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Objectives: Despite the clinical significance of neuropsychiatric systemic lupus erythematosus (NPSLE), which is a severe complication of SLE, clinical and genetic studies on NPSLE remain limited. This study aimed to identify the clinical features of NPSLE and explore genetic factors associated with NPSLE in a prospective lupus cohort.

Methods: The clinical features, disease activity and organ damage of 1205 Korean patients with SLE were assessed at least annually, and genome-wide genotyping with imputation was performed. The clinical and genetic associations of NPSLE, excluding minor events, and its specific subsets (seizure or psychosis) compared with those of non-NPSLE were analysed using genome-wide association studies (GWASs). The biological relevance of the identified loci was investigated through functional analyses.

Results: A total of 271 patients with NPSLE exhibited more clinically diverse manifestations (p=2.40×10^-4), especially in patients with seizure (N=84, p=4.86×10^-14) and psychosis (N=26, p=8.29×10^-5), compared with 934 patients with non-NPSLE. Notably, NPSLE patients significantly had greater organ damage (total Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score: OR 1.49, p=3.28×10^-17; non-NP SDI score: OR 1.22, p=7.61×10^-5) than patients with non-NPSLE, adjusting for age, sex, hypertension, disease duration and antiphospholipid antibodies. GWAS revealed nine NPSLE-associated loci at a suggestive significance level (p<5×10⁻⁶). The nine nearest mapped genes were exclusively expressed in the brain (adjusted p=5.28×10^-4), particularly in the basal ganglia, cortex and hippocampus (adjusted p<0.05).

Conclusions: Neuropsychiatric involvement in SLE increases clinical manifestations and extends organ damage beyond the nervous system, with NPSLE-related genetic variants highlighting their potential functional roles in various brain regions.

Objectives: To evaluate disease evolution, diagnostic transitions, time to biologic treatment initiation and mortality in patients with spondyloarthritis (SpA) after 17 years from the original Spanish Registry of Spondyloarthritis (REGISPONSER).

Methods: Spondyloarthritis Registry 3 (REGISPON-3) is a two-timepoint longitudinal study with patients fulfilling the European Spondyloarthropathy Study Group criteria participating in the REGISPONSER study and re-evaluated after 17 years. Clinical, laboratory, radiological and treatment data were collected and compared with baseline. Diagnostic changes according to the rheumatologist's judgement and their associated factors were analysed using multivariable logistic regression. Time to initiation of biologic therapy was evaluated using Kaplan-Meier survival analysis.

Results: A total of 536 patients from the REGISPONSER study conducted in 2004 were contacted in 2021 for the REGISPON-3 visit. Of these, 411 were physically re-evaluated, while 125 were confirmed deceased. Among the 411 patients, 31.6% experienced a change in diagnosis in the REGISPON-3 visit, mainly from undifferentiated SpA to axial SpA or psoriatic arthritis. In multivariable analysis, dactylitis, younger age and lower Bath Ankylosing Spondylitis Radiology Index scores were associated with diagnostic change. The use of biologic disease-modifying antirheumatic drugs (bDMARDs) increased from 13.1% to 52.1%. However, the median time to first bDMARD from symptom onset was 32 years (95% CI 30 to 35) and 28 years from diagnosis (95% CI 26 to 32). Among the 125 patients who died, the leading causes were infections (21.6%), cardiovascular (CV) events (20.0%) and cancer (19.2%).

Conclusions: This long-term reassessment reveals significant diagnostic changes in SpA and a mortality burden mainly attributed to infections and CV diseases.

Objective: To estimate risk and to identify risk factors for preterm birth in pregnant women with psoriatic arthritis (PsA) in relation to maternal characteristics, treatment and disease activity, both before and during pregnancy.

Methods: We linked clinical rheumatology registers to medical birth registers in Sweden, Denmark and Norway and identified PsA pregnancies and control pregnancies 2006-2021, matched 1:10 on age, parity, country and birth year. Adjusted ORs (aORs) for preterm birth in PsA pregnancies vs control pregnancies were calculated overall and stratified by maternal characteristics, antirheumatic treatment and disease load (9 months before and during pregnancy).

Results: We observed 54 preterm births among 688 PsA pregnancies (7.8%) versus 312 among 6880 control pregnancies (4.5%); aOR, 95% CI: 1.80, 1.29 to 2.51. The risk estimate was largely unaffected by parity, smoking and body mass index. PsA pregnancies exposed to a combination of biologic and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and/or glucocorticoids during pregnancy had a markedly increased risk of preterm birth compared with control pregnancies (4.44, 2.07 to 9.50), whereas exposure to biological DMARD (bDMARD) monotherapy (primarily tumour necrosis factor inhibitors) had not (0.73, 0.22 to 2.42). High disease load before pregnancy was associated with increased risk. The proportion of preterm birth was higher in those stopping bDMARD during the first trimester (21%) opposed to those continuing past the first trimester (10%) based on few events.

