Yonatan Lean,Carrie Richardson,Anthony Esposito,Katy Bedjeti,George E Georges
OBJECTIVEHigh intensity conditioning autologous hematopoietic stem cell transplantation (AHSCT) is standard of care for patients with advanced SSc. The role of reduced intensity conditioning (RIC) prior to AHSCT in this population remains unclear. We conducted this study to determine the long-term outcomes of RIC AHSCT in SSc patients with cardiac involvement.METHODSWe evaluated 42 participants who sequentially underwent RIC AHSCT five years after the last participant was treated. Progression was defined as reinitiation of DMARDs or worsening end-organ failure. We determined overall survival (OS) and progression-free survival (PFS) by the Kaplan-Meier method and identified pre-transplant characteristics associated with OS or PFS by multivariable Cox regression.RESULTSAll participants had evidence of SSc with cardiac involvement. 95% of participants had interstitial lung disease. The median percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide was 62% and 45%, respectively. The five-year OS was 75% (95% confidence interval [CI]: 63-90%), and five-year PFS was 59% (95% CI: 46-76%). Pre-transplant supplemental oxygen use (HR: 7.88, p<.01) and elevated B-type natriuretic peptide (BNP [HR: 1.005 per pg/mL, p<.01]) was associated with mortality. Anti-Scl-70 antibody positivity (HR: 3.03, p=.02) was associated with progression. 24 participants (57%) who did not use supplemental oxygen and had BNP < 100 pg/mL pre-transplant had a five-year OS of 91% (95% CI: 80-100%).CONCLUSIONRIC AHSCT is safe for patients with severe manifestations from SSc. Supplemental oxygen use, elevated BNP, and anti-Scl-70 antibody positivity were risk factors for worse outcomes after RIC AHSCT.
{"title":"Long-Term Outcomes of Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation for Systemic Sclerosis Patients with Impaired Cardiac Function.","authors":"Yonatan Lean,Carrie Richardson,Anthony Esposito,Katy Bedjeti,George E Georges","doi":"10.1002/art.70031","DOIUrl":"https://doi.org/10.1002/art.70031","url":null,"abstract":"OBJECTIVEHigh intensity conditioning autologous hematopoietic stem cell transplantation (AHSCT) is standard of care for patients with advanced SSc. The role of reduced intensity conditioning (RIC) prior to AHSCT in this population remains unclear. We conducted this study to determine the long-term outcomes of RIC AHSCT in SSc patients with cardiac involvement.METHODSWe evaluated 42 participants who sequentially underwent RIC AHSCT five years after the last participant was treated. Progression was defined as reinitiation of DMARDs or worsening end-organ failure. We determined overall survival (OS) and progression-free survival (PFS) by the Kaplan-Meier method and identified pre-transplant characteristics associated with OS or PFS by multivariable Cox regression.RESULTSAll participants had evidence of SSc with cardiac involvement. 95% of participants had interstitial lung disease. The median percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide was 62% and 45%, respectively. The five-year OS was 75% (95% confidence interval [CI]: 63-90%), and five-year PFS was 59% (95% CI: 46-76%). Pre-transplant supplemental oxygen use (HR: 7.88, p<.01) and elevated B-type natriuretic peptide (BNP [HR: 1.005 per pg/mL, p<.01]) was associated with mortality. Anti-Scl-70 antibody positivity (HR: 3.03, p=.02) was associated with progression. 24 participants (57%) who did not use supplemental oxygen and had BNP < 100 pg/mL pre-transplant had a five-year OS of 91% (95% CI: 80-100%).CONCLUSIONRIC AHSCT is safe for patients with severe manifestations from SSc. Supplemental oxygen use, elevated BNP, and anti-Scl-70 antibody positivity were risk factors for worse outcomes after RIC AHSCT.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"93 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ellen Romich,Joshua F Baker,Thomas R Riley,Ian Green,Rennie L Rhee,Carol A McAlear,Ulrich Specks,Rona M Smith,David R Jayne,Peter A Merkel,
OBJECTIVETo determine risk factors for relapse of ANCA-associated vasculitis (AAV) after re-induction of remission with rituximab and discontinuation of maintenance therapy.METHODSThis is a post-hoc analysis of the RITAZAREM clinical trial. Patients 15 years or older with AAV and a positive test for anti-proteinase-3 (PR3-) or anti-myeloperoxidase (MPO)-ANCA who achieved remission after re-induction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time-varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4-24) and off-treatment (months 24-48).RESULTSAmong 170 patients (median (IQR) age 59 (48-68) years, disease duration 5 (2-10) years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio (OR) [95% confidence interval (CI)]: 2.8 [1.1, 7.2], p=0.03) and higher patient global assessment (OR [95% CI]: 1.1 [1.0, 1.2], p=0.04) were associated with relapse. During the off-treatment phase, presence of CD19+ B-cells (OR [95% CI]: 2.5 [1.2, 5.1], p=0.01) and reappearance of ANCA (OR [95% CI]: 3.2 [1.3, 7.7], p=0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and immunoglobulin A) associated with relapse.CONCLUSIONSRisk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.
