# Remission versus low disease activity as treatment targets in rheumatoid arthritis: how to strike the right balance between too strict and too lenient targets? A meta-epidemiological study of individual patient data

Catia Duarte, Johannes Jacobs, Ricardo Ferreira, Paco Welsing, Laure Gossec, Pedro Machado, Désirée van der Heijde, Jose Antonio Pereira da Silva

► To cite this version:

Catia Duarte, Johannes Jacobs, Ricardo Ferreira, Paco Welsing, Laure Gossec, et al.. Remission versus low disease activity as treatment targets in rheumatoid arthritis: how to strike the right balance between too strict and too lenient targets? A meta-epidemiological study of individual patient data. RMD Open, 2024, 10 (4), pp.e004387. 10.1136/rmdopen-2024-004387. hal-05440942

HAL Id: hal-05440942

https://hal.science/hal-05440942v1

Submitted on 5 Jan 2026

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
# Remission versus low disease activity as treatment targets in rheumatoid arthritis: how to strike the right balance between too strict and too lenient targets? A meta-epidemiological study of individual patient data

**AUTHORS:** C. Duarte<sup>1,2</sup> J. W. G. Jacobs<sup>3</sup>, R. J. O. Ferreira<sup>4,5</sup>, P. Welsing<sup>3</sup>, L. Gossec<sup>6,7</sup>, P. M. Machado<sup>8</sup>, D. van der Heijde<sup>9</sup>, J. A. P. Da Silva<sup>1,2</sup>

**Corresponding Author**

José A. P da Silva, PhD
Rheumatology Department,
Centro Hospitalar e Universitário de Coimbra
Praceta Mota Pinto
3030-004 Coimbra, Portugal
Email:jdasilva@ci.uc.pt
tel: +351917568433

<footnote n="1"><sup>1</sup>Rheumatology Department, Centro Hospitalar Universitário de Coimbra, HUC, Coimbra, Portugal</footnote>

<footnote n="2"><sup>2</sup>Coimbra Institute for Clinical and Biomedical Research - Faculty of Medicine, University of Coimbra, Coimbra, Portugal</footnote>

<footnote n="3"><sup>3</sup>UMC Utrecht, Rheumatology & Clinical Immunology, Utrecht, the Netherlands</footnote>

<footnote n="4"><sup>4</sup>Nursing Research, Innovation and Development Centre of Lisbon (CIDNUR), Nursing School of Lisbon (ESEL), Portugal</footnote>

<footnote n="5"><sup>5</sup>Health Sciences Research Unit: Nursing (UICISA: E), Nursing School of Coimbra, Coimbra, Portugal;</footnote>

<footnote n="6"><sup>6</sup>INSERM, Institut Pierre Louis d'Epidemiologie et de Santé Publique, Sorbonne Université, Paris</footnote>

<footnote n="7"><sup>7</sup>Rheumatology Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, France</footnote>

<footnote n="8"><sup>8</sup>University College London, Centre for Rheumatology & Department of Neuromuscular Diseases, London, United Kingdom</footnote>

<footnote n="9"><sup>9</sup>LUMC, Rheumatology, Leiden, the Netherlands</footnote>
# ABSTRACT

**Objectives:** To evaluate the impact of using SDAI-LDA (low disease activity) versus different definitions of remission as a treatment target in established rheumatoid arthritis.

**Methods:** A meta-epidemiological study of Individual-patient data from 8 randomised controlled trials was performed. Four definitions of the target were considered at 6 months: i) SDAI-LDA: SDAI≤11; ii) SDAI-Remission: SDAI≤3.3; iii) 4V-Remission: Tender and swollen 28-joint counts and CRP (mg/dl) all≤1 and patient global assessment (PGA)≤2; iv) 3V-Remission: as 4V, excluding PGA. The mean radiographic change in the modified total Sharp-van der Heijde score (mTSS) and the Good Radiographic Outcome (GRO) rates (change≤0.5 units mTSS) over two years were compared among target definitions. Radiographic progression and the distribution of the individual criteria of the Boolean definition in the only-LDA subgroup (3.3<SDAI≤11) were analysed.

**Results:** In total, 4374 patients (mean disease duration of 5.9 years (95%CI:4.6;7.1)) were included. The pooled rate of SDAI-LDA at 6 months was 48.9%, with 12.9% in SDAI-remission. The 4V- and 3V-Remission were achieved by 16.2% and 23.1%, respectively. Mean radiographic progression was 0.55(0.14;0.96) units for SDAI-LDA and 0.22(-0.09;0.54), 0.28(-0.07;0.62), 0.28(-0.10;0.65) for SDAI-Remission, 4V- and 3V-Remission states, respectively. Patients with SDAI Pure-LDA presented significantly more radiographic progression than patients in SDAI-Remission (mean 0.74 vs 0.22 units, p<0.05). Over 53% of all patients achieving SDAI-LDA were not in 3V-Remission and had more mean radiographic progression over two years than those who met both targets (0.70 vs 0.25 units, p=0.014). Among patients with SDAI-LDA but not in SDAI-Remission, 40% scored PGA>2, reflecting relevant disease impact.

**Conclusion:** SDAI-LDA is associated with more structural damage over two years than any of the definitions of remission. It also allows substantial disease impact to go unchecked and uncontrolled. Physicians should strive for remission whenever possible and safe, while also taking into account the different individual disease activity parameters included in the adopted definition.

