RMD Open最新文献

Objective: Previous technical limitations prevented the proof of Fcγ-receptor (FcγR)-activation by soluble immune complexes (sICs) in patients. FcγRIIIa (CD16) is a risk factor in rheumatoid arthritis (RA). We aimed at determining the presence of CD16-activating sICs in RA and control diseases.

Methods: Sera from an exploratory cohort (n=50 patients with RA) and a validation cohort (n=106 patients with RA, 20 patients with psoriasis arthritis (PsA), 22 patients with systemic lupus erythematosus (SLE) and 31 healthy controls) were analysed using a new reporter cell assay. Additionally, 26 synovial fluid samples were analysed, including paired serum/synovial samples.

Results: For the first time using a reliable and sensitive functional assay, the presence of sICs in RA sera was confirmed. sICs possess an intrinsic capacity to activate CD16 and can be found in both synovial fluid and in blood. In low experimental dilutions, circulating sICs were also detected in a subset of healthy people and in PsA. However, we report a significantly increased frequency of bioactive circulating sICs in RA. While the bioactivity of circulating sICs was low and did not correlate with clinical parameters, synovial sICs were highly bioactive and correlated with serum autoantibody levels. Receiver operator curves indicated that sICs bioactivity in synovial fluid could be used to discriminate immune complex-associated arthritis from non-associated forms. Finally, circulating sICs were more frequently found in SLE than in RA. The degree of CD16 bioactivity showed strong donor-dependent differences, especially in SLE.

Conclusions: RA is characterised by the presence of circulating and synovial sICs that can engage and activate CD16.

Introduction: The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren's disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD.

Material and methods: Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis.

Results: BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3⁺ regulatory and CD3⁺CD4^-CD8^- double negative T-cell numbers in SGs.

Conclusion: A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. The increase in regulatory T-lymphocyte populations might underlie the efficacy of this treatment.

Objectives: This study aimed to evaluate the long-term safety and efficacy profiles of ozoralizumab in patients with rheumatoid arthritis (RA) from the OHZORA, NATSUZORA and HOSHIZORA trials.

Methods: This study conducted an integrated analysis of the three trials. Patients who completed the OHZORA trial with concomitant treatment of ozoralizumab and methotrexate (MTX) or the NATSUZORA trial without MTX were eligible to participate in the long-term extension HOSHIZORA trial. Safety assessment was performed in the safety analysis set, and the incidence rate per 100 person-year (PY) was calculated for a summary of adverse events (AEs) and AEs of special interests (AESIs). The efficacy was analysed in terms of disease activity index response rates and functional remission.

Results: The OHZORA and NATSUZORA trials enrolled 521 patients, of whom 401 patients entered the HOSHIZORA trial and 279 completed the long-term extension treatment with a mean treatment duration of 200 weeks and total exposure of 1419.34 PY in all enrolled patients. Of the patients, 96.9% demonstrated ≥1 AEs, which is mostly mild to moderate. One death was observed, but no conspicuous AEs emerged and no specific concerns in AESIs were found through the long-term administration. The efficacy assessment revealed the maintained American College of Rheumatology response rates of 20%, 50%, and 70% during the trials.

Conclusion: This integrated analysis revealed no new safety concerns, and the efficacy was maintained in patients with RA under long-term ozoralizumab administration.

Trial registration number: jRCT2080223971, jRCT2080223973, NCT04077567.

Background: MicroRNAs (miRNAs) can regulate gene expression, controlling numerous cellular processes. Dysregulation of miRNA function is linked to various diseases, making them attractive diagnostic and therapeutic targets. Examples include hsa-miR-92a-3p, hsa-miR-126-3p, hsa-miR-143-3p, hsa-miR-145-5p and hsa-miR-204-5p, which are associated with endothelial function. Their prevalence in Sjögren's disease (SjD) is unknown. We assessed the prevalence of these miRNAs in serum of patients with SjD, correlating levels with cardiovascular risk factors and carotid intima-media thickness (cIMT) to evaluate their utility in risk stratification.

Methods: 199 patients with SjD and 100 age and sex-matched healthy controls (HC) were included in the study. Five different miRNAs (hsa-miR-92a-3p; hsa-miR-126-3p; hsa-miR143-3p; hsa-miR-145-5p; hsa-miR-204-5p) were analysed by quantitative real-time PCR. The miRNA results were compared with known clinical and disease-related parameters.

Results: Four miRNAs showed significantly different expressions compared with HC. MiR-92a-3p was upregulated (p=0.025) and miR-126-3p (p=0.044), miR-143-3p (p=0.006) and miR-204-5p (p=0.009) downregulated in SjD compared with HC. The comparison between HC and SjD with/without organ involvement revealed descriptively increased miR-92a-3p levels in patients with SjD with organ involvement (p=0.087). Furthermore, miR-92a-3p levels correlated positively with cIMT as an expression of subclinical atherosclerosis (r=0.148, p=0.04).

