ACR open rheumatology最新文献

Objective: To characterize clinical and transcriptomic differences in juvenile scleromyositis overlap (jOverlap) compared to juvenile systemic sclerosis (jSSc) and juvenile dermatomyositis (JDM), focusing on autoantibody profiles, organ involvement, treatment, and peripheral blood gene expression.

Methods: Peripheral blood bulk RNA sequencing was performed on children with jSSc (n = 25), JDM (n = 25), and jOverlap (n = 26), and healthy controls (HCs; n = 21) from two tertiary referral centers. Disease category was assigned by treating physicians. Clinical data and autoantibody profiles were collected. RNA was sequenced using the Illumina NextSeq 500 platform. Differentially expressed genes (DEGs) were identified using Partek Flow and DESeq2, applying a log₂ fold change cutoff of ±1.5 and a false discovery rate of <0.1.

Results: Patients with jOverlap, predominantly White girls, had distinct autoantibody patterns enriched for PM-Scl, U1-RNP, and U3-RNP. Compared to HCs, patients with jSSc, JDM, and jOverlap demonstrated a unique gene expression profile, with up-regulation of type-1 interferon-related genes, specifically SIGLEC1 and IFI27. Compared to patients with JDM, patients with jOverlap showed higher expression of RAB13 (linked to sclerosing neurodegenerative disease), MMEL1 (inflammatory arthritis), and MMP19 (pulmonary fibrosis). t-distributed stochastic neighbor embedding clustering revealed that although HC, jSSc, and JDM samples each formed distinct clusters, jOverlap samples were distributed across all clusters, highlighting their heterogeneity.

Conclusion: Patients with jOverlap exhibited a distinct immunophenotype and clinical profile compared to patients with jSSc and JDM. Their broad transcriptional heterogeneity suggests disease category alone does not explain gene expression patterns. Further analysis correlating DEGs with autoantibodies, age, and clinical features is warranted to better define this overlapping disease entity.

Objective: Juvenile-onset systemic sclerosis (jSSc) is a rare, heterogeneous pediatric autoimmune disease. Existing severity tools are often adapted from adult systemic sclerosis and lack pediatric-specific validation. The Juvenile Systemic Sclerosis Severity Score (J4S) was developed to address this gap by capturing multiorgan disease burden. This study evaluated the clinical use of the J4S using data from the National Registry for Childhood Onset Scleroderma (NRCOS).

Methods: We applied the J4S to 58 patients in the NRCOS cohort, analyzing scores at baseline and at one-, two-, and three-year follow-ups. Subdomain scores were assessed to evaluate organ-specific trends. An exploratory version with equal domain weighting was also tested for sensitivity.

Results: At baseline, the mean J4S was 8.18 (±3.64), with respiratory involvement as the primary contributor. Although no significant change in total scores was observed at one (P = 0.264) or two years (P = 0.06), domain-specific improvements were noted, particularly in the skin, vascular, gastrointestinal, and musculoskeletal systems. By three years, total scores declined significantly (P = 0.028). Two patients experienced sharp score increases due to respiratory decline; one patient died during the study. The exploratory equal-weight scoring approach improved sensitivity to change and identified significant declines at each time point.

Conclusion: The J4S is a valuable longitudinal tool for tracking disease severity and organ involvement in jSSc. It can identify both stable and progressive disease and may help detect patients at risk for poor outcomes. Modifying domain weighting may enhance responsiveness. Future multicenter validation and clinical trial integration are warranted.

Objective: Behçet syndrome (BS) is a systemic autoimmune vasculitis characterized by immune dysregulation involving multiple immune cell subsets. CD161⁺ Treg cells exhibit proinflammatory properties and impair immune regulation during inflammation. This study aimed to investigate the alterations in CD161⁺ Treg cells in BS and their clinical relevance, particularly in disease pathogenesis and neurologic involvement.

Methods: This prospective multicenter study included 182 patients diagnosed with BS at the three hospitals between 2018 and 2024, 166 patients with systemic lupus erythematosus (SLE) and 149 patients with rheumatoid arthritis (RA) and 114 patients with healthy controls (HCs). Demographic and clinical data were recorded. CD4⁺CD25^highCD127^lowCD161⁺ T cells (CD161⁺ Treg cells) in peripheral blood were analyzed via flow cytometry. Statistical analysis included the Wilcoxon rank-sum test, Fisher's exact test, and logistic regression, with P < 0.05 considered significant.

Results: Patients with BS had a significantly higher proportion among total Treg cells and CD4⁺ T cells, as well as higher absolute number of CD161⁺ Treg cells compared to HCs. CD161⁺ Treg cell levels negatively correlated with Foxp3⁺ Treg cells and positively correlated with Teff cells. Patients with BS had higher absolute number of CD161⁺ Treg cells than that in patients with SLE and in patients with RA. Moreover, patients with BS with higher erythrocyte sedimentation rate or C-reactive protein or with neurologic involvement exhibited higher CD161⁺ Treg cells, which were identified as a risk factor for neurologic involvement. Among 41 patients with BS observed after treatment, CD161⁺ Treg cells significantly decreased, correlating with reduced disease activity.