**Keywords:** Rheumatoid Arthritis, Remission, Low Disease Activity, Patient Global Assessment, Treatment-to-target, Dual-Target strategy, radiographic damage

# KEY MESSAGES

## What is already known about this subject?

* The T2T is the gold standard in the management of RA, aiming for the best possible long-term outcome regarding structural integrity and physical function.

* Treatment should be aimed at reaching a target of sustained remission or low disease activity in every patient

* The SDAI and the 2022 Boolean ACR/EULAR definition of remission are the recommended treatment targets

* Prior research has shown that the 3VBoolean (excluding the PGA) provides a numerically more accurate prediction of GRO than the other definitions

## What does this study add?
* The mean radiographic progression over 2 years in the SDAI-LDA was higher than observed in all the other definitions of targets, including the 3V-Remission

* Patients in the Pure-LDA subgroup showed significantly higher radiographic progression during the two years of follow-up year when compared with patients in remission

* Patients in the Pure-LDA subgroup present clinically relevant signs of inflammation with an emphasis on swollen joints and CRP >1, and a sizeable proportion of patients (~40%) still present a substantial impact of the disease (PGA>2)

## How this study might affect research, practice or policy

* SDAI-LDA allows considerable disease activity to go unchecked, with additional radiographic progression of joint damage and a substantial residual impact of the disease.
## INTRODUCTION

The treat-to-target (T2T) (1) paradigm has become a gold standard in the management of rheumatoid arthritis (RA), (2, 3) aiming at the best possible long-term outcome regarding structural integrity and physical function. According to T2T, disease activity should be assessed frequently through validated measures, and immunosuppressive therapy should be modified as needed to ensure that the treatment target is achieved as early and consistently as possible. (1)

This bestows a crucial importance on the definition of the treatment target. A too stringent target may lead to overtreatment, unwarranted side effects and costs, as well as patient dissatisfaction. Conversely, a too lenient target may result in undertreatment, leading to higher disease impact along with patient dissatisfaction and preventable accrual of irreversible structural damage and/or functional disability.

In 2011, the American College of Rheumatology (ACR) and the European Alliance of Association for Rheumatology (EULAR) established strict definitions of remission for use in scientific studies aimed at limiting the number of false positives. However, the committee also suggested these might be useful as treatment targets for RA. Such definitions of remission include: the Boolean definition [swollen and tender 28-joint counts (SJC28, TJC28), C-reactive protein (CRP) and Patient Global Assessment (PGA) all ≤1), or a Simplified Disease Activity Index (SDAI) score <3.3 (sum of TJC28, SJC28, CRP, PGA and Physician Global Assessment (PhGA)]. A Clinical Disease Activity Index (CDAI) score ≤2.8 is also appropriate for clinical practice (no CRP included). These definitions have been criticised for being too stringent. It was demonstrated that by using the Boolean definition, as many as 19% of all RA patients in clinical practice and clinical trials would be recommended incremental immunosuppression due solely to a PGA score>1, when otherwise in remission, the so-called PGA-Near-Remission status.(4, 5) This represents an unwarranted risk of overtreatment, given that, in such circumstances, PGA does not reflect subclinical inflammation, (6-8) nor predicts worsened structural joint damage. (5, 9, 10) ACR and EULAR have recently changed the Boolean remission definition by mitigating the PGA criterion to ≤2.(9) This reduces but does not eliminate the problem: PGA >2 is responsible for 47% of all cases where the remission definition is unmet due to a single criterion in clinical trials. (9) In a cross-sectional study, among patients in PGA-Near-Remission 70% scored PGA >2.(11)

A disruptive argument has been put forth to resolve this problem by excluding PGA from the Boolean definition and adopting the resulting 3-variable (3V) variant.(12) This reduces the number of patients selected for incremental immunosuppression by T2T without leading to increased radiographic joint damage, even considering the updated ACR/EULAR definition. Thus, the 3V-remission would diminish the risk of overtreatment.(5, 13) This proposal has been opposed, arguing that "low disease activity rather than remission is the prime therapeutic target in patients with established RA",(2) which would diminish the risk of overtreatment. However, SDAI-LDA (SDAI≤11) incorporates both patients in pure-LDA (<3.3<SDAI≤11) and patients in pure-remission (SDAI ≤3.3). Its implication in terms of radiographic damage progression remains unclear.

This study aimed to evaluate the risks of under and overtreatment of SDAI-LDA versus remission definitions as treatment targets, by 1) evaluating the rates of radiographic progression and good radiographic outcome (GRO) over 2 years, and 2) evaluating the radiographic progression and the distribution of the individual criteria of the Boolean definition of remission in the pure LDA subgroup.

## MATERIAL AND METHODS

This was an individual-patient data (IPD) meta epidemiological study of published randomised controlled trials (RCTs) selected through a systematic literature review, as described elsewhere.(14)
RCTs were included when they tested the efficacy of biological disease-modifying anti-rheumatic drugs (bDMARDs) on ≥2-year radiographic outcomes in patients fulfilling the 1987 ACR or the 2010 ACR/EULAR criteria for RA.(15, 16) Only RCTs with available IPD were included.

## Outcomes and remission definitions

### *Outcomes:*

The primary outcome was the mean of radiographic progression according to the modified total Sharp-van der Heijde score (mTSS) from baseline to 2-year's follow-up.(16) The percentage of individuals with good radiographic outcome (GRO), defined as a change (Δ) ≤0.5 units mTSS during the same period, was the secondary outcome. This ≤0.5 cut-off of GRO was preferred because 0.5 is considered the optimal cut-off if the average of two readers is used.(17, 18) The time period of 24 months was considered over the usual 12 months to cover the full duration of treatment.