Conclusion: In conclusion, patients with SjD demonstrated differences in their expression of miRNAs linked to regulation of endothelial function. Reduction of specific miRNAs was associated with increased cardiovascular risk, suggesting a potentially protective role for these miRNAs. Furthermore, miR-92a-3p could be helpful for molecular detection of early-stage atherosclerosis and increased cardiovascular risk in SjD.

Objective: Rheumatoid arthritis (RA) is characterised by the presence of autoantibodies, among which those targeting the constant region of immunoglobulin G (IgG), called rheumatoid factors (RF). Despite this link, RFs can also be found in other disorders and the healthy population, which hampers its use as a diagnostic tool. We recently showed that a subset of RA-derived RFs target a distinct epitope on the IgG-Fc, a feature that is currently not used in the clinic.

Methods: We determined immunoglobulin M (IgM)-RF levels specific against an RA-associated epitope (using our engineered next-generation RF antigen 'T3-17') in a prospective cohort of 475 patients with seropositive (for IgM-RF or aCCP) arthralgia that were followed for 5 years or until the development of arthritis.

Results: The presence of RFs targeting T3-17 was more strongly associated with progression to arthritis in comparison to traditional RF measurements. Within the group of patients positive for T3-17 RF the risk of arthritis development was increased as compared with wild-type RF, HR=3.2 (95% CI 2.4 to 4.3) vs HR=2.2 (95% CI 1.7 to 3.0). Predictive power of T3-17 RF was improved in combination with aCCP titres, HR=6.4 (4.7-8.7) vs HR=5.1 (3.9-6.8). This combination performed better than aCCP detection on its own.

Conclusion: The detection of disease-specific RF is feasible and seems to improve the diagnostic power of RF and should be considered to be implemented in the clinic.

Objectives: Rheumatoid arthritis (RA) is associated with an increased risk for osteoporosis and osteoporotic fractures. Since the treatment of RA has improved significantly in recent years, we can expect RA-associated osteoporosis to decrease with good disease control. Therefore, we conducted a retrospective study to investigate whether the frequency of osteoporosis and osteoporotic fractures has changed during 24 years in RA.

Methods: We analysed the data of 1.086 RA patients from the time of the first osteological assessment with bone mineral density (BMD) measurement and collection of osteologically important data during the years 1996 and 2019 at our clinic. According to the treatment period, the patients were divided into cohort 1 (investigation between 1996 and 2004; n=539) and cohort 2 (investigation between 2005 and 2019; n=547). The data of the two cohorts were compared, and predictors of BMD were analysed by linear regression analysis.

Results: Prevalence of osteoporosis (28.3% vs 48.4%; p<0.001) as well as osteoporotic peripheral fractures (11.5% vs 21%; p<0.001) and vertebral fractures (6.6% vs 10.9%; p=0.011) were significantly lower and treatment with biologicals (19.7% vs 5.0%; p<0.001) significantly more common and glucocorticoid use was significantly less common (p=0.005) in cohort 2. In RA patients with a disease duration of more than 2 years, BMD was significantly higher under treatment with biologicals (p<0.001) despite increased cumulative glucocorticoid dosages (p<0.001).

Conclusion: Our study showed a significant decline in osteoporosis and osteoporotic fractures in RA for 24 years. This positive effect is associated with the more frequent use of biologicals in the years between 2005 and 2019.

Objectives: The objectives of this study are to study the risk of developing cardiac arrhythmia and its subtypes over time in patients with systemic sclerosis (SSc), to assess potential risk factors for arrhythmia in SSc and to explore whether arrhythmia is associated with mortality.

Methods: We used nationwide Swedish registers to identify patients with incident SSc 2004-2019 and matched general population comparators (1:10). The primary outcome was incident arrhythmia. Follow-up started at the date of SSc diagnosis and ended at the primary outcome, death, emigration or 31 December 2019. We estimated the incidence of arrhythmia overall and stratified by subtype and explored the relative risk in relation to time since diagnosis using flexible parametric models. We used Cox regression to study risk factors for arrhythmia and the association of arrhythmia with mortality.

Results: We identified 1565 patients and 16 009 comparators. The overall incidence of arrhythmia was 255 (95% CI 221 to 295) and 119 (95% CI 112 to 127) per 10 000 person years in patients with SSc and comparators, respectively, corresponding to an IRR of 2.1 (95% CI 1.8 to 2.5). The greatest hazard difference between patients with SSc compared with the comparators was seen in the first year of follow-up (HR for arrhythmia 3.0; 95% CI 2.3 to 3.8). Atrial fibrillation and flutter were the most common arrhythmia subtypes. Male sex, index age and pulmonary arterial hypertension were significant risk factors for arrhythmia in SSc. Incident arrhythmia was significantly associated with mortality (HR 2.2; 95% CI 1.6 to 3.0).