Conclusion: Patients with BS exhibit an increased CD161⁺ Treg cells in peripheral blood, which may contribute to immune dysregulation and neurologic involvement. The reduction of CD161⁺ Treg cells following treatment suggests their potential role as a biomarker for disease activity in BS.

Objective: Juvenile dermatomyositis (JDM) is a rare childhood inflammatory myopathy, whereas spondyloarthritis (SpA) is an inflammatory arthropathy characterized by enthesitis and peripheral or axial involvement. We describe a series of patients diagnosed with JDM in childhood who later fulfilled classification criteria for SpA, a sequential phenotype that has not been well characterized.

Methods: This institutional review board-exempt retrospective study (2024-180) reviewed demographics, clinical features, laboratory tests, imaging, treatments, and outcomes in a convenience sample of patients who met criteria for JDM before age 18 and subsequently fulfilled the Assessment of Spondyloarthritis International Society (ASAS) or Classification for Psoriatic Arthritis (CASPAR) criteria. Patients with SpA preceding JDM were excluded. Descriptive statistics were used to explore potential predictors of SpA development.

Results: Seven patients met the inclusion criteria; 57% were female and 86% were White. The median age at JDM diagnosis was 8 years (interquartile range [IQR] 5-10 years). The median interval time to SpA diagnosis was 7 years (IQR 5-14 years). All tested patients had elevated neopterin and magnetic resonance imaging evidence of myositis; 71% experienced complications before SpA onset. All met ASAS criteria for peripheral SpA, and 29% met CASPAR criteria. HLA-B27 was positive in 20% of those tested. Most (83%) responded to standard SpA therapies; one required rituximab and azathioprine for calcinosis.

Conclusion: This preliminary small study highlights a possible evolution from JDM, an adaptive immune disease, to SpA, an innate-driven illness. These findings suggest potential predictors of disease overlap and warrant future studies to clarify mechanisms and inform predictive models.

Objective: To assess the predictive performance of inflammatory biomarkers, including C-reactive protein (CRP) and Krebs von den Lungen 6 (KL-6), for the development of progressive pulmonary fibrosis (PPF) in patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD).

Methods: A total of 135 patients with SSc-ILD were retrospectively selected from a single-center prospective registry. The predictive performance of individual biomarkers and their combinations for PPF development was evaluated using area under the curve (AUC) values from receiver operating characteristic analysis. A time-varying Cox proportional hazards model was used to assess the prognostic significance of near-term dynamic changes in KL-6 levels.

Results: During a median follow-up of 43 months, 26 patients (19%) developed PPF. Baseline CRP and KL-6 levels did not correlate with each other. Patients with high baseline KL-6 (≥1,000 U/mL) had more extensive ILD and reduced forced vital capacity compared to those with low levels. Baseline KL-6 demonstrated superior predictive performance for ILD progression (with the highest AUC) compared to CRP. The PPF-free survival rate was significantly lower in the high KL-6 group than in the low KL-6 group (P = 0.02). A doubling of KL-6 levels at any time from 12 months to 6 months before PPF assessment or censoring was associated with a significantly higher risk of subsequent PPF development (hazard ratio 1.66 [95% confidence interval 1.13-2.45]).

Conclusion: Baseline KL-6 and CRP values identify distinct subsets of SSc-ILD patients. Elevated baseline KL-6 levels and a significant rise over the subsequent six months are associated with an increased risk of PPF, supporting their potential as prognostic biomarkers.

Objective: Adults with rheumatic diseases are at increased risk for herpes zoster (HZ). Recommendations for the recombinant zoster vaccine (RZV) were expanded in 2021 to include those aged ≥19 years at increased risk for HZ due to immunodeficiency or immunosuppression because of disease or therapy, but the impact of these expanded recommendations is unclear. This study assessed the impact of the updated recommendations on RZV uptake among adults with rheumatic disease in the US.

Methods: A retrospective cohort analysis used open-source claims data to estimate RZV uptake, series completion, and dosing schedule compliance among unvaccinated adults with rheumatic disease from October 2021 to June 2023. Interviews with rheumatologists were conducted and thematically analyzed to characterize RZV vaccination practices related to managing patients with rheumatic disease.

Results: RZV uptake among adults with rheumatic disease and without prior RZV over the 20-month period following the updated recommendations was gradual (7.0%-10.4% across conditions) and low, and was particularly less likely among adults <50 years of age. The odds of RZV uptake were higher among those of older age, those with a household income greater than or equal to $50,000, and those of a non-White race or ethnicity. Financial concerns, lack of formal processes for tracking vaccination records and delivering reminders, and insufficient education and awareness were key barriers to RZV vaccination according to rheumatologists.

Conclusion: RZV uptake among adults with rheumatic disease has gradually increased, and opportunities to improve HZ prevention exist, some of which may be addressed through targeted educational efforts.

Objective: Immune checkpoint inhibitors (ICIs) are effective cancer therapies but often cause serious immune-related adverse events (irAEs). Patients with preexisting autoimmune diseases, including vasculitis, are excluded from trials. We aimed to evaluate the frequency, severity, and outcomes of vasculitis flares and irAEs in this population.