Given the low rates of change compared to the full range in van der Heijde mTSS (0 to 448) and Genant mTSSs (0 to 202) and the similar performances of these scoring methods,(19) numerical change data from LITHE was used for calculations without adaptation.

Joint Counts, CRP and PGA scores at six months were taken as tertiary outcomes in the Pure-LDA subgroup.

### *Definitions:*

The following definitions of “treatment target” were assessed at 6 months of follow-up:

1. **SDAI-LDA:** TJC28 + SJC28 + PGA + PhGA + CRP (mg/dl) ≤11.(20)

2. **SDAI-Remission:** SDAI ≤3.3.(20)

3. **4V-Remission (ACR/EULAR Boolean):** TJC28≤1, SJC28≤1, CRP (mg/dl)≤1 and PGA≤2.(9)

4. **3V-Remission:** TJC28≤1, SJC28≤1 and CRP (mg/dl)≤1.

The following definitions were also considered

5. Patients in the SDAI Pure-LDA: SDAI score >3.3 and ≤11,(21)

6. **PGA-Near-Remission:** TJC28≤1, SJC28≤1, CRP (mg/dl) ≤1 and PGA>2

These definitions are not mutually exclusive: patients may simultaneously meet several of them (e.g., all patients in 4V-Remission are also in 3V-Remission, but the reverse is not necessarily true).

Please note that SDAI-LDA is the combination of SDAI-Remission + SDAI Pure-LDA subgroup, while 3V-Remission equals the combination of 4V-Remission + PGA-Near-Remission.

The decision to assess the target at 6 months was made to emulate the methods used by the recent ACR-EULAR task force to reappraise the definition of remission (9) and to mirror the decision faced by the treating physician at 6 months after the initiation of a new treatment regime: to reinforce or maintain the ongoing immunosuppressive therapy.

## Data analyses and synthesis

Only patients with available data both on remission and radiographic outcome were included, without imputation of missing data. Analyses were performed with SAS software (V.9.4) within the Vivli® (Center for Global Clinical Research Data) online secure platform.

The damage progression in patients meeting each treatment target in each trial was weighted and pooled by meta-analytic techniques, disregarding treatment allocation, through the OpenMeta[Analyst] software (V 10.12), using the DerSimonian-Laird random-effects methods and the double arcsine transformation. Double arcsine transformation was used as the preferred method to correct the error estimation of prevalence when multiple categories are considered and
to mitigate heteroscedasticity. (22) The I² of Higgins and Thompson was calculated to quantify heterogeneity.(23)

The Positive (LR+) and Negative (LR-) Likelihood ratios of meeting GRO associated with each definition of treatment target were calculated based on the True Positive (TP), True Negative (TN), False positive (FP) and False Negative (FN) results.

To explore the impact of including patients in “Pure-LDA category” in the SDAI-LDA target, we compared the mean radiographic progression and the rate of GRO between the Pure-LDA category and the SDAI-Remission subgroups, as they are mutually exclusive. Similar analyses were performed comparing patients in 4V-Remission and in PGA-Near-Remission.

Additionally, in patients in the Pure-LDA subgroup, we evaluated the proportions of patients meeting or not meeting individual components of the ACR/EULAR remission criteria.

Among patients reaching the target SDAI-LDA, we compared the proportion of patients with GRO and the mean radiographic progression observed in those who were and those who were not in 3V-Remission.

## Exploratory analysis

An exploratory analysis of the potential use of the OMERACT Minimal Disease Activity (MDA) as a target was performed. MDA is defined as ≥ five out of seven criteria (TJC28≤1; SJC28≤1; HAQ ≤0.5; Pain VAS (0-10) ≤2.0; PhGA VAS (0-10) ≤1.5, PGA VAS (0-10) ≤2.0 and erythrocyte sedimentation rate (ESR) ≤20.(24)

# RESULTS

## Patients and Target-achievement rates

In total, 4374 patients among the 6392 patients included in the 8 RCTs (25-32) were considered. The included trials tested as active arms Adalimumab (DE019, DE013), Etanercept (TEMPO and COMET), Certolizumab (RAPID 1 and RAPID 2) and Tocilizumab (LITHE and Function).

Patients were predominantly female (78%, 95% CI: 75; 81); mean age was 52.2 years (95% CI: 50.7 to 53.6) and disease duration was 5.9 years (95% CI: 4.6-7.1). Disease duration and treatment histories varied for the individual trials. (Supplementary table S1). As expected, patients presented with high disease activity at baseline (mean DAS28-3v-CRP: 5.1; 95% CI: 4.9; 5.2) and moderate to severe functional impairment (mean HAQ-DI: 1.6; 95% CI:1.5; 1.6).

Excluded patients (n=2018, 31.5%) had slightly higher age and higher PGA, PhGA, and HAQ scores at baseline than included patients, but they were similar regarding gender, disease duration, joint counts, CRP, and baseline radiographic damage" (Supplementary table S2).

Taking all treatment arms together (Table 1), the pooled proportion of patients achieving the SDAI-LDA target at 6 months was 49% (95%CI: 43;55), with 35% (95%CI: 33;38) being in the Pure-LDA subgroup and 13% (95%CI:9;15) in SDAI-Remission. The updated ACR/EULAR 4V-Remission was met by 16%, with 6% of all patients failing to meet the ACR/EULAR remission definition solely due to a PGA score >2 (PGA-Near-Remission) i.e., 28% of all patients who were otherwise in remission. 3V-Remission was achieved by 23% (95%CI: 18; 29) of all patients at 6 months.

