Background/Purpose: Emerging data indicate an uncoupling between pain and inflammation during the RA disease course, and comorbid fibromyalgia – thought to stem from central pain sensitization – is displayed in up to 25% of patients. It has been hypothesized that sensitization could be induced by a period of insufficiently treated inflammation, although this remains to be explored. The current study thus aimed to 1) investigate the dynamics of persistent pain with and without inflammatory control after RA onset; and 2) examine if cumulative inflammation during the first 6 months is linked to subsequent non-inflammatory pain.

Methods: NORD-STAR is an investigator-initiated, open-label trial of early (<24 months symptom duration) RA patients randomized to methotrexate combined with (a) other csDMARDs/corticosteroids or steroids alone, (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Here, the latter group was omitted to allow for CRP analysis, and patients were analyzed irrespective of randomized therapy. Assessment was performed at 0, 4, 8, 12, 16, 24, 32, 40 and 48 weeks (w) including unacceptable pain ( >40 mm [0-100] on a Visual Analogue Scale [VAS]), and refractory pain (unacceptable pain despite inflammation control: VAS pain >40 mm + CRP< 10 mg/L + swollen joint count [SJC; of 66] ≤1)1. Differences in pain outcomes between EULAR response groups were analyzed by Chi-2/Fisher’s exact test. Associations between cumulative inflammatory load (area-under-the-curve [AUC] from 0-24w for CRP/SJC) and unacceptable/refractory pain at 48w, as well as 48w fibromyalgic RA (by the published definition tender joint count [TJC]-SJC ≥7 [of 68/66]2), were respectively estimated by logistic regression, adjusted for age, sex, ACPA positivity and BMI.

Results: Included RA patients (n=624) were 69% women, 82% ACPA positive and with mean age/symptom duration of 55/0.6 years. At baseline, 73% reported unacceptable pain, declining to 10% after 48w, whereas the fraction with refractory pain was 0% (baseline) and 6% (48w). Refractory pain constituted 62% of all remaining unacceptable pain at 48w (Figure 1). Further, unacceptable pain at 12w was strongly linked to EULAR 12w response (7% in good responders versus 67% in non-responders; p< 0.001), while for refractory pain the relationship was weaker (6% versus 17%, p=0.074), with refractory pain accounting for 88% of remaining unacceptable pain in good responders (Figure 2). AUC for SJC (0-24w) was positively associated with 48w unacceptable pain (p=0.007) and fibromyalgic RA (p=0.018) in adjusted analysis, with a trend also for refractory pain (p=0.083). AUC for CRP (0-24w) was not associated with the pain outcomes (Table 1).

Conclusion: A relevant proportion of early, aggressively treated RA patients have persistent unacceptable pain after 1 year, with pain indicative of a non-inflammatory mechanism accounting for over 60% of this pain load. Our findings also suggest that a prolonged inflammatory period could entail more future non-inflammatory pain, underscoring the importance of rapid and sustained inflammation resolution.1. Olofsson et al. Arthritis Care Res 2021;73:1312-212. Pollard et al. Rheumatology 2010;49:924-28Jon Lampa and Tor Olofsson contributed equally

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pain-patterns-in-a-multicenter-randomized-trial-of-early-ra-link-between-initially-sustained-joint-inflammation-and-subsequent-non-inflammatory-pain-outcomes/