Conclusion: SSc is associated with higher incidence of cardiac arrhythmia compared with general population. Arrhythmia seems to be an early manifestation of SSc and is associated with higher mortality.

Objectives: To compare the sensitivity of 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria against 1997 ACR criteria for systemic lupus erythematosus (SLE), for incident SLE cases in the presumably complete population-based Nor-SLE cohort from Southeast Norway (2.9 million inhabitants).

Methods: All cases International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coded as SLE during 2000-2017 were individually reviewed. Those with a confirmed SLE diagnosis by expert clinical assessment were included in the Nor-SLE cohort. Core clinical data were recorded, and the cases were classified according to 2019 EULAR/ACR and 1997 ACR criteria. Juvenile SLE was defined as <16 years at diagnosis and adult SLE was defined as ≥16 years at diagnosis.

Results: We included 737 incident SLE cases (701 adults, 36 juveniles). At diagnosis, 2019 EULAR/ACR criteria were more sensitive than 1997 ACR criteria for adults (91.6% vs 77.3%; p<0.001), but not for juveniles (97.2% vs 88.9%). The 2019 EULAR/ACR counts at diagnosis differed by age group and ethnicity, being higher in young cases and those originating from Asia. From time of diagnosis to study end the fulfilment rate of 2019 EULAR/ACR criteria for the adult cohort increased from 92.5% and 86.5% to 94.6% and 91.0%, respectively, for females and males (mean disease duration of 7.5 years).

Conclusion: Showing 92% criteria fulfilment already at time of SLE diagnosis by 2019 EULAR/ACR criteria versus 77% by 1997 ACR criteria, the results from this population-based study suggest that the 2019 EULAR/ACR criteria will achieve its goal of capturing more early-SLE cases for clinical trials.

Objective: Previous research has identified that gout impacts various domains of daily life. However, there have been no qualitative studies focusing on employment. This study aimed to understand the impact of gout on employment.

Methods: Semistructured interviews were conducted in Spain and Aotearoa/New Zealand, in people with gout (according to the 2015 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria) who had experienced a gout flare during their employment. The interviews were guided by questions exploring the impact on employment, job changes, disclosure and co-workers' reactions. Data were analysed thematically.

Results: Eighteen participants were interviewed (89% male, mean age 52.9 years). Six themes were identified. The characteristics of the disease (pain intensity, tophi and joints affected) and the job itself (including physical job requirement and workplace flexibility) determined the experience of working with gout. The experiences were divided into physical (from total incapacity to working despite pain), emotional (feeling responsible, embarrassment, guilt and depression) and social (including disclosure responses and financial impact). Gout management strategies including rapid gout flare management and urate-lowering therapy reduced the number of flares and the intensity of pain, and allowed work attendance and participation.

Conclusion: Both gout and work characteristics influence the employment experience for people with gout. Effective management of gout led to improved work experiences in all its domains.

Objectives: The aim of this study was to assess the histopathological features of the parotid glands in patients with paediatric-onset Sjögren's disease (pedSjD) in comparison to patients with adult-onset Sjögren's disease (adSjD).

Methods: This study was performed in Groningen, the Netherlands. Patients with pedSjD from a diagnostic paediatric cohort (n=19), patients with adSjD from a diagnostic adult cohort (n=32) and patients with adSjD who participated in a clinical trial (n=42) with a baseline parotid gland biopsy were included. Parotid gland biopsies were analysed after (immuno)histological staining for SjD-related histopathological markers and compared between groups.

Results: All characteristic histopathological features of adSjD were also observed in pedSjD. There were no significant differences in lymphoepithelial lesions or immunoglobulin A (IgA)/IgG plasma cell shift between the pedSjD and the adSjD cohorts. However, compared with the diagnostic adSjD cohort (with comparable total EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scores), pedSjD showed more severe lymphocytic infiltration as reflected by a higher focus score (p=0.003), a higher relative surface area of CD45+ infiltrate (p=0.041), higher numbers of B and T lymphocytes/mm² (p=0.004 and p=0.029, respectively), a higher B/T lymphocyte ratio (p=0.013), higher numbers of CD21+ follicular dendritic cell networks/mm² (p=0.029) and germinal centres (GC)/mm² (p=0.002). Compared with the trial adSjD cohort, with significant higher total ESSDAI scores (p=0.001), only the B/T lymphocyte ratio and numbers of GC/mm² were significantly higher in the pedSjD cohort (p=0.023 and p=0.018, respectively).

Conclusion: Patients with pedSjD exhibit more pronounced histopathological features compared with patients with adSjD at diagnosis. Notably, the histopathology of patients with pedSjD aligns more closely with that observed in an adSjD clinical trial cohort, with even stronger B lymphocyte involvement.