{"title":"Risk factors for relapse in ANCA-associated vasculitis among patients with relapse after induction of remission with rituximab.","authors":"Ellen Romich,Joshua F Baker,Thomas R Riley,Ian Green,Rennie L Rhee,Carol A McAlear,Ulrich Specks,Rona M Smith,David R Jayne,Peter A Merkel, ","doi":"10.1002/art.70025","DOIUrl":"https://doi.org/10.1002/art.70025","url":null,"abstract":"OBJECTIVETo determine risk factors for relapse of ANCA-associated vasculitis (AAV) after re-induction of remission with rituximab and discontinuation of maintenance therapy.METHODSThis is a post-hoc analysis of the RITAZAREM clinical trial. Patients 15 years or older with AAV and a positive test for anti-proteinase-3 (PR3-) or anti-myeloperoxidase (MPO)-ANCA who achieved remission after re-induction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time-varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4-24) and off-treatment (months 24-48).RESULTSAmong 170 patients (median (IQR) age 59 (48-68) years, disease duration 5 (2-10) years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio (OR) [95% confidence interval (CI)]: 2.8 [1.1, 7.2], p=0.03) and higher patient global assessment (OR [95% CI]: 1.1 [1.0, 1.2], p=0.04) were associated with relapse. During the off-treatment phase, presence of CD19+ B-cells (OR [95% CI]: 2.5 [1.2, 5.1], p=0.01) and reappearance of ANCA (OR [95% CI]: 3.2 [1.3, 7.7], p=0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and immunoglobulin A) associated with relapse.CONCLUSIONSRisk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"1 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matteo Trevisan, Manuela Pardeo, Ivan Caiello, Claudia Bracaglia, Arianna de Matteis, Valentina Matteo, Elena Loricchio, Fabrizio De Benedetti, Giusi Prencipe
Objective To evaluate the prognostic utility of circulating Interleukin‐18 (IL‐18) levels in predicting disease activity, macrophage activation syndrome (MAS), and disease course in Still's disease (SD) patients receiving first‐line IL‐1 inhibitors (IL‐1i). Methods We retrospectively analyzed 66 biologic‐naïve SD patients who received first‐line treatment with IL‐1i. Plasma IL‐18 levels were measured at baseline and at 3, 6, and 12 months after IL‐1i initiation. Associations between IL‐18 levels and clinical outcomes were assessed using mixed‐effects models, receiver operating characteristic (ROC) curve analysis, and multivariate logistic regression. Results Median baseline IL‐18 levels were 61,425 pg/ml (IQR 16,194‐235,746) and declined significantly after IL‐1 blockade (p<0.0001). Higher IL‐18 levels persisted in patients with active disease (p<0.0001). Baseline IL‐18 >45,000 pg/ml predicted active disease at 12 months (AUC 0.82, p=0.0002), MAS development within 24 months (AUC 0.78, p=0.01), and a chronic‐persistent course (AUC 0.73, p=0.007). In multivariate models, elevated baseline IL‐18 and delayed IL‐1i initiation >3 months independently predicted adverse outcomes. Strikingly, at 3 months, IL‐18 >15,000 pg/ml was a stronger predictor of chronic‐persistent course (AUC 0.92, p<0.0001), independent of clinical disease activity (OR 25.6; p=0.01), with the multivariate model explaining 67% of variance (AUC 0.95). Conclusions In biologic‐naïve SD patients, IL‐18 levels, especially reassessed 3 months after IL‐1i initiation, robustly predict long‐term disease activity, MAS risk, and chronic‐persistent trajectory. Early measurement and dynamic monitoring of IL‐18 may enable risk stratification and guide timely therapeutic escalation or treatment adjustment to improve outcomes. image