Conclusion: We identified an 80% increased risk of preterm birth in PsA pregnancies compared with control pregnancies. Antirheumatic combination therapy during and high disease load before pregnancy constituted risk factors. Discontinuing bDMARD treatment in early pregnancy further increased the risk. Our findings support that a subgroup of PsA pregnancies should be considered high-risk pregnancies.

Objectives: To explore the prevalence and distribution of ultrasound-detected inflammation and structural damage in the joints, tendons and entheses of patients who developed new-onset arthritis or arthralgia following exposure to immune checkpoint inhibitor (ICI) therapy, including a comparison between those with ICI-induced arthritis and those with ICI-induced arthralgia.

Methods: Patients with cancer who developed clinical arthritis or arthralgia (ie, joint pain without clinical synovitis) after receiving ICIs were consecutively recruited from six international centres. Patients underwent a full clinical assessment and ultrasound evaluation of 18 joints, 15 tendons and 5 entheses bilaterally, using the Outcome Measures in Rheumatology definitions.

Results: A total of 101 patients were included: 53 (52.5%) had ICI-arthralgia (absent clinical synovitis). Among them, 25 (47.2%) had ultrasound-detected subclinical synovitis, 10 (18.9%) tenosynovitis, 1 (1.9%) digital extensor peritendinitis and 13 (24.5%) enthesitis. In the 48 patients with ICI-arthritis, ultrasound-detected synovitis was more prevalent than in ICI-arthralgia (93.8% vs 47.2%, p<0.001), particularly in the wrists (56.3% vs 20.8%, p<0.001) and the knees (54.2% vs 13.2%, p<0.001), which were the most frequently affected joints. Tenosynovitis (52.1% vs 18.9%, p<0.001), peritendinitis (10.4% vs 1.9%, p=0.099) and bone erosions (25% vs 7.5%, p=0.027) were also more frequent in ICI-arthritis. 'Active' enthesitis was similar between groups (31.3% vs 24.5%), with no significant differences.

Conclusions: This multicentre study reveals a higher burden of ultrasound-detected changes in ICI-arthritis compared with ICI-arthralgia, with diverse patterns across joints, tendons and entheses in both subtypes. Significant subclinical inflammation suggests that many cases of non-specific ICI-arthralgia may benefit from targeted interventions.

Early data have shown the potential of chimeric antigen receptor (CAR) T-cell therapies to expand the therapeutic landscape in systemic lupus erythematosus (SLE). While many CAR T-cell therapy learnings can be drawn from the experience of this modality in oncology, key questions remain regarding clinical development considerations unique to lupus. To assess and discuss these issues, the Lupus Accelerating Breakthroughs Consortium, a public-private partnership, convened a multi-partner working group to collect the diverse perspectives of academics/clinicians (including rheumatologists and oncologists), industry representatives (including SLE as well as CAR T-cell clinical development experts), regulators and people living with lupus on this potentially ground-breaking therapy. The working group considered the risk/benefit considerations for eligibility criteria in lupus, early-phase dosing and dose-limiting toxicity challenges, incorporation of comparator arms in late-phase registrational trial design, SLE-specific issues in conditioning therapy and immune monitoring and the limitations of SLE pre-clinical models for studying cell therapies. The key future 'calls to action' for the field include the need for well-defined severity/refractoriness-based eligibility criteria, the need for long-term monitoring infrastructure and the need for educational and logistical support for rheumatologists and patients.

Multisystem inflammatory syndrome in children (MIS-C) is a severe SARS-CoV-2-associated condition that shares clinical features with Kawasaki disease (KD), characterised by a distinct polyclonal expansion of Vβ21.3+ T cells. We report five patients diagnosed with breakthrough MIS-C despite COVID-19 immunisation, all within a limited time period at the beginning of the Omicron wave, to assess whether breakthrough MIS-C cases share the same TCR Vβ21.3 skewing seen in non-vaccinated MIS-C cases. We retrospectively reviewed five MIS-C patients hospitalised between December 2021 and April 2022 despite previous immunisation against SARS-CoV-2 (BNT162b2, an mRNA vaccine against S-protein). Immunophenotyping, including TCR Vβ subset distribution, was performed in four patients.Patients (100% male, 12.2-17.2 years) had a natural breakthrough SARS-CoV-2 infection following prior immunisation (between August 2021 and February 2022). Recent infection was proven by positive SARS-CoV-2 PCR and/or IgG antibodies against the nucleocapsid protein. Blood samples of four patients were available. All presented with Vβ21.3+ T cell expansion, similar to MIS-C patients and in contrast to vaccinated historical KD patients (n=10). The two patients with the earliest sampling post-illness displayed frequencies of Vβ21.3+ T cells exceeding the reference mean value+10×SD. These Vβ21.3+ T cells showed increased surface expression of activation (HLA-DR, CD38) and exhaustion (PD-1, TIM-3) markers.In conclusion, breakthrough MIS-C patients presented with features consistent with unvaccinated MIS-C patients, including the hallmark Vβ21.3+ T cell expansion, indicating that prior immunisation with an mRNA vaccine targeting the Wuhan strain did not fully protect against MIS-C at the wave of a novel emerging variant early 2022. Trial registration number: NL41023.018.12.