**Table 1:** Pooled Frequency of target achievement at 6 months in the 8 included trials. Values are n (%) unless stated otherwise.
<table><thead><tr><th>Study acronym</th><th>SDAI-LDA</th><th>SDAI-Remission</th><th>4V-Remission</th><th>3V-Remission</th></tr></thead><tbody><tr><td>DE019 (2004)<sup>(25)</sup></td><td>164 (39)</td><td>26 (6)</td><td>47 (11)</td><td>57 (13)</td></tr><tr><td>TEMPO (2004)<sup>(26)</sup></td><td>205 (47)</td><td>46 (11)</td><td>79 (18)</td><td>112 (26)</td></tr><tr><td>COMET (2008)<sup>(27)</sup></td><td>194 (59)</td><td>42 (13)</td><td>72 (22)</td><td>124 (38)</td></tr><tr><td>RAPID1 (2008)<sup>(28)</sup></td><td>361 (55)</td><td>122 (19)</td><td>129 (20)</td><td>179 (28)</td></tr><tr><td>RAPID2 (2009)<sup>(29)</sup></td><td>170 (41)</td><td>35 (8)</td><td>40 (10)</td><td>69 (17)</td></tr><tr><td>LITHE (2011)<sup>(30)</sup></td><td>312 (41)</td><td>66 (9)</td><td>77 (10)</td><td>132 (17)</td></tr><tr><td>DE013 (2013)<sup>(31)</sup></td><td>268 (51)</td><td>88 (17)</td><td>81 (16)</td><td>91 (17)</td></tr><tr><td>FUNCTION (2016)<sup>(32)</sup></td><td>482 (57)</td><td>207 (25)</td><td>218 (26)</td><td>276 (33)</td></tr><tr><td>Pooled, %<br>(95% CI)</td><td>49<br>(43;55)</td><td>13<br>(9;18)</td><td>16<br>(12;21)</td><td>23<br>(18;29)</td></tr></tbody></table>

All meta-analyses used the double arcsine transformation. (22)

**SDAI-LDA:** SDAI≤11; **SDAI-Remission:** SDAI≤3.3; **4V-Remission:** 2022 ACR/EULAR Boolean definition: TJC28≤1, SJC28≤1, CRP (mg/dl) ≤1 and PGA≤2; **3V-Remission:** TJC28≤1, SJC28≤1, CRP≤1 (mg/dl).

The mean of SDAI for each treatment target, per trial is presented in supplementary table S3. Patients in SDAI-At least LDA had a higher mean SDAI (5.23 (5.11; 5.42)) when compared with the other targets, including 3v-remission (3.45; (2.90; 4.06)).

### Radiographic progression according to target definitions

The mean (95% CI) radiographic progression of joint damage in the SDAI-LDA was 0.55 (95%CI: 0.14;0.96) mTSS units at year two (Table 2). This was higher than observed in all the other definitions of targets, including the 3V-Remission (0.28; 95%CI: -0.09; 0.52). The mean radiographic progression of joint damage over two years per trial is presented in the supplementary table S34.

The proportion of patients presenting a radiographic progression >5 units during the two years of follow-up was very low for all target definitions at 6 months (range 2.8 to 5.8%). Altogether, 1134 (54%; 95%CI: 43; 56 %) of all patients classified as being in SDAI-LDA did not meet 3V-Remission, the least stringent remission definition, i.e., they did not meet at least one of the three criteria ≤1 (SJC28, TCJ28, CRP (mg/dL)). Patients fulfilling the SDAI-LDA but not 3V-Remission presented more radiographic progression than patients who simultaneously fulfilled the criteria for 3V-Remission (0.70 vs 0.25 units, p=0.014).

No statistically significant differences were observed between the two subgroups integrating 3V-Remission.

<table><caption>**Table 2:** Pooled mean radiographic progression and proportions of good radiographic outcome over 2 years associated with meeting the different treatment targets at 6 months</caption><thead><tr><th>Definition</th><th>Radiographic progression<br>(mean ΔmTSS, 95%CI)</th><th>p<sup>a</sup></th><th>Good Radiographic Outcome<br>(%, 95%CI)</th><th>p<sup>a</sup></th></tr></thead><tbody><tr><td>SDAI Remission</td><td>0.22 (-0.09;0.54)</td><td>0.03</td><td>76 (69;83)</td><td>0.19</td></tr></tbody></table>
<table><tr><td>SDAI Pure-LDA</td><td>0.72 (0.28;1.16)</td><td></td><td>73 (66;79)</td><td></td></tr><tr><td>SDAI LDA</td><td>0.55 (0.14;0.96)</td><td>--</td><td>73 (67;80)</td><td>--</td></tr><tr><td>4V-Remission</td><td>0.28 (-0.07;0.62)</td><td></td><td>75 (68;82)</td><td>0.68</td></tr><tr><td>PGA-Near-Remission</td><td>0.24 (-0.15;0.63)</td><td>0.31</td><td>78 (73;84)</td><td></td></tr><tr><td>3V-Remission</td><td>0.28 (-0.10;0.65)</td><td>--</td><td>76 (70;81)</td><td>--</td></tr></table>

a. Comparison between the two SDAI mutually exclusive subgroups and the Boolean mutually exclusive subgroups.