{"title":"Interleukin‐18 levels are associated with disease course in patients with Still's disease treated with IL ‐1 inhibitors","authors":"Matteo Trevisan, Manuela Pardeo, Ivan Caiello, Claudia Bracaglia, Arianna de Matteis, Valentina Matteo, Elena Loricchio, Fabrizio De Benedetti, Giusi Prencipe","doi":"10.1002/art.70024","DOIUrl":"https://doi.org/10.1002/art.70024","url":null,"abstract":"Objective To evaluate the prognostic utility of circulating Interleukin‐18 (IL‐18) levels in predicting disease activity, macrophage activation syndrome (MAS), and disease course in Still's disease (SD) patients receiving first‐line IL‐1 inhibitors (IL‐1i). Methods We retrospectively analyzed 66 biologic‐naïve SD patients who received first‐line treatment with IL‐1i. Plasma IL‐18 levels were measured at baseline and at 3, 6, and 12 months after IL‐1i initiation. Associations between IL‐18 levels and clinical outcomes were assessed using mixed‐effects models, receiver operating characteristic (ROC) curve analysis, and multivariate logistic regression. Results Median baseline IL‐18 levels were 61,425 pg/ml (IQR 16,194‐235,746) and declined significantly after IL‐1 blockade (p<0.0001). Higher IL‐18 levels persisted in patients with active disease (p<0.0001). Baseline IL‐18 >45,000 pg/ml predicted active disease at 12 months (AUC 0.82, p=0.0002), MAS development within 24 months (AUC 0.78, p=0.01), and a chronic‐persistent course (AUC 0.73, p=0.007). In multivariate models, elevated baseline IL‐18 and delayed IL‐1i initiation >3 months independently predicted adverse outcomes. Strikingly, at 3 months, IL‐18 >15,000 pg/ml was a stronger predictor of chronic‐persistent course (AUC 0.92, p<0.0001), independent of clinical disease activity (OR 25.6; p=0.01), with the multivariate model explaining 67% of variance (AUC 0.95). Conclusions In biologic‐naïve SD patients, IL‐18 levels, especially reassessed 3 months after IL‐1i initiation, robustly predict long‐term disease activity, MAS risk, and chronic‐persistent trajectory. Early measurement and dynamic monitoring of IL‐18 may enable risk stratification and guide timely therapeutic escalation or treatment adjustment to improve outcomes. <jats:boxed-text content-type=\"graphic\" position=\"anchor\"> <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/art70024-toc-0001-m.png\"> <jats:alt-text>image</jats:alt-text> </jats:graphic> </jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"13 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amala Ambati, Feiyang Ma, Katarina Kmetova, Sherwin Navaz, Claire K. Hoy, Cyrus Sarosh, Ajay Tambralli, Erika Navarro‐Mendoza, Johann E. Gudjonsson, J. Michelle Kahlenberg, Jacqueline A. Madison, Alí Duarte‐García, Jason S. Knight, Yu Zuo
Objective Antiphospholipid syndrome ( APS ) is a thrombo‐inflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody ( aPL )‐positive patients using whole‐blood transcriptomics. Methods Whole‐blood RNA sequencing was performed on 174 aPL‐positive patients, including those with primary APS (n=102), secondary APS (n=29), and aPL‐positivity without classifiable APS (n=43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes. Results Four transcriptionally distinct clusters were identified. At one end of the spectrum, Cluster 1 showed upregulation of ribosomal and metabolic pathways and downregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. In contrast, Cluster 4 exhibited the opposite pattern, with strong upregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. Cluster 2 demonstrated modest enrichment in mRNA processing and amino acid metabolism, and Cluster 3 showed biosynthetic suppression with mild Hippo/IL‐6 activation. Clinically, Cluster 4 stood out with higher aCL and aβ2GPI IgG positivity, elevated neutrophil counts, and increased urine protein‐to‐creatinine ratios. Immune deconvolution revealed distinct cell‐type profiles: Cluster 1 was lymphoid‐predominant; Cluster 2 had a balanced composition; Cluster 3 was enriched in regulatory T cells, NK cells, macrophages, mast cells, and memory B cells; and Cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features including white matter lesions, seizures, and cardiac valve disease. Conclusion This study reveals four endotypes of aPL‐positive patients, a step toward personalized medicine for APS through pathway‐informed stratification and therapy.
{"title":"Molecular stratification of antiphospholipid syndrome through integrative analysis of the whole‐blood RNA transcriptome","authors":"Amala Ambati, Feiyang Ma, Katarina Kmetova, Sherwin Navaz, Claire K. Hoy, Cyrus Sarosh, Ajay Tambralli, Erika Navarro‐Mendoza, Johann E. Gudjonsson, J. Michelle Kahlenberg, Jacqueline A. