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Published on: May 16, 2025
Characterising subgroups of difficult-to-treat rheumatoid arthritis in real-world clinical settings
Yvonne Tan1,2,3, George Rogers4, Rudresh Shukla1
1Kellgren Centre of Rheumatology, Manchester University NHS Foundation Trust, Manchester, UK.
Objectives:
To evaluate the proportion of persistent inflammatory refractory rheumatoid arthritis (PIRRA) and noninflammatory refractory rheumatoid arthritis (NIRRA) of difficult-to-treat rheumatoid arthritis (D2T-RA) using musculoskeletal ultrasound (MSUS) and to compare clinical characteristics across PIRRA, NIRRA, and disease-controlled refractory rheumatoid arthritis (RA) subgroups.
Methods:
A retrospective single-centre cohort study identified patients (May 2021 to December 2022) with inadequate response to ≥2 different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and disease activity score in 28 joints-erythrocyte sedimentation rate (ESR) of >3.2 as European Alliance of Associations for Rheumatology-defined D2T-RA. MSUS classified this group into PIRRA (power Doppler present) or NIRRA (no power Doppler synovitis). A comparator group of controlled refractory RA (≥2 b/tsDMARD failures but sustained low disease activity) was also assessed. Clinical data were collected and analysed.
Results:
Of the 85 patients, 45 had D2T-RA (25 [56%] PIRRA; 20 [44%] NIRRA), and 40 had controlled refractory RA. PIRRA subgroup had higher C-reactive protein (CRP), but NIRRA subgroup higher ESR. Fibromyalgia was more prevalent in PIRRA and NIRRA than that in controlled refractory RA (48%, 40%, and 17.5%, respectively; P = .02). Nearly half of patients in the controlled refractory group (17/37 [46%]) had subclinical synovitis on MSUS. Rates of radiographic erosions were similar across PIRRA, NIRRA, and controlled refractory groups.
Conclusions:
MSUS-based stratification of D2T-RA into PIRRA and NIRRA reveals distinct associations to CRP and ESR and comparable chronic pain. Subclinical inflammation is present even in ostensibly controlled disease, suggesting risk of re-falling into an active D2T-RA state. Identifying such subphenotypes can inform on monitoring strategies, support mechanistic investigation, and enable more targeted treatments to improve outcomes of D2T-RA.
Insights
Musculoskeletal ultrasound (MSUS) identified distinct inflammatory (PIRRA) and non-inflammatory (NIRRA) subtypes in difficult-to-treat rheumatoid arthritis (D2T-RA). Subclinical inflammation was found even in controlled RA, highlighting the need for targeted monitoring and treatment strategies.
Area of Science:
- Rheumatology
- Medical Imaging
- Inflammation Research
Background:
- Difficult-to-treat rheumatoid arthritis (D2T-RA) presents a significant clinical challenge.
- Stratification of D2T-RA into inflammatory and non-inflammatory subtypes is crucial for effective management.
- Musculoskeletal ultrasound (MSUS) offers a potential tool for objective disease assessment.
Purpose of the Study:
- To determine the proportions of persistent inflammatory refractory rheumatoid arthritis (PIRRA) and noninflammatory refractory rheumatoid arthritis (NIRRA) within D2T-RA using MSUS.
- To compare clinical characteristics between PIRRA, NIRRA, and controlled refractory rheumatoid arthritis (RA) subgroups.
- To investigate the utility of MSUS in differentiating D2T-RA phenotypes.
Main Methods:
- A retrospective single-centre cohort study included patients with D2T-RA (inadequate response to ≥2 b/tsDMARDs, DAS28-ESR >3.2) and a controlled refractory RA comparator group.
- Patients were classified using MSUS into PIRRA (power Doppler present) or NIRRA (no power Doppler synovitis).
- Clinical data, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibromyalgia prevalence, and radiographic erosions, were collected and analyzed.
Main Results:
- Of 85 patients, 45 had D2T-RA (25 PIRRA, 20 NIRRA) and 40 had controlled refractory RA.
- PIRRA showed higher CRP, while NIRRA had higher ESR.
- Fibromyalgia was more prevalent in PIRRA and NIRRA (48%, 40%) compared to controlled RA (17.5%). Notably, 46% of controlled RA patients exhibited subclinical synovitis on MSUS.
Conclusions:
- MSUS stratification of D2T-RA into PIRRA and NIRRA reveals distinct associations with CRP and ESR, and comparable chronic pain levels.
- Subclinical inflammation is detectable even in seemingly controlled RA, indicating a risk of relapse.
- Identifying these RA subphenotypes using MSUS can guide monitoring, mechanistic research, and targeted therapies for improved patient outcomes.
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