RMD Open最新文献

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by the synovitis and bone erosion. The combination therapy of glucocorticoids (GCs) and methotrexate (MTX) is recommended in early RA management, although the precise underlying mechanism of action remains unclear. This study is aimed to clarify the mechanism of MTX in combined with GC in treating RA.

Methods: GC-induced osteoporosis (GIOP) mouse model was used to investigate the bone-protective role of MTX. Lipopolysaccharide-induced arthritis mouse model was used to evaluate the anti-inflammatory effects of GCs and MTX. Functional role of MTX on osteoclastogenesis was assessed by trap staining and micro-computer tomography. Western blot, RT-qPCR and coimmunoprecipitation were used to explore the underlying mechanisms.

Results: We demonstrate that GCs, but not MTX, rapidly inhibited synovitis in arthritis model. MTX treatment was observed to inhibit osteoclastogenesis induced by GC in vitro and mitigate bone loss attributed by GIOP. GCs were found to augment the interaction between the membrane GC receptor (mGR) and signal transducer and activator of transcription 1 (STAT1), leading to the suppression of IFN-γR/STAT1 signalling pathways. Interestingly, MTX was found to inhibit osteoclastogenesis induced by GCs through the enhancement of the A2AR and IFN-γR interaction, thereby activating the IFN-γR/STAT1 signalling cascade. Consequently, this process results in a reduction in the mGR and STAT1 interaction.

Conclusions: Our study provides compelling evidence that MTX can make GCs effectively to suppress synovitis and reduce bone loss induced by GCs. This sheds light on the potential mechanistic insights underlying the efficacy of GCs in conjunction with MTX for treating RA.

Objectives: To evaluate the impact of using Simplified Disease Activity Index (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 eight randomised controlled trials was performed. Four definitions of the target were considered at 6 months: (1) SDAI-LDA: SDAI≤11; (2) SDAI-Remission: SDAI≤3.3; (3) 4V-Remission: Tender and swollen 28-joint counts and C reactive protein (mg/dL) all ≤1 and patient global assessment (PGA)≤2 and (4) 3-variable (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 rates (defined as a change of ≤0.5 units mTSS) over 2 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

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 49%, with 13% in SDAI-remission. The 4V-Remission and 3V-Remission were achieved by 16% and 23%, 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-Remission and 3V-Remission states, respectively. Patients with SDAI Pure-LDA presented significantly more radiographic progression than patients in SDAI-Remission (mean 0.72 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 2 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 2 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.

Objectives: Chronic kidney disease (CKD) is a comorbidity in psoriatic arthritis (PsA). We aimed to define the prevalence of CKD in patients with PsA, describe their long-term renal outcomes and identify risk factors for CKD development.

Methods: We included patients with PsA followed by our prospective observational cohort. We defined CKD as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² for at least 3 months. We characterised long-term renal outcomes of CKD cases identified following clinic entry. We used time-dependent Cox regression models to identify factors associated with CKD development.

Results: Of 1336 patients included in the study, 123 (9.2%) had CKD. Of these, 25 (20.3%) were observed to have CKD at clinic entry and 98 (79.7%) developed CKD during follow-up at a median (IQR) of 8.2 (2.8-14.0) years from baseline. Doubling of baseline creatinine was observed in 18 of 98 (18.3%) new patients with CKD. 49 (50%) patients developed a sustained ≥40% reduction in baseline eGFR. Two patients developed eGFR <15 mL/min/1.73 m². In the multivariate Cox regression model adjusted for age at study entry, sex and baseline eGFR, factors independently associated with the development of CKD included diabetes mellitus (HR 2.58, p<0.001), kidney stones (HR 2.14, p=0.01), radiographic damaged joint count (HR 1.02, p=0.02), uric acid (HR 1.21, p<0.001; 50-unit increase), daily use of non-steroidal anti-inflammatory drugs (NSAIDs) (HR 1.77, p=0.02) and methotrexate use (HR 0.51, p=0.01).

