Background/Purpose: Joint swelling and tenderness are clinical hallmarks of rheumatoid arthritis (RA) and central to disease assessment. Regardless of treatment type, stringent remission based on the ACR/EULAR index (SDAI, CDAI) and Boolean definitions is associated with a reduction in joint damage and an increase in physical function. Using the patient global assessment in defining remission may hinder achieving it, as some patients experience high pain despite resolved inflammation, potentially not benefitting from immune-directed therapies. To date, it is unclear how many patients in randomized controlled trials (RCTs) reach an inflammation-free state but continue to report high pain levels.Here, we analysed patients achieving inflammatory control while still reporting high pain levels at endpoints in RA RCTs and compared their characteristics at baseline and longitudinally to those with inflammatory control without residual pain.

Methods: We analyzed data from 2,640 patients receiving biologic DMARDs across 7 RCTs. Patients achieving inflammatory control (CRP≤0.5 mg/dL & SJC66=0) at trial endpoint (24 weeks) were divided by pain levels: low (≤5/10 VAS) vs high ( >5/10 VAS). We then compared demographics and outcomes of these groups at baseline (disease activity, PROs, CRP, ESR and radiographic damage). Between-group comparisons used t-tests or Mann-Whitney U tests. We also assessed longitudinal differences between the groups using longitudinal linear mixed models.

Results: Of 2,405 patients with 24-week data, 305 (13%) achieved inflammatory control. Only 15 (< 1% of all; 5% of those with resolved inflammation) showed persistently elevated pain levels despite control of inflammation (Figure 1). These patients showed a trend toward older age (52.8±11.1 vs 47.6±12.4) and a higher subjective disease burden at baseline (Figure 2) in TJC68 (31.8±16 vs 24.3±12.8), HAQ-DI (1.6±0.5 vs 1.2±0.6) and PGA (6.7±1.8 vs 5.1±2.2). Notably, objective measures including CRP (2.1±5.2 vs 1.9±2.2), ESR (30.5±23.4 vs 37.1±20.4), SJC66 (14.0±10.7 vs 14.5±8.6) and EGA (5.6±1.9 vs 5.6±1.7) and composite measures (CDAI, DAS28) were nearly identical between groups. However, erosion scores were twice as high in the high-pain group (19.0±23.4 vs 9.7±15.2) suggesting a higher disease burden. Longitudinal analyses (Figure 3) revealed persistent and significant differences in TJC68, pain, PGA, EGA HAQ-DI as well as composite measures (CDAI, SDAI, DAS28-ESR). Results using a lower cut-off for pain (≤3/10cm VAS) were confirmatory (data not shown).

Conclusion: In this pooled analysis of 7 RCTs, < 1% of patients treated across 7 RCTs experienced high pain levels despite complete inflammatory control revealing that such discrepancy is very rare. Patients with persistent pain had higher subjective disease burden as well as radiographic damage at baseline, suggesting that persistent pain may be attributed to structural damage and/or potential central pain sensitization, rather than inflammation.

Figure 1: Flow chart of patient selection for analysis of pain discordance in RA.

Figure 2: Comparison of baseline disease activity measures between patients who have achieved complete inflammatory control with high (>5; n=15) versus low (≤5; n=290) pain at week 24. Box plots show median (horizontal line), interquartile range (box), and range (whiskers). Dots represent outliers.

Figure 3: Longitudinal analyses of disease activity measures between patients who have achieved complete inflammatory control with high (>5; n=15) versus low (≤5; n=290) pain at Week 24. The mean linear mixed model estimates of different disease activity parameters over time are graphed.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/persistent-pain-despite-inflammatory-control-in-ra-a-pooled-analysis-of-7-rcts/