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Objective: The PD-1 axis promotes protection against autoimmunity. Immune checkpoint (IC) molecules performance in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unknown. This study aims to assess the IC pathway's role in the AAV's pathophysiology.

Methods: We recruited 88 AAV from our centre as a discovery cohort (acute=42, remission=46) and 30 patients from another institution for external validation (acute=16, remission=14).Serum, urine and peripheral blood mononuclear cells (PBMCs) were collected. In vitro IC molecules production by lymphocytes was studied with and without MPO/PR3 antigen stimulus. Cell culture supernatant (SN) was obtained by centrifugation. PD-1, PD-L1 and PD-L2 concentrations were assessed in serum (s), urine (u) and SN of AAV and healthy controls (HC) using a multiplex assay. PD-1 and PD-L1's expression was analysed in six diagnostic kidney biopsies.

Results: uPD-1 and uPD-L2's concentration was lower in AAV than HC (p<0.0001, p=0.0075). Acute patients exhibited lower uPD-L2 levels compared with those in remission (p=0.036). Similarly, PBMCs showed reduced PD-1 production than HC (stimulated group p=0.04, unstimulated p=0.0074). Furthermore, patients with inflammatory renal lesions had fewer PD-1-positive interstitial cells/staining intensity compared with those with sclerotic lesions. Contradictorily, sPD-1 and sPD-L1's concentration was higher in AAV than HC (p=0.007, p<0.0001) with acute patients exhibiting elevated sPD-1 levels compared with those in remission (p=0.0051). Serum and urine findings were confirmed in the validation cohort.

Conclusions: Results in urine, SN and histology suggest IC pathway abolition during acute disease restored in remission and contribute to understand PD-1 axis's role in AAV proposing it as a new biomarker of disease activity.

Background: Conventional radiographs of hands and feet are used to depict structural damage in rheumatoid arthritis (RA). This is also commonly done in clinical practice in symptomatic patients at risk for RA (clinically suspect arthralgia (CSA)), but its rationale is unclear. We aimed to investigate the prevalence of radiographic erosive disease in patients with CSA and its progression over time.

Methods: Patients with symptomatic arthralgia of the Leiden CSA cohort were studied during 2-year follow-up or until development of inflammatory arthritis (IA). Erosive disease was defined according to the radiologist, or according to the RA-specific erosive definition in light of the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2010 RA criteria. Serial radiographs were evaluated according to the Sharp van der Heijde Scoring method (SHS) and radiographic erosive progression was determined. Additionally, it was evaluated if baseline erosive disease associated with IA development. Analyses were stratified for anticitrullinated protein antibody status.

Results: 1497 radiographs of hands and feet of 749 patients with CSA were studied. Median SHS-erosion score at baseline was 0 (IQR 0-1). RA-specific erosive disease was present in 1.7% according to the radiologist, and 2.5% according to the ACR/EULAR criteria. No patients with CSA progressed ≥5 SHS-erosion points during follow-up. Erosive disease at CSA onset was not associated with IA development (HR 0.98 (95% CI 0.40 to 2.44)).

Conclusions: At CSA onset, radiographic erosive disease is rare. In addition, it is rarely progressive within the CSA phase and not predictive for IA development. Therefore, for clinical practice, routinely made radiographs of hands and feet (such as regularly done at RA diagnosis) can be omitted in the at-risk stage of arthralgia.

Objectives: Secondary prevention of rheumatoid arthritis (RA) is generally considered potentially impactful because the entire RA population is believed to experience a symptomatic 'pre-RA' phase. We wondered whether this dogma is correct. Therefore we investigated an inception cohort of patients with newly diagnosed RA and studied among them patients who did and did not present with preceding arthralgia at risk for RA.

Methods: Consecutively diagnosed patients with RA between 2012 and 2022 were studied (n=699). These patients had either directly presented with clinically apparent arthritis, or had first presented with clinically suspect arthralgia (CSA). Clinical characteristics at symptom onset and RA diagnosis were compared. Whether certain characteristics frequently occurred together was studied using a K-means algorithm after dimension reduction with partial least squares discriminant analysis. To validate that groups differed in long-term outcomes, sustained disease-modifying anti-rheumatic drug-free remission (SDFR) of the groups was studied during a median follow-up of 5.3 years.

Results: Patients with RA who had first presented with CSA were younger, more often had a gradual symptom onset and were more often anti-citrullinated protein antibodies (ACPA)-positive. Studying characteristics at symptom onset and RA diagnosis revealed four patient clusters, of which two clusters included almost all patients with a preceding CSA phase. Patients in these two clusters (55% of RA population) were younger, had a gradual symptom onset, longer symptom duration and were more frequently ACPA-positive. Patients with RA in these clusters achieved SDFR less often (HR 0.51 (95% CI 0.37 to 0.68)) than the patients with RA in the two clusters where preceding CSA was infrequent/absent.

Conclusion: These data suggest the notion that the entire RA population has an identifiable symptomatic risk stage should be refuted. This may impact on the scope of preventive interventions targeting the symptomatic risk phase.

Immunoglobulin 4-related disease (IgG4-RD) is known for its potential to affect nearly every organ, particularly a preference for large and middle-sized arteries when vascular involvement occurs. However, instances of splenic artery aneurysms are exceedingly rare with only two cases reported in the literature. We have summarised the clinical manifestations and laboratory characteristics of the three patients we reported along with the two patients previously reported. It is noteworthy that all five patients had involvement of the salivary glands and only one patient had other arterial involvement. The three patients we reported had no new organ onset or worsening of existing organ involvement and normal or not significantly elevated serum IgG4 levels when the artery aneurysm was identified. These aneurysms may be the result of vascular damage from prior involvement that was not recognised previously. The cases we reported here highlight a potential association between IgG4-RD and concurrent splenic artery aneurysms.

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.