Legend: GRO: Good Radiographic outcome; ΔmTSS: change in the van der Heijde modified total Sharp score; SDAI-LDA: SDAI≤11; SDAI-Remission: SDAI≤3.3; SDAI Pure-LDA: 3.3>SDAI≤11; 4V-Remission: 2022 ACR/EULAR Boolean definition: TJC28≤1, SJC28≤1, CRP (mg/dl) ≤1 and PGA≤2; 3V-Remission: TJC28≤1, SJC28≤1, CRP≤1 mg/dl; 95% CI: 95% Confidence Interval.

Note: SDAI-LDA assemblage patients in SDAI-Remission and those in SDAI Pure-LDA. Similarly, 3V-Remission assemblage patients in 4V-Remission and those in PGA-Near-Remission.

### Good radiographic outcome according to target definitions

Good radiographic outcome was achieved by 67% of all patients. No statistically significant differences were observed according to the different targets considered: SDAI-LDA 73.2% (67;80), SDAI-Remission 76% (69;83), 4V-Remission 75% (68;82), and 3V-Remission 76% (70;81) (Table 2).

The Likelihood Ratios for GRO are presented in Table 3. LR+ of GRO was highest (i.e. clinically desirable) for 3V-Remission (1.41) and lowest for the SDAI-LDA (1.31). There was, however, an overlap between the 95% CI for all definitions. Conversely, LR- of GRO was lowest for LDA (0.80).

<table><caption>**Table 3:** Pooled likelihood ratios (95%CI) for good radiographic outcome for the different treatment targets</caption><thead><tr><th>Definition</th><th>LR+ (95%CI)</th><th>I<sup>2</sup> (%)</th><th>LR- (95%CI)</th><th>I<sup>2</sup> (%)</th></tr></thead><tbody><tr><td>SDAI-LDA</td><td>1.32 (1.15;1.51)</td><td>72</td><td>0.80 (0.71;0.89)</td><td>56</td></tr><tr><td>SDAI-Remission</td><td>1.34 (1.13;1.60)</td><td>0</td><td>0.95 (0.80;1.13)</td><td>0</td></tr><tr><td>4V-Remission</td><td>1.36 (1.06;1.76)</td><td>59</td><td>0.96 (0.82;1.12)</td><td>0</td></tr><tr><td>3V-Remission</td><td>1.41 (1.15;1.73)</td><td>58</td><td>0.92 (0.81;1.00)</td><td>0</td></tr></tbody></table>

LR+: positive likelihood ratio, sensitivity/(1-specificity); LR-: negative likelihood ratio, (1-sensitivity)/specificity; I²: I² of Higgins to quantify heterogeneity;

SDAI-LDA: SDAI≤11; SDAI-Remission: SDAI≤3.3; 4V-Remission TJC28≤1, SJC28≤1, CRP (mg/dl) ≤1 and PGA≤2; 3V-Remission: TJC28≤1, SJC28≤1, CRP≤1 mg/dl.

In the subgroup of patients who achieved the SDAI-LDA but not 3V-Remission the percentage of patients without GRO was 28% higher than patients who simultaneously fulfilled both criteria.
However, the rate of GRO was not statistically significantly different between these former and latter subgroups (70. vs 77%, p=0.065).

No statistically significant differences were observed between the two subgroups integrating 3V-Remission.

## Characterisation of the Pure-LDA subgroup within the SDAI-LDA group

There were 1524 patients (35%) in the Pure-LDA subgroup at 6 months. Considering the 28-joint count, in 38% of these patients >1 swollen joint was observed, with 7% presenting ≥5 swollen joints, with a maximum of 8 SJC. Similar findings were made regarding tender joints (Figure 1). CRP was >1 mg/dl in 12%, and the PGA score >2 in 40% of these Pure-LDA Category patients.

Patients in the Pure-LDA subgroup at 6 months showed significantly higher radiographic progression during the two years of follow-up year (0.72 vs 0.22 units; p=0.03) but a non-significant lower rate of good radiographic outcome at 2 years (73 vs 76%, p>0.05), when compared with patients in SDAI-Remission.

## Exploratory analysis

For this exploratory analysis, data was available from 3612 patients from all RCTs, except TEMPO and COMET trials (26, 27). At six months, MDA was achieved by 1188 (31%) patients. GRO was observed at two years in 69% (95%CI: 63; 74) of these patients with MDA, with a mean radiographic progression of 0.67 (95%CI: 0.17; 1.16). The LR+ of GRO was 1.45 (95%CI: 1.13; 1.87), and the LH- of GRO was 0.85 (95%CI: 0.76; 0.95), results that overlap with the 95% CI for all definitions included in the main analysis.

## DISCUSSION

Our study demonstrates that adopting SDAI-LDA as a treatment target in established RA would result in higher radiographic progression in comparison with using either SDAI-Remission or –the less stringent– 3V-Remission. This is largely attributable to the subgroup of patients who meet the target of SDAI-LDA while not being in SDAI-remission (the Pure-LDA subgroup). In fact, over 50% of these patients in Pure-LDA subgroup present clinically relevant signs of inflammation with emphasis on up to 8 swollen joints and CRP >1. SJC, TJC and CRP, but not PGA, are associated with the development of joint damage,(33-39), justifying the need to increment immunosuppressive therapy. In addition, our study showed that ~40% of all those patients in the Pure-LDA subgroup still score PGA>2, also reflecting a high unattended impact of the disease. Patients in SDAI-LDA and PGA>2 would also need special attention for the unabated domains of impact and the implementation of adequate co-adjunctive treatment, as described in our Dual-Target Strategy proposal.(12, 40) This strategy includes not only a disease activity treatment target, but also is focused on the disease impact upon the patient’s life as second, equally important, treatment target.

