 252.
For objective 2, among patients who achieved remission, time to achieving remission was calculated in months up to Week 48 and used as a continuous variable in the model (the conversion factor used was 1 month = 4.35 weeks). For this analysis, it was not required that patients had to remain in remission (i.e. they could relapse later) but were required to have at least one visit in remission from baseline to Week 48.

For objective 3, time in remission was calculated in months up to Week 48 by a midpoint calculation method. Briefly, at any visit when patients were in remission, the time in remission for that visit was calculated as half of the duration from the earlier visit, plus half of the duration until next visit. Total time in remission was the sum of all duration at the calculation of remission visit based on the midpoint method. The conversion factor used was 1 month = 4.35 weeks.

Nominal *p*-values are reported; a *p*-value <0.05 was considered statistically significant.

## 142 Results

### 143 Patient demographic and clinical characteristics

Of 885 patients, 28% (247/885) achieved rapid remission at Week 12 (Supplementary Table 2). In general, baseline demographic and clinical characteristics were similar between patients achieving versus not achieving rapid remission. However, patients not achieving rapid remission had numerically higher TJC28, SJC28, and pain scores at baseline. Briefly, patients achieving rapid remission had a mean age of 53.0 ± 12.4 years, with a mean 8.2 ± 7.8 years since RA diagnosis; most patients were female (74.1%) and were receiving concomitant oral glucocorticoids (60.3%).

### 151 Objective 1: the impact of achieving rapid remission on CRO/PROs

Patients who achieved remission at 12 weeks had significantly (*p*<0.001) greater mean change difference (95% CI) from baseline in all outcomes at Week 26 compared with patients who did not achieve rapid remission (Table 1). The highest numerical differences at Week 26 were for PGA (–19.7 [–23.1, –16.2]), pain VAS (–19.1 [–22.5, –15.7]), and PhGA (–13.4 [–16.1, –10.7]).

Patients achieving remission maintained significant mean change differences (*p*≤0.05) in most outcomes up to Week 252.

Achievement of rapid remission was associated with significantly higher likelihood of achieving MCIDs and/or normative values for the outcomes assessed (Fig. 1). Indeed, relative to those not achieving rapid remission, patients who achieved remission by Week 12 had significantly higher odds of achieving MCID in pain VAS (5.6 [3.2, 10.0]; *p*<0.001), PGA (4.8 [2.9, 8.2]; *p*<0.001), FACIT-Fatigue (2.2 [1.5, 3.2]; *p*<0.001), SF-36 PCS (2.6 [1.6, 4.3]; *p*<0.001), and HAQ-DI (3.3 [2.0, 5.3]; *p*<0.001) at Week 26 (Fig. 1A). Odds for achieving MCID remained significantly (*p*<0.05) higher for pain, PGA, and HAQ-DI for up to 252 weeks. Odds ratios for SF-36 MCS (1.2 [0.8, 1.7]) at Week 26 were numerically higher but did not reach statistical significance.

Similarly, odds for achieving normative values in outcomes at Week 26 were significantly (*p*<0.001) higher in those achieving versus not achieving rapid remission. Odds of achieving normative values in SJC28, TJC28, PGA, FACIT-Fatigue, SF-36 MCS, SF-36 PCS, and HAQ-DI were 6.1 (4.4, 8.7), 9.8 (6.8, 14.0), 5.9 (4.1, 8.4), 2.2 (1.5, 3.1), 2.0 (1.4, 2.8), 4.8 (3.3, 7.0), and 4.2 (2.9, 6.0), respectively (Fig. 1B); odds remained statistically significant (*p*<0.05) up to Week 252 for all outcomes (except FACIT-Fatigue and SF-36 PCS/MCS, which were not measured). Overall, among patients achieving rapid remission, the proportion of patients
achieving MCIDs or normative values in CRO/PROs was consistent for each outcome over time
(Supplementary Fig. 1).