Conclusion: CKD is not infrequent in PsA. Its development is associated with related comorbidities, joint damage and NSAID use. Methotrexate seems to be protective.

Objectives: To re-evaluate cut-offs for disease activity states according to the Axial Spondyloarthritis Disease Activity Score (ASDAS), and study the impact of sex, age, calendar time, disease and symptom duration on ASDAS and ASDAS cut-offs in a large contemporary cohort.

Methods: Data from 2939 patients with axial spondyloarthritis (axSpA) starting their first tumour necrosis factor inhibitor in nine European registries were pooled and analysed. Receiver operating characteristic analyses were performed to identify cut-offs against external criteria. Six-month data including patient and physician global assessments, both ≤1 (0-10 integer scale), and Assessment of SpondyloArthritis International Society partial remission were used for separation of inactive disease (ID) from low disease activity (LDA), while patient and physician global ≤3 were applied as external criteria to separate LDA from high disease activity (HDA). Patient and physician global ≥6 were applied to separate HDA from very high disease activity in baseline data.

Results: The three ASDAS cut-offs identified to separate the four disease activity states in the overall patient population were <1.3, <2.0 and >3.5. Cut-offs for ID and LDA in women were higher (<1.5 and <2.0, respectively) than in men (<1.3 and <1.9), as were cut-offs in patients ≥45 years (<1.5 and <2.2) versus ≤34 years (<1.2 and <1.9) and 35-44 years (<1.3 and <1.8). Cut-offs were independent of calendar time and disease duration.

Conclusions: Re-evaluation of ASDAS cut-offs for disease activity states in a large multi-national axSpA cohort resulted in cut-offs similar to those currently endorsed. Differences in cut-offs between sex and age groups for ID and LDA were observed, but the differences were minor.

Objective: To investigate the association between musculoskeletal sonographic features and clinical features, as well as treatment outcomes, in patients with active psoriatic arthritis (PsA).

Methods: A prospective cohort study was conducted involving patients with active PsA. Disease activity was assessed clinically at baseline and 3-6 months after initiating therapy, with a Disease Activity Index for PsA (DAPSA) score calculated. A baseline ultrasound examination of 64 joints, 28 tendons and 16 entheses evaluated the following lesions: synovitis, peritenonitis, enthesitis, tenosynovitis, new bone formation and erosions. Total scores for each lesion and total inflammatory and structural scores were calculated. The association between baseline sonographic scores and treatment outcomes was assessed using Cox proportional hazards models (for drug persistence) and generalised estimating equation models for DAPSA change.

Results: A total of 135 treatment periods (107 patients) were analysed. Multivariable analysis showed that a greater reduction in DAPSA score at follow-up was associated with higher baseline synovitis (β -3.89), peritenonitis (β -3.93) and enthesitis structural scores (β -2.91). Additionally, the total inflammatory score independently predicted DAPSA change (β -5.23) regardless of the total structural damage score. Drug persistence was analysed in 105 treatment periods, revealing that a higher sonographic erosion score was associated with earlier drug discontinuation (adjusted HR 1.28, 95% CI 1.03 to 1.61).

Conclusion: The study results provide preliminary evidence supporting the utility of musculoskeletal ultrasound in predicting treatment response and drug persistence in PsA.

Background: In many patients with axial spondyloarthritis (axSpA), pain persists despite anti-inflammatory medication. Quantitative sensory testing (QST) indirectly assesses altered somatosensory function, though its clinical practicality is limited. The Central Sensitisation Inventory (CSI) could be an alternative in the initial assessment of central sensitisation (CS). This study aimed to investigate the value of the CSI in evaluating CS in patients with axSpA by (1) assessing somatosensory function related to CS with QST and (2) exploring associations between CSI, QST, patient and disease characteristics and pain-related psychosocial factors.

Methods: Consecutive outpatients from the Groningen Leeuwarden AxSpA cohort underwent QST, including pressure pain threshold (PPT), temporal summation (TS) and conditioned pain modulation (CPM). Participants completed questionnaires assessing CS (CSI), illness perception (Revised Illness Perception Questionnaire, IPQ-R), pain-related worrying (Pain Catastrophising Scale, PCS), fatigue (Modified Fatigue Impact Scale, MFIS), anxiety/depression (Hospital Anxiety and Depression Scale, HADS) and coping. QST measurements were stratified for CSI≥40.

