ANA-associated arthritis: clinical and biomarker characterization of a population for basket trials
Jack Arnold1,2, Lucy M Carter1,2, Md Yuzaiful Md Yusof1,2
1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
Objectives:
ANA-associated rheumatic and musculoskeletal (MSK) diseases (RMDs) [SLE, primary SS (pSS), scleroderma, inflammatory myositis, MCTD and UCTD] make up a disease spectrum with overlapping clinical and immunological features. MSK inflammation is common and impactful across ANA-associated RMDs. The objectives of this study were to evaluate MSK inflammation (ANA-associated arthritis) prevalence in a multidisease ANA-associated RMD study, assess its clinical impact across ANA-associated RMD diagnoses, propose new basket groupings of patients, and evaluate immunological profiles in legacy and new basket contexts.
Methods:
An observational study enrolled patients with ANA-associated RMDs. Demographic variables, comorbidities, therapies, disease activity instruments [BILAG, SLEDAI, the EULAR SS disease activity index (ESSDAI), physician visual analogue scale (VAS)], patient-reported outcomes [SF36, FACIT-Fatigue, EQ5D, ICECAP-A, Work Productivity and Activity impairment (WPAI), patient VAS] and the biomarker profile (six-gene expression scores, flow cytometry, autoantibody profile) were analysed. Reclustering utilized Gaussian mixture modelling (GMM). The clinical and immune features of new and legacy clusters were compared.
Results:
Inflammatory MSK symptoms were prevalent across ANA-associated RMDs, in 213/294 patients. In ANA-associated arthritis patients, most variables did not differ between diagnoses, with the exception of the EQ5D-5L index and mobility domains (lower in MCTD/pSS, both P < 0.05). FM and OA prevalence were similar across diagnoses. Therapy use differed significantly, the use of biologics being greatest in SLE (P < 0.05). GMM yielded two multidisease clusters: High MSK disease activity (n = 89) and low MSK disease activity (n = 124). The high MSK disease activity cluster included all patients with active joint swelling, and they had significantly higher prednisolone usage, physician global assessment (PGA), Sm/RNP/SmRNP/chromatin positivity, Tetherin mean fluorescence intensity (MFI), and IFN Score-A activity, along with numerically lower FM and OA prevalence.
Conclusion:
We defined ANA-associated arthritis, a more clinically and immunologically homogeneous population than existing RMD populations for trials, and a more prevalent population for therapies in the clinic.
Insights
This study found that musculoskeletal inflammation is common in ANA-associated rheumatic diseases. Defining ANA-associated arthritis created a more homogeneous patient group for clinical trials and therapies.
Area of Science:
- Rheumatology and Immunology
- Autoimmune Diseases
- Musculoskeletal Health
Background:
- Antinuclear antibody (ANA)-associated rheumatic and musculoskeletal diseases (RMDs) encompass a spectrum including SLE, primary SS, scleroderma, inflammatory myositis, MCTD, and UCTD.
- Musculoskeletal (MSK) inflammation is a frequent and significant issue across these ANA-associated RMDs.
Purpose of the Study:
- To determine the prevalence of MSK inflammation, termed ANA-associated arthritis, within a diverse group of ANA-associated RMD patients.
- To assess the clinical impact of MSK inflammation across different ANA-associated RMD diagnoses.
- To propose novel patient groupings (basket groupings) and analyze their immunological profiles.
Main Methods:
- An observational study collected demographic data, comorbidities, therapies, disease activity scores (BILAG, SLEDAI, ESSDAI, VAS), patient-reported outcomes (SF36, FACIT-Fatigue, EQ5D, ICECAP-A, WPAI, VAS), and biomarker profiles (gene expression, flow cytometry, autoantibodies).
- Gaussian mixture modeling (GMM) was used for patient reclustering.
- Clinical and immune features of existing and newly defined patient clusters were compared.
Main Results:
- Inflammatory MSK symptoms were present in 213 out of 294 patients across ANA-associated RMDs.
- In patients with ANA-associated arthritis, most clinical variables were similar across diagnoses, except for EQ5D-5L index and mobility, which were lower in MCTD/pSS.
- GMM identified two clusters: High MSK disease activity (n=89) and low MSK disease activity (n=124). The high activity cluster showed more active joint swelling, higher prednisolone use, greater PGA, and specific autoantibody/biomarker positivity.
Conclusions:
- ANA-associated arthritis represents a more clinically and immunologically homogeneous patient population compared to existing RMD classifications.
- This defined group is more prevalent and suitable for clinical trials and therapeutic development.
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