176 **Objective 2: the impact of time to achieving remission on CRO/PROs**

177 The mean change difference in outcome was assessed based on the time to achieving
178 remission up to Week 48 (Table 2). For every month delay in achieving remission, there was a
179 statistically significant (*p*<0.001) increase (indicating worsening) in pain VAS (1.8 [1.2, 2.4]),
180 PGA (1.5 [0.9, 2.2]), PhGA (1.0 [0.6, 1.4]), and HAQ-DI (0.04 [0.03, 0.06]) scores at Week 48.
181 Likewise, there were significant decreases in FACIT-Fatigue (−0.3 [−0.6, −0.1]) and SF-36 PCS
182 (−0.6 [−0.9, −0.4]) scores, which also indicates worsening outcomes.

183 For every 1-month delay in achieving remission, odds of achieving MCIDs were reduced by
184 14% for pain VAS and SF-36 PCS, 12% for PGA, and 11% for FACIT-Fatigue and HAQ-DI (all
185 *p*<0.05; **Fig. 2A**). Similarly, odds of achieving normative values in PROs were also impacted by
186 the time to achieving remission (**Fig. 2B**). Likelihood of achieving normative values decreased
187 by up to 24% (for TJC28; *p*<0.001), with a mean reduction of 16% (for SJC28, PGA, SF-36
188 PCS, HAQ-DI; all *p*≤0.01) for every month delay in achieving remission.

189 **Objective 3: the impact of time in sustained remission on CRO/PROs**

190 For every additional month in remission up to Week 48, patients experienced significant
191 (*p*<0.001) improvements in all outcomes assessed (Table 2) and significantly (*p*≤0.05) greater
192 odds of reaching MCIDs for pain VAS (1.4 [1.3, 1.5]), PGA (1.5 [1.3, 1.6]), FACIT-Fatigue (1.3
193 [1.2, 1.3]), SF-36 MCS (1.1 [1.0, 1.1]), SF-36 PCS (1.4 [1.3, 1.5]), and HAQ-DI (1.3 [1.2, 1.4];
194 **Fig. 3A**). Odds of achieving normative values were 60% higher for each additional month in
195 remission for TJC28 (1.6 [1.5, 1.7]), 40% higher for SJC (1.4 [1.3, 1.4]) and PGA (1.4 [1.4, 1.5]),
196 and 30% higher for SF-36 PCS (1.3 [1.2, 1.4]) and HAQ-DI (1.3 [1.2, 1.4]; **Fig. 3B**). For all
197 outcomes, odds of achieving normative values were highly statistically significant (*p*<0.001).

198
199 **Discussion**
200 These data further confirm existing evidence of the impact of achieving rapid and sustained
201 remission on long-term CROs and PROs in patients with moderately-to-severely active RA and
202 illustrate the magnitude of achievable outcomes with b/tsDMARDs in patients with an
203 inadequate response to MTX treatment. Patients who achieved rapid remission had significantly
204 higher odds of achieving MCIDs and normative values in most PROs as early as Week 26; this
205 was maintained for up to 252 weeks. Similarly, these data demonstrated that, for every month
206 delay in achieving remission, the likelihood of achieving MCIDs or normative values in these
207 PROs was significantly reduced. In contrast, for every additional month a patient was in
208 sustained remission, odds were significantly higher.

209 This analysis is consistent with previous studies which have shown that achieving remission
210 earlier has a significant impact on clinical outcomes [8, 9]. Indeed, a study in patients with RA
211 receiving MTX with or without certolizumab pegol showed that patients who did not achieve
212 clinical remission after 12 weeks had significantly greater radiographic disease progression at
213 Week 52 than those who achieved remission earlier [8]. Studies have shown, however, that
214 achieving remission also has a significant impact on long-term patient-reported HRQoL and
215 work and activity ability [2-4]. A study among 356 consecutive patients with RA on a
216 heterogenous mix of treatment regimens showed that patients who achieved remission had SF-
217 36 PCS scores of 46.0 (≥50 is normative value) compared with a score of 29.8 among patients
218 with moderate-to-high disease activity [3]. Similarly, patients achieving remission reported <12%
impairment in work productivity or activity ability, versus 46% impairment reported by patients with moderate-to-high disease activity [3].