In our exploratory analysis, the proportion of patients achieving OMERACT MDA was close to 30%, which is higher than that observed with SDAI-remission and all Boolean targets but lower than SDAI-LDA. These patients showed a lower rate of GRO than all alternatives. The mean radiographic progression over two years was similar to that observed with SDAI-LDA, higher than observed for other targets. Comparisons between MDA and other target definitions should be performed with caution, as MDA could only be evaluated in six trials.
Adequate control of disease activity and disease impact might be at risk if, as stated in the recent EULAR and ACR recommendations, "*low disease activity rather than remission is the prime therapeutic target in patients with established RA*"(2) or "*conditionally recommended over a goal of remission*".(3) However, EULAR does not recommend to replace the target of remission by the alternative target of low-disease activity but rather intends that "*if remission cannot be achieved for any reason (such as in patients with long-standing disease), low-disease activity is an alternative and valid target*".(1) In the group with LDA, a frequent cause of not meeting remission criteria is a PGA score >1 or >2, unrelated to disease activity (41, 42) and, thus, unamenable to incremental immunosuppression, and not leading to progressive joint damage. But this pure-LDA group also would include patients with disease activity leading to joint damage progression. The Dual-Target Strategy might discriminate between these two subgroups.

The suggestion that SDAI-LDA is a reasonable alternative to remission is unsupported by evidence: the difference between these two states regarding radiographic progression has been scarcely investigated. The establishment of SDAI cut-offs (20) was based on purely clinical grounds and did not consider the structural implications of these two treatment aims. Using data from the ESPOIR cohort, SDAI-remission at 1 year was associated with better radiographic outcomes at three years in patients with early RA than SDAI-LDA.(43) Similar findings were reported by Hirano et al. in a mixed RA sample.(44) Our study, which includes almost exclusively patients with established disease, confirms that SDAI-LDA is associated with higher radiographic progression when compared with SDAI-remission.

The findings of our study must be considered in light of some limitations and strengths. The use of IPD of over 4000 patients and their inclusion in stringent RCT conditions are important strengths. This study does not include the newest RCTs, particularly considering new drugs as Jak inhibitors, but the RCTs included were similar to the ones used by ACR/EULAR task forces to define the currently recommended targets. (9, 10) Data were derived from RCTs, with high disease activity at baseline and established disease, with inadequate response to other DMARDs, high baseline joint damage and, consequently with a higher propensity to have damage progression than regular clinic patients. This may question the generalizability of the results to clinical practice, although similar progression rates, as seen in RCTs, have been observed in cohorts from clinical practice. (43-45) Furthermore, in line with our results, also in clinical cohorts, a greater rate of progression has been shown in pursuing SDAI-LDA than in pursuing remission. (43, 44) Our study considers remission only at 6 months, so the impact of persistent remission or LDA was not addressed. Radiographic progression was considered over a 24-month evaluation instead of the 12-month evaluation usually considered, which is, in fact, a more strict definition of good radiographic progression. This time period was considered to cover the full duration of treatment and compensate for the generally low radiographic progression observed in recent decades. Our results should be interpreted in light of low mean radiographic progression and a high percentage of GRO observed. However, it is in agreement with the trend for lower progression of joint damage observed in recent decades.(46)

The included studies investigated the effects of starting bDMARDs, a class of drugs known to have a less clear relationship between disease activity during this therapy and ensuing progression of radiographic joint damage, compared with conventional DMARDs (cDMARDs). (47, 48) This implies that our results would pave been even more outspoken if we had (also) included studies with patients on cDMARDs, initiating another cDMARD. It should be noted that about one-third of patients were excluded due to missing data. These patients were similar to those included regarding factors known as relevant for radiographic outcomes, i.e. SJC28, TJC28, CRP, baseline radiographic damage, and disease duration. This makes it unlikely that the exclusion of these patients has affected our findings on the outcomes under consideration."

The findings discussed above support the hypothesis that, if taken without further consideration, SDAI-LDA is a too-lenient target to guide immunosuppressive therapy to prevent radiographic progression, the ultimate goal of the treat-to-target strategy. Furthermore, our study shows that this
treatment target allows considerable impact (related and unrelated to inflammation) to go
unnoticed and, therefore, unaddressed.

We acknowledge that clinicians will certainly not rigidly and strictly adhere to the outcome of index
definitions in all situations and consider the individual patient features and needs. This is in this
respect essentially not different from applying treat-to-target strategies in clinical practice using
DAS28, which has been common practice for many years. This issue should, in our view, be discussed
by treatment recommendations. Then, addressing the specific individual patient's features and
needs would be greatly facilitated by the separate consideration of PGA or alternative patient-
reported outcomes.

The rate of radiographic progression was significantly higher with SDAI pure LDA than with SDAI
remission. Although the differences are small, the prevention of radiographic damage is a core
objective of the T2T strategy and should be pursued whenever possible. Conversely, there was no
significant difference in mean radiographic progression or good radiographic outcomes between
PGA-Near (i.e. 3V-) and 4V-Boolean remission. Allowing PGA-Near-remission does not affect the
predictive value of remission, thus supporting 3V-Remission as the most suitable guide to
immunosuppressive treatment.