Results: 201 patients with axSpA were included; 63% male, 64% radiographic axSpA, median symptom duration 12 years (IQR 5-24), mean Axial Spondyloarthritis Disease Activity Score 2.1±1.0. Patients with CSI≥40 had significantly lower PPTs and higher TS than CSI<40 (p<0.004). No significant differences in CPM were observed. In multivariable linear regression, sex, PCS, IPQ-R Identity, MFIS and HADS anxiety were independently associated with CSI (78% explained variance).

Conclusion: In this large cross-sectional study in patients with axSpA, the CSI appears as a useful initial CS assessment questionnaire. When CSI scores indicate CS, considering pain-related psychosocial factors is important. These results emphasise the need for a biopsychosocial approach to manage chronic pain in patients with axSpA.

Objective: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different biologic therapies affect levels of PON1 and oxylipins.

Methods: 1213 adult patients with RA in the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions cohort study with moderate-to-high disease activity (Clinical Disease Activity Index (CDAI) >10) who initiated a new biologic (tocilizumab (TCZ), n=296; abatacept, n=374; tumour necrosis factor inhibitors, n=427; rituximab, n=116) were followed prospectively with serum specimens analysed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and PON assays at baseline and after 6 months of biologic therapy. A targeted panel of oxylipins was evaluated by liquid chromatography-mass spectrometry/mass spectrometry in a subset of patients with the lowest and highest 6-month Disease Activity Score 28 (DAS28)-C reactive protein (CRP) responses in each treatment group.

Results: PON1 activity generally increased in the entire cohort after 6 months of new biologic therapy, showing the greatest, most consistent increases in the TCZ group. Increases in all three PON1 domains associated with significant decreases in disease activity in DAS28-CRP/CDAI (p<0.05), and increases in LAC/ARYL were significantly associated with the American College of Rheumatology 20/50/70 responses (OR (95% CI) of 1.12 (1.04, 1.22) and 1.13 (1.04, 1.23), p<0.01, respectively), after controlling for other RA disease characteristics. Some oxylipins, including 12-hydroxyeicosatetraenoic acid correlated with RA disease activity measures.

Conclusion: Improvement in disease activity across four classes of biologics is associated with enhanced PON1 activity, which has significant implications for cardiovascular safety.

Objective: To compare spinal symptoms and spinal/hip mobility at baseline and 2 years in early axial spondyloarthritis (axSpA) and non-axSpA chronic back pain (BP) patients.

Methods: Baseline and 2 years data of the SPondyloarthritis Caught Early cohort were analysed. Outcomes assessed: overall BP, BP at night, morning stiffness (MS) intensity, MS duration, occiput-to-wall distance (OWD), cervical rotation, chest expansion, lateral spinal flexion (LSF), modified Schober test (mSchober), intermalleolar distance (IMD) and Bath Ankylosing Spondylitis Metrology Index (BASMI). Linear or zero-inflated negative binomial regression was used to compare 2 years outcomes between groups (adjusting for baseline value, sex, age and use of non-steroidal anti-inflammatory drugs).

Results: There were 294 axSpA and 123 non-axSpA patients (mean symptom duration: 13 months). At baseline, non-axSpA patients had worse symptoms and mobility, except OWD (eg, mean(SD): BP at night 3.6 (2.9) axSpA vs 4.6 (2.7) non-axSpA; OWD 0.5 (1.2) vs 0.1 (0.7)). After 2 years, all symptoms and cervical rotation significantly improved in both groups, but LSF and mSchober only in axSpA. In multivariable analyses, axSpA was associated with larger improvements in BP at night (β (95% CI): -0.85 (-1.47; -0.23)), mSchober (0.26 (0.03; 0.50)), IMD (4.86 (1.93; 7.80)) and BASMI (-0.24 (-0.41; -0.08)), and with lower likelihood of a normal OWD (OR (95% CI): 0.09 (0.01; 0.83)).