This analysis showed that time to remission had a significant impact on PROs, with those achieving remission earlier reporting better outcomes. This is consistent with an analysis of participants in the tREACH (treatment in the Rotterdam Early Arthritis CoHort) study, which demonstrated that patients who achieve remission in the first year reported better physical functioning and less pain and fatigue in the subsequent years compared with patients not achieving remission in the first year [12]. Moreover, a survey of patients with RA demonstrated that, for patients, the duration of remission, as well as the perception of returning to normal, is a key component of the concept of remission [13].

A Dutch longitudinal study of patients with RA showed that the likelihood of ever achieving sustained remission was significantly reduced with increasing time to remission, further highlighting the importance of rapid remission in long-term outcomes of patients with RA [7]. Moreover, a separate study of patients with RA receiving tumor necrosis factor inhibitors with or without MTX showed that the disease activity observed within the first 3 months of treatment was significantly related to disease activity at 1 year [9]. Compared with those who do not achieve remission, patients with RA achieving remission also had up to 52% lower direct medical costs and up to 75% lower indirect costs [4]. Thus, achieving remission also reduces the economic burden of disease.

This study used data from the phase 3 SELECT-COMPARE trial. Hence, the quality and completeness of the data are better compared to an observational study. The open-label extension phase of the study also provides data for up to 5 years, making it possible to examine the associations between the variables of interest over a long period of time. This is the first study to evaluate the association between rapid and sustained remission and CRO/PROs in patients with RA using advanced therapies. Due to the specific inclusion and exclusion criteria of the clinical trial program, the patients included in this study may not represent the overall population of patients with RA and therefore the results of this study may not be generalizable to all patients with RA. However, the intention of this analysis was to assess the impact of achieving rapid remission independent of active drug, thus allowing the results to be more generalizable to a larger population of patients with RA. This is a post hoc analysis of two groups of patients, thus the characteristics of patients achieving remission versus those not achieving remission may not be uniformly distributed. Despite controlling for patients' baseline remission status and the baseline score of the outcome being evaluated, confounders may still exist.

## Conclusions

This post hoc analysis demonstrated that patients with moderately-to-severely active RA who achieved rapid remission with UPA or ADA, compared with those who did not, had less subsequent pain and fatigue. Moreover, patients achieving rapid remission reported better physical function and quality of life for up to 5 years versus patients who did not reach rapid remission. Shorter time to achieving remission, as well as longer time spent in sustained remission, also correlated with sustained improvement in CRO/PROs. Overall, these data highlight the benefits of effective therapy and achieving rapid remission on long-term disease-related burden in patients with moderately-to-severely active RA.

## Declarations

## Competing Interests
264 LG has received grants or contracts from AbbVie, Biogen, Lilly, Novartis, and UCB; consulting
265 fees from AbbVie, BMS, Celltrion, Janssen, Novartis, Pfizer, and UCB; honoraria for lectures
266 from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, Stada, and UCB;
267 support for attending meetings and/or travel from Biogen, MSD, and Pfizer; medical writing
268 support from AbbVie, Amgen, Janssen, Pfizer, and UCB; and serves as the EULAR treasurer.

269 JP, AK, SF, and YP are employees of AbbVie and may own stock, stock options, or patents.

270 SS is a former employee of AbbVie and may own stock, stock options, or patents

271 PCT reports grants/contracts from Galapagos to University of Oxford; consulting fees from
272 AbbVie, Biogen, Fresenius, Takeda, Galapagos, Gilead, Janssen, Lilly, Nordic Pharma, Pfizer,
273 UCB, and Acelyrin Inc.; and participation on a Data Safety Monitoring Board/Advisory Board for
274 Immunovant, Sanofi, and Moonlake.

275 AÖ has been a consultant, served on Advisory boards, and has undertaken clinical trials for
276 AbbVie, Janssen, Lilly, Novartis, Pfizer, and GSK.

277 **Authors' contributions**

278 All authors substantially contributed to study conception and design, interpretation of data, and
279 drafting and revising of the manuscript for intellectual content. Y Peng and S Fang contributed
280 substantially to acquisition and analysis of data.