These findings, in addition to the previous evidence that the 3v-Remission has the highest accuracy
in predicting GRO in comparison to both SDAI-Remission and the original ACR/EULAR 4V Boolean
remission definition, (5, 13) suggest that 3V-Remission deserves consideration as the most
appropriate guide to immunosuppressive treatment.

This proposal must be seen in the context of a Dual-Target Strategy, whereby the 3V-Remission is
adopted as the Biological Target, while a second target, focused on the disease's impact upon the
patient's life, is simultaneously assessed and pursued.(40) PGA is a valid PRO, but other validated
instruments can convey more discriminative information, thus deserving preferred consideration.
(40)
**Acknowledgement:** This publication is based on research using data from data contributors AbbVie, Roche, Pfizer, UCB that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.

**Contributors:** All authors designed the study and protocol, which was firstly drafted by CD, RJOF and JAPS. CD, RJOF and PMJW performed the data analyses. CD and JAPS wrote the initial draft of the manuscript, which was critically revised and refined by all authors. All authors formally approved the final manuscript.

**Funding:** This manuscript is based on research using data from data contributors AbbVie, Pfizer, Roche and UCB that have been made available through Vivli, Inc.

**Competing of Interest:** RJOF reports a research grant from Medac, Consulting fees from Sanofi Genzyme, and support for attending meetings from Medac and speaker fees from Sanofi Genzyme, unrelated with this work LG has received grants or contracts from AbbVie, Biogen, Lilly, Novartis, UCB, consulting fees from AbbVie, BMS, Celltrion, Janssen, Novartis, Pfizer, UCB, honoraria for lectures from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, has received support for attending meetings and/or travel from MSD, Novartis, Pfizer, has received medical writing support from AbbVie, Amgen, Galapagos, Janssen, Pfizer, UCB.PM: reports consulting/speakers fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB Pharma and is supported by NIHR, UCLH and BRC; unrelated with this work. DvdH is Director of Imaging Rheumatology BV and reports speaker fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB Pharma, unrelated with this work. JAPS reports a research grant from Medac, Consulting fees from Amgen, MSD and AbbVie, speaker fees from Amgen, MSD and AbbVie and Support for attending meetings from Amgen, AbbVie and Pfizer, unrelated with this work. Patient and public involvement: Patients and/or public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

**Patient Informed Consent:** Not required

**Ethics Approval:** Ethical approval to this study was granted by the Centro Hospitalar e Universitário de Coimbra Ethics Committee (CHUC-047-17).

**Provenance and peer review:** Not commissioned; externally peer-reviewed

**Data availability statement:** Data may be obtained from a third party and are not publicly available.
REFERENCES

1. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3-15.

2. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18.

3. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2021;73(7):1108-23.

4. Ferreira RJO, Santos E, Gossec L, et al. The patient global assessment in RA precludes the majority of patients otherwise in remission to reach this status in clinical practice. Should we continue to ignore this? Semin Arthritis Rheum. 2020;50(4):583-5.

5. Ferreira RJO, Welsing PMJ, Jacobs JWG, et al. Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: an individual meta-analysis of 5792 patients. Ann Rheum Dis. 2021;80(3):293-303.

6. Brites L, Rovisco J, Costa F, et al. High patient global assessment scores in patients with rheumatoid arthritis otherwise in remission do not reflect subclinical inflammation. Joint Bone Spine. 2021;88(6):105242.

7. Nakabo S, Tsuji Y, Inagaki M, et al. Severe joint deformity and patient global assessment of disease are associated with discrepancies between sonographic and clinical remission: A cross-sectional study of rheumatoid arthritis patients. Mod Rheumatol. 2021;31(2):334-42.

8. Paulshus Sundlisæter N, Sundin U, Aga AB, et al. Inflammation and biologic therapy in patients with rheumatoid arthritis achieving versus not achieving ACR/EULAR Boolean remission in a treat-to-target study. RMD Open. 2022;8(1).

9. Studenic P, Aletaha D, de Wit M, et al. American College of Rheumatology/EULAR remission criteria for rheumatoid arthritis: 2022 revision. Ann Rheum Dis. 2023;82(1):74-80.

10. Studenic P, Felson D, de Wit M, et al. Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal? Ann Rheum Dis. 2020;79(4):445-52.

11. Ferreira RJO, Dougados M, Kirwan JR, et al. Drivers of patient global assessment in patients with rheumatoid arthritis who are close to remission: an analysis of 1588 patients. Rheumatology (Oxford). 2017;56(9):1573-8.

12. Ferreira RJO, Ndosi M, de Wit M, et al. Dual target strategy: a proposal to mitigate the risk of overtreatment and enhance patient satisfaction in rheumatoid arthritis. Ann Rheum Dis. 2019;78(10):e109.

13. Duarte C, Ferreira RJO, Welsing PMJ, et al. Remission definitions guiding immunosuppressive therapy in rheumatoid arthritis: which is best fitted for the purpose? RMD Open. 2024;10(1).

14. Ferreira RJO, Welsing PMJ, Gossec L, et al. The impact of patient global assessment in the definition of remission as a predictor of long-term radiographic damage in patients with rheumatoid arthritis: protocol for an individual patient data meta-analysis. Acta Reumatol Port. 2018;43(1):52-60.

15. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315-24.

16. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-81.