Methods: We performed a retrospective review of cancer patients with prior vasculitis treated with ICIs at our institution and conducted a literature search for additional cases. Data included baseline features, vasculitis flares, irAEs, treatments, and tumor response.

Results: Twenty-five patients were identified (16 from our institution and 9 from the literature). Median age was 71 years; 13 (52%) were female. Vasculitis types included giant cell arteritis (GCA, n = 9), granulomatosis with polyangiitis (GPA, n = 8), eosinophilic granulomatosis with polyangiitis (EGPA, n = 2), leukocytoclastic vasculitis (n = 2), other cutaneous vasculitis (n = 2), and Henoch-Schönlein purpura and Behçet disease (1 each). Cancer types were diverse. Most patients received anti-programmed death-1 monotherapy (n = 17). Eight patients (31%) experienced a vasculitis flare after ICI initiation (2/9 GCA, 4/8 GPA, 2/4 cutaneous vasculitis). Flares occurred after a median of seven weeks. Treatment included glucocorticoids in seven patients, combined with biologic or cytotoxic agents depending on vasculitis type. Seven of eight flares resolved, and four patients continued ICI therapy. Three additional patients developed de novo irAEs: severe hepatitis (n = 1), grade 3 colitis (n = 1), and grade 3 autoimmune hemolytic anemia (n = 1), all improving with treatment. One patient with GCA died due to a flare; no deaths were attributed to de novo irAEs. Overall, more than one-third of patients achieved a favorable tumor response.

Conclusion: Nearly one-third of patients with preexisting vasculitis experienced a disease flare during ICI therapy, with one fatal case. For most, outcomes were favorable with effective flare management. Preexisting vasculitis should not be considered an absolute contraindication for cancer immunotherapy with ICI.

Objective: Diffuse alveolar hemorrhage (DAH) is a life-threatening presentation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients with AAV are at an increased risk of venous thromboembolic events (VTEs). These manifestations can co-occur; however, the prognosis and management of these patients are poorly understood.

Methods: In this retrospective observational study, we included patients diagnosed with AAV who presented with both DAH and VTE during the same outpatient visit or in the same inpatient treatment episode.

Results: Among 121 patients with proven DAH secondary to AAV managed at our institution, 14 (11.6%) were also diagnosed with VTE. Patients were predominantly men (71%) with median age at diagnosis of 67 (interquartile range 56-72) years. Five patients were diagnosed with DAH followed by VTE, four patients were diagnosed with VTE before developing DAH (T-AAV), and five patients were diagnosed with VTE and DAH simultaneously (HT-AAV). Inferior vena cava filters were placed in 13 patients (93%). Although most patients received systemic anticoagulation within 30 days of DAH diagnosis, anticoagulation management was individualized based on clinical presentation. One patient with preexisting interstitial lung disease died of respiratory failure after initially presenting with pulmonary embolism and later developing DAH during hospitalization. Bleeding complications, including recurrent DAH or retroperitoneal hematoma, were observed in six patients (43%). Three patients (21%) experienced progression or recurrence of VTE within 90 days.

Conclusion: Management of patients with DAH and VTE is challenging and should be guided by the severity of DAH, additional organ manifestations of AAV, and risk stratification of the presenting VTE.

Objective: Multisystem inflammatory syndrome in children (MIS-C) is a rare hyperinflammatory syndrome that follows SARS-CoV-2 infection. Prior plasma proteomic analysis from a 2020 cohort of patients with MIS-C at our center revealed a profile characterized by thrombotic microangiopathy (TMA), macrophage activation syndrome (MAS)-associated proteins, and dysregulated interferon-γ (IFNγ) responses. However, a limitation of that study was that samples were often acquired after treatment. The objective of this study was to identify plasma proteomic signatures that uniquely define MIS-C versus other viral syndromes unconfounded by treatment effects in an independent cohort.

Methods: Plasma proteomics was performed using the Olink Explore HT platform on plasma from patients enrolled at emergency department admission with suspected MIS-C (final diagnoses N = 12 MIS-C, N = 30 other viral syndromes). Plasma autoantibody analysis was performed using a custom microbead-based protein array.

Results: Consistent with findings in the 2020 cohort, TMA- and MAS-associated proteins were more highly expressed, and there was a higher CXCL9 response to IFNγ in MIS-C compared to viral infection. In contrast to the 2020 cohort, patients with MIS-C did not have lower expression of the IFNγ suppressive protein TRIM21. On reanalysis of the 2020 cohort, only patients who received intravenous Ig (IVIg) treatment before sampling had low TRIM21 (also known as Ro52/SSA). IVIg recipients also had anti-Ro52 autoantibodies.

Conclusion: We have validated several unique features of the plasma proteome of patients with MIS-C first identified in 2020. Discrepant TRIM21 expression in these two cohorts is due to anti-Ro52 autoantibodies in IVIg-treated patients. These data support the use of plasma cytokine profiling to rapidly diagnose MIS-C.