281 **Funding**

282 AbbVie funded the study. AbbVie participated in the study design, research, interpretation of the
283 data, review, and approval. All authors had access to the relevant data and participated in the
284 drafting, review, and approval of the abstract. No honoraria or payments were made for
285 authorship.

286 **Acknowledgements**

287 Medical writing services were provided by Samantha D. Francis Stuart, PhD, of Fishawack
288 Facilitate Ltd, part of Avalere Health, and funded by AbbVie.

289 **Ethics approval and consent to participate**

290 This study used data from the phase 3 trial SELECT-COMPARE, which was conducted as per
291 the International Conference on Harmonisation guidelines, the Declaration of Helsinki, and any
292 other applicable regulations. Study-related documents were approved by the US Central
293 Institutional Review Board (Quorum #31009) and other local institutional ethics committees and
294 review boards.

295 **Consent for publication**

296 All participants provided written consent for publication.

297 **Availability of data and materials**

298 The datasets analyzed for the current study are available from the corresponding author on
299 reasonable request.

300

301 **List of abbreviations**

302 (b/ts)DMARD, biologic or targeted synthetic DMARD
303 ADA, adalimumab
304 aOR, adjusted odds ratio
305 bDMARD, biologic DMARD
306 CI, confidence interval
307 CRO, clinician-reported outcome
308 CRP, C-reactive protein
309 DAS28, Disease Activity Score 28
310 DMARD, disease-modifying antirheumatic drug
311 FACIT-Fatigue, Functional Assessment of Chronic Illnesses Therapy-Fatigue
312 HAQ-DI, Health Assessment Questionnaire – Disability Index
313 HRQoL, health-related quality of life
314 JAK, Janus kinase
315 MCID, minimal clinically important difference
316 MCS, Mental Component Summary
317 MTX, methotrexate
318 NA, not applicable
319 NC, data not collected at this time point
320 PCS, Physical Component Summary
321 PGA, Patient's Global Assessment
322 PhGA, Physician's Global Assessment
323 PRO, patient-reported outcome
324 RA, rheumatoid arthritis
325 SD, standard deviation
326 SF-36, 36-item Short Form survey
327 SJC(28), swollen joint count (in 28 joints)
328 TJC(28), tender joint count (in 28 joints)
329 tREACH, treatment in the Rotterdam Early Arthritis CoHort
330 UPA, upadacitinib
331 VAS, visual analog scale
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375

376
<table><thead><tr><th>Mean change<br>difference<sup>a</sup><br>(95% CI)</th><th>Week 26</th><th>Week 48</th><th>Week 156</th><th>Week 252</th></tr></thead><tbody><tr><td>Pain VAS</td><td>-19.1<br>(-22.5, -15.7)***</td><td>-16.1<br>(-19.5, -12.6)***</td><td>-9.6<br>(-13.4, -5.8)***</td><td>-9.1<br>(-12.8, -5.4)***</td></tr><tr><td>HAQ-DI</td><td>-0.4<br>(-0.5, -0.3)***</td><td>-0.4<br>(-0.5, -0.3)***</td><td>-0.3<br>(-0.4, -0.2)***</td><td>-0.2<br>(-0.3, -0.1)***</td></tr><tr><td>SF-36 PCS</td><td>6.1<br>(5.0, 7.2)***</td><td>5.7<br>(4.4, 6.9)***</td><td>NC</td><td>NC</td></tr><tr><td>SF-36 MCS</td><td>2.7<br>(1.3, 4.0)***</td><td>1.6<br>(0.3, 2.9)</td><td>NC</td><td>NC</td></tr><tr><td>FACIT-Fatigue</td><td>4.3<br>(3.0, 5.6)***</td><td>4.2<br>(2.8, 5.6)***</td><td>NC</td><td>NC</td></tr><tr><td>TJC28</td><td>-3.2<br>(-3.8, -2.5)***</td><td>-2.5<br>(-3.1, -1.9)***</td><td>-1.4<br>(-2.0, -0.9)***</td><td>-0.6<br>(-1.0, -0.1)*</td></tr><tr><td>SJC28</td><td>-2.0<br>(-2.5, -1.5)***</td><td>-1.3<br>(-1.7, -0.9)***</td><td>-0.9<br>(-1.3, -0.5)***</td><td>-0.1<br>(-0.4, -0.2)</td></tr><tr><td>PGA</td><td>-19.7<br>(-23.1, -16.2)***</td><td>-17.1<br>(-20.7, -13.5)***</td><td>-11.9<br>(-15.8, -8.1)***</td><td>-9.5<br>(-13.2, -5.8)***</td></tr><tr><td>PhGA</td><td>-13.4<br>(-16.1, -10.7)***</td><td>-11.3<br>(-13.9, -8.7)***</td><td>-5.3<br>(-7.7, -2.9)***</td><td>-2.8<br>(-4.9, -0.7)**</td></tr></tbody></table>