Conclusion: Over 2 years, all spinal symptoms and some mobility measures improved in both groups, but impairments remained prevalent (particularly in non-axSpA). Nevertheless, axSpA was associated with larger improvements in BP at night, mSchober, IMD and BASMI, but with more OWD impairment.

Background: Janus kinase inhibitors are an effective option for achieving sustained remission or low disease activity in patients with rheumatoid arthritis (RA) following inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs. Filgotinib is a Janus kinase 1-preferential inhibitor available in two doses for moderate-to-severe RA. We report the long-term efficacy and safety of filgotinib.

Methods: In the ongoing long-term extension study FINCH 4 (NCT03025308), patients continue filgotinib 200 mg or 100 mg from FINCH 1, 2 or 3 or receive filgotinib 200 mg or 100 mg de novo. Efficacy assessments up to week 156 include American College of Rheumatology 20% response (ACR20), Disease Activity Score 28 using C-reactive protein of <2.6, Clinical Disease Activity Index of ≤2.8, Simplified Disease Activity Index of ≤3.3 and Boolean remission (1.0 and 2.0) with non-responder imputation.

Results: In patients with an inadequate response to methotrexate, 60.2% and 54.6% receiving de novo filgotinib 200 mg and 100 mg had an ACR20 at week 156, respectively, as did 67.3% and 59.5% of those who continued filgotinib 200 mg and 100 mg. At week 156, Boolean remission 1.0 was achieved by 18.8% and 15.4% of patients treated with de novo filgotinib 200 mg and 100 mg, respectively, and by 21.1% and 18.5% when Boolean 2.0 criteria were applied. Similar efficacy data were seen in patients from FINCH 2 and 3. Safety data were consistent with the known safety profile of filgotinib.

Conclusion: In FINCH 4, filgotinib 200 mg and 100 mg (continuous or de novo) demonstrated sustained efficacy up to week 156 in patients enrolled from FINCH 1, 2 or 3, with no unexpected safety results.

Background: The modified Short QUestionnaire to ASsess Health-enhancing physical activity (mSQUASH) was originally developed and validated in Dutch patients with axial spondyloarthritis (axSpA). To support world-wide distribution, applicability and comparability of measuring physical activity, our aim was to perform translation and cross-cultural adaptation of the mSQUASH into English, field testing in other rheumatic diseases and clinical validation in patients with axSpA.

Methods: The Dutch mSQUASH was translated into English according to forward-backward Beaton protocol. Semistructured interviews were conducted in representative samples of patients with axSpA (n=13), Sjögren's disease (n=10), systemic lupus erythematosus (n=10) and giant cell arteritis/polymyalgia rheumatica (n=10) to verify relevance, comprehensiveness and comprehensibility. For construct validity (n=95), Spearman correlations were used with clinical outcome assessments. For test-retest reliability (n=82), intraclass correlation coefficients (ICC) were calculated. For responsiveness (n=80), standardised response means (SRM) were calculated stratified by Anchor method.

Results: Translation and cross-cultural adaptation of the mSQUASH into English were successfully carried out, which can serve as basis for other translations. Only minor adaptations and clarifications were implemented. Fair correlations were found between mSQUASH and Axial Spondyloarthritis Disease Activity Score (ρ=-0.31), Bath Ankylosing Spondylitis Functional Index (ρ=-0.37) and Assessment of SpondyloArthritis International Society-Health Index (ρ=-0.30). Test-retest reliability was very good (ICC: 0.87). Responsiveness corresponded to the direction of self-reported changes in physical activity (SRM: 0.72 for improved, 0.06 for stable and -0.74 for worsened).

Conclusion: The mSQUASH showed good linguistic and face validity according to field testing in different rheumatic diseases. Clinical validation confirmed good construct validity, test-retest reliability and responsiveness in patients with axSpA, which supports the use of the mSQUASH in clinical practice and research.