17. Ory PA. Interpreting radiographic data in rheumatoid arthritis. Ann Rheum Dis. 2003;62(7):597-604.

18. van der Heijde D, Simon L, Smolen J, et al. How to report radiographic data in randomized clinical trials in rheumatoid arthritis: guidelines from a roundtable discussion. Arthritis Rheum. 2002;47(2):215-8.
19. Peterfy CW, C. Szechinski, J. DiCarlo, J. Lu, Y. Genovese, M. Strand, V. Genant, HK. Comparison of the Genant-modified Sharp and van der Heijde-modified Sharp scoring methods for radiographic assessment in rheumatoid arthritis. Int J Clin Rheumatol. 2011;6(1):15-24.

20. Aletaha D, Ward MM, Machold KP, et al. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. Arthritis Rheum. 2005;52(9):2625-36.

21. Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford). 2003;42(2):244-57.

22. Barendregt JJ, Doi SA, Lee YY, et al. Meta-analysis of prevalence. J Epidemiol Community Health. 2013;67(11):974-8.

23. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-58.

24. Wells GA, Boers M, Shea B, et al. Minimal disease activity for rheumatoid arthritis: a preliminary definition. J Rheumatol. 2005;32(10):2016-24.

25. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400-11.

26. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum. 2006;54(4):1063-74.

27. Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372(9636):375-82.

28. Keystone E, Heijde D, Mason D, Jr., et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 2008;58(11):3319-29.

29. Smolen J, Landewé RB, Mease P, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis. 2009;68(6):797-804.

30. Fleischmann RM, Halland AM, Brzosko M, et al. Tocilizumab inhibits structural joint damage and improves physical function in patients with rheumatoid arthritis and inadequate responses to methotrexate: LITHE study 2-year results. J Rheumatol. 2013;40(2):113-26.

31. Breedveld FC, Weisman MH, Kavanaugh AF, 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(1):26-37.

32. Burmester GR, Rigby WF, van Vollenhoven RF, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75(6):1081-91.

33. Vastesaeger N, Xu S, Aletaha D, et al. A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford). 2009;48(9):1114-21.

34. Aletaha D, Smolen JS. Joint damage in rheumatoid arthritis progresses in remission according to the Disease Activity Score in 28 joints and is driven by residual swollen joints. Arthritis Rheum. 2011;63(12):3702-11.

35. Weinblatt ME, Keystone EC, Cohen MD, et al. Factors associated with radiographic progression in patients with rheumatoid arthritis who were treated with methotrexate. J Rheumatol. 2011;38(2):242-6.

36. Markatseli TE, Voulgari PV, Alamanos Y, et al. Prognostic factors of radiological damage in rheumatoid arthritis: a 10-year retrospective study. J Rheumatol. 2011;38(1):44-52.
37. Ferreira RJO, Fautrel B, Saraux A, et al. Patient Global Assessment of Disease Activity and Radiographic Progression in Early Arthritis: Three-Year Results From the ESPOIR Cohort. Arthritis Care Res (Hoboken). 2021;73(9):1300-5.

38. Navarro-Compán V, Gherghe AM, Smolen JS, et al. Relationship between disease activity indices and their individual components and radiographic progression in RA: a systematic literature review. Rheumatology (Oxford). 2015;54(6):994-1007.

39. Gessl I, Hana CA, Deimel T, et al. Tenderness and radiographic progression in rheumatoid arthritis and psoriatic arthritis. Ann Rheum Dis. 2022.

40. Duarte C, Ferreira RJO, Santos EJF, et al. Treating-to-target in rheumatology: Theory and practice. Best Pract Res Clin Rheumatol. 2022;36(1):101735.

41. Silva CFR, Duarte C, Ferreira RJO, et al. Depression, disability and sleep disturbance are the main explanatory factors of fatigue in rheumatoid arthritis: a path analysis model. Clin Exp Rheumatol. 2020;38(2):314-21.

42. Brkic A, Łosińska K, Pripp AH, et al. Remission or Not Remission, That's the Question: Shedding Light on Remission and the Impact of Objective and Subjective Measures Reflecting Disease Activity in Rheumatoid Arthritis. Rheumatol Ther. 2022;9(6):1531-47.

43. Ruyssen-Witrand A, Guernec G, Nigon D, et al. Aiming for SDAI remission versus low disease activity at 1 year after inclusion in ESPOIR cohort is associated with better 3-year structural outcomes. Ann Rheum Dis. 2015;74(9):1676-83.

44. Hirano F, Yokoyama W, Yamazaki H, et al. Achieving simplified disease activity index remission in patients with active rheumatoid arthritis is associated with subsequent good functional and structural outcomes in a real-world clinical setting under a treat-to-target strategy. Mod Rheumatol. 2017;27(5):811-9.

45. Ramiro S, Landewé R, van der Heijde D, et al. Stricter treat-to-target in RA does not result in less radiographic progression: a longitudinal analysis in RA BIODAM. Rheumatology (Oxford). 2023;62(9):2989-97.

46. Park YJ, Gherghe AM, van der Heijde D. Radiographic progression in clinical trials in rheumatoid arthritis: a systemic literature review of trials performed by industry. RMD Open. 2020;6(2).

47. Smolen JS, Han C, van der Heijde DM, et al. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis. 2009;68(6):823-7.

48. Smolen JS, Avila JC, Aletaha D. Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction. Ann Rheum Dis. 2012;71(5):687-93.
<figure><img src="image_2.png" /><figcaption>**Figure 1:** Distribution of swollen and tender 28-joint counts of patients in the Pure-LDA subgroup (n=1524).</figcaption></figure>

Numbers are percentages. **28-SJC:** Swollen joint count assessing 28 joints; **28-TJC:** Tender joint count assessing 28 joints.