ªMean change difference between patients who achieved versus did not achieve rapid remission and 95% CI were evaluated using multivariable linear regression adjusting for age, sex, RA diagnosis duration group, baseline MTX dose group, baseline oral glucocorticoid dose group, baseline DAS28-CRP status, and baseline value of each outcome evaluated.

CI, confidence interval; CRO, clinician-reported outcome; DAS28-CRP, Disease Activity Score 28 with C-reactive protein; FACIT-Fatigue, Functional Assessment of Chronic Illnesses Therapy-Fatigue; HAQ-DI, Health Assessment Questionnaire – Disability Index; MCS, Mental Component Summary; MTX, methotrexate; NC, data not collected at this time point; PCS, Physical Component Summary; PhGA, Physician's Global Assessment; PGA, Patient's Global Assessment; PRO, patient-reported outcome; RA, rheumatoid arthritis; SF-36, 36-item Short Form survey; SJC28, swollen joint count in 28 joints; TJC28, tender joint count in 28 joints; VAS, visual analog scale.

<footnote>*p≤0.05; **p≤0.01; ***p<0.001.</footnote>
<table><thead><tr><th rowspan="2">Mean change difference<sup>a</sup><br>(95% CI)</th><th>For every month delay in<br>achieving remission</th><th>For every additional month<br>spent in remission</th></tr><tr><th>Week 48</th><th>Week 48</th></tr></thead><tbody><tr><td>Pain VAS</td><td>1.8<br>(1.2, 2.4)***</td><td>-3.5<br>(-3.9, -3.1)***</td></tr><tr><td>HAQ-DI</td><td>0.04<br>(0.03, 0.06)***</td><td>-0.08<br>(-0.09, -0.07)***</td></tr><tr><td>SF-36 PCS</td><td>-0.6<br>(-0.9, -0.4)***</td><td>1.2<br>(1.0, 1.3)***</td></tr><tr><td>SF-36 MCS</td><td>0.03<br>(-0.2, 0.3)</td><td>0.4<br>(0.2, 0.5)***</td></tr><tr><td>FACIT-Fatigue</td><td>-0.3<br>(-0.6, -0.1)**</td><td>0.9<br>(0.7, 1.0)***</td></tr><tr><td>TJC28</td><td>0.2<br>(0.1, 0.2)***</td><td>-0.6<br>(-0.6, -0.5)***</td></tr><tr><td>SJC28</td><td>0.1<br>(0.0, 0.1)**</td><td>-0.3<br>(-0.4, -0.3)***</td></tr><tr><td>PGA</td><td>1.5<br>(0.9, 2.2)***</td><td>-3.6<br>(-4.0, -3.2)***</td></tr><tr><td>PhGA</td><td>1.0<br>(0.6, 1.4)***</td><td>-2.3<br>(-2.5, -2.0)***</td></tr></tbody></table>

<sup>a</sup>Mean change difference between patients for every month delay in achieving remission and every month spent in remission and 95% CI were evaluated using multivariable linear regression adjusting for age, sex, RA diagnosis duration group, baseline MTX dose group, baseline oral glucocorticoid dose group, baseline DAS28-CRP status, and baseline value of each outcome evaluated.