Objective: Patients with systemic lupus erythematosus (SLE) commonly develop lupus nephritis (LN), the most frequent severe organ manifestation of this systemic autoimmune disease. Using serum and urine samples from a phase 2 trial in LN, we investigated that how the LN metabolome is modulated in response to type I interferon receptor blockade with anifrolumab, an approved treatment for moderate to severe SLE.

Methods: Patients in TULIP-LN (NCT02547922) received standard therapy plus intravenous anifrolumab or placebo. Untargeted metabolomics analysis was performed on serum and urine samples from 128 and 119 patients, respectively. Metabolites impacted by anifrolumab and their associations with clinical, serological and kidney measures of LN disease activity were examined. An in vitro model was used to validate the impact of anifrolumab on metabolite-induced inflammation.

Results: In serum, indoxyl sulfate (IS) and cytosine were the metabolites most modulated by anifrolumab, while baseline levels correlated with measures of kidney damage. In urine, uracil and cytosine were the most modulated by anifrolumab and levels of these metabolites were associated with serological markers of disease activity. Anifrolumab reduced markers of vascular dysfunction and inflammation upregulated by IS in in vitro models. Baseline urine uracil levels predicted response to anifrolumab intensive regimen at Week 52.

Conclusion: Our findings establish a connection between type I interferon signalling, pyrimidine metabolism and uremic toxins in patients with LN and support the evaluation of urine uracil as a potential biomarker of response to anifrolumab.

Background: This study evaluated the efficacy and safety of avacopan versus a prednisone taper in the subgroup of patients with antineutrophil cytoplasmic antibody-associated vasculitis (granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)) receiving cyclophosphamide (CYC) followed by azathioprine (or mycophenolate mofetil) in the ADVOCATE trial.

Methods: Key efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included glucocorticoid toxicity, estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR) and safety.

Results: Of 330 patients receiving study medication, 116 (35.2%) received CYC (avacopan group, n=59; prednisone taper group, n=57). Remission at week 26 and sustained remission at week 52 were achieved by 37/59 (62.7%) and 33/59 (55.9%) patients in the avacopan group and 34/57 (59.6%) and 30/57 (52.6%) in the prednisone taper group, respectively. Over 52 weeks, relapses were observed in 13.0% in the avacopan group and 22.6% in the prednisone taper group. Improvement in eGFR, speed of albuminuria reduction and differences in glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 55.9% and 56.1% of patients in the avacopan and prednisone taper groups, respectively.

Conclusions: This subgroup analysis of patients who received CYC shows similar rates of remission in the avacopan and prednisone taper groups. Compared with the prednisone taper regimen, the avacopan regimen was associated with a numerically lower relapse rate, greater improvement in eGFR, faster reduction in UACR, lower glucocorticoid-related toxicity and similar overall safety. These results support the use of avacopan in combination with CYC to treat GPA or MPA.

Trial registration number: NCT02994927.

Objective: Organ damage is a key determinant of poor prognosis and increased mortality in systemic lupus erythematosus (SLE). However, no validated clinical tools for predicting damage accumulation currently exist. We sought to develop a machine learning-based model to predict early organ damage in patients with SLE.

Methods: Classification criteria (American College of Rheumatology (ACR)-1997, Systemic Lupus International Collaborating Clinics (SLICC)-2012, European League Against Rheumatism (EULAR)/ACR-2019) and non-criteria features of a cohort of 914 patients with SLE were analysed to predict damage (defined as SLICC/ACR Damage Index (SDI)) within 5 years since diagnosis. Feature selection and model construction were performed using the least absolute shrinkage and selection operator-logistic regression (LASSO-LR). The best model in 10-fold cross-validation was tested in an external cohort (n=50).

Results: A LASSO-LR model incorporating 16 criteria and non-criteria features predicted early organ damage with area under the receiver operating characteristic curve (AUC) values of 0.80 (95% CI 0.74 to 0.87) and 0.86 (95% CI 0.76 to 0.97) in the derivation and external validation cohorts, respectively, outperforming the ACR-1997 (AUC 0.70; 95% CI 0.62 to 0.78), SLICC-2012 (AUC 0.74; 95% CI 0.66 to 0.81) and EULAR/ACR-2019 (AUC 0.70; 95% CI 0.63 to 0.78) classification systems. Features most strongly associated with damage included the SLICC-2012 neurological disorder, EULAR/ACR-2019 class III/IV lupus nephritis and among non-criteria manifestations, myocarditis and interstitial lung disease. Operating the model as a binary classifier (early damage versus no damage), it demonstrated high specificity (0.90, 95% CI 0.78 to 0.95). The model can be converted to a simplified scoring system, with a threshold of ≥3 achieving an AUC of 0.86 (95% CI 0.75 to 0.96).

Conclusion: We developed and validated a clinician-friendly model for early organ damage prediction in SLE, facilitating risk stratification.