CI, confidence interval; CRO, clinician-reported outcome; DAS28-CRP, Disease Activity Score 28 with C-reactive protein; FACIT-Fatigue, Functional Assessment of Chronic Illnesses Therapy-Fatigue; HAQ-DI, Health Assessment Questionnaire – Disability Index; MCS, Mental Component Summary; MTX, methotrexate; NC, data not collected at this time point; PCS, Physical Component Summary; PGA, Patient's Global Assessment; PhGA, Physician's Global Assessment; PRO, patient-reported outcome; RA, rheumatoid arthritis; SF-36, 36-item Short Form survey; SJC28, swollen joint count in 28 joints; TJC28, tender joint count in 28 joints; VAS, visual analog scale.

<footnote>*p≤0.05; **p≤0.01; ***p<0.001.</footnote>

<footnote n="387">387 *p≤0.05; **p≤0.01; ***p<0.001.</footnote>
388 Models were adjusted for the following variables: age, sex, RA diagnosis duration group,
389 baseline MTX dose group, baseline oral glucocorticoid dose group, baseline DAS28-CRP
390 status, and baseline value of each outcome being evaluated.

391 aOR, adjusted odds ratio; CI, confidence interval; DAS28-CRP, Disease Activity Score 28 with
392 C-reactive protein; FACIT-Fatigue, Functional Assessment of Chronic Illnesses Therapy-
393 Fatigue; HAQ-DI, Health Assessment Questionnaire – Disability Index; MCID, minimal clinically
394 important difference; MCS, Mental Component Summary; MTX, methotrexate; PCS, Physical
395 Component Summary; PGA, Patient's Global Assessment; RA, rheumatoid arthritis; SF-36, 36-
396 item Short Form survey; SJC28, swollen joint count in 28 joints; TJC28, tender joint count in 28
397 joints; VAS, visual analog scale.

398
399 Fig. 2 Odds of achieving MCID or normative values for every month delay in achieving
400 remission

401 *p*≤0.05; **p*≤0.01; ***p*<0.001.

402 Models were adjusted for the following variables: age, sex, RA diagnosis duration group,
403 baseline MTX dose group, baseline oral glucocorticoid dose group, baseline DAS28-CRP
404 status, and baseline value of each outcome being evaluated.

405 aOR, adjusted odds ratio; CI, confidence interval; DAS28-CRP, Disease Activity Score 28 with
406 C-reactive protein; FACIT-Fatigue, Functional Assessment of Chronic Illnesses Therapy-
407 Fatigue; HAQ-DI, Health Assessment Questionnaire – Disability Index; MCID, minimal clinically
408 important difference; MCS, Mental Component Summary; MTX, methotrexate; PCS, Physical
409 Component Summary; PGA, Patient's Global Assessment; RA, rheumatoid arthritis; SF-36, 36-
410 item Short Form survey; SJC28, swollen joint count in 28 joints; TJC28, tender joint count in 28
411 joints; VAS, visual analog scale.

412
413 Fig. 3 Odds of achieving MCID or normative values for every month in sustained remission at
414 48 weeks

415 *p*≤0.05; **p*≤0.01; ***p*<0.001.

416 Models were adjusted for the following variables: age, sex, RA diagnosis duration group,
417 baseline MTX dose group, baseline oral glucocorticoid dose group, baseline DAS28-CRP
418 status, and baseline value of each outcome being evaluated.

419 aOR, adjusted odds ratio; CI, confidence interval; DAS28-CRP, Disease Activity Score 28 with
420 C-reactive protein; FACIT-Fatigue, Functional Assessment of Chronic Illnesses Therapy-
421 Fatigue; HAQ-DI, Health Assessment Questionnaire – Disability Index; MCID, minimal clinically
422 important difference; MCS, Mental Component Summary; MTX, methotrexate; PCS, Physical
423 Component Summary; PGA, Patient's Global Assessment; RA, rheumatoid arthritis; SF-36, 36-
424 item Short Form survey; SJC28, swollen joint count in 28 joints; TJC28, tender joint count in 28
425 joints; VAS, visual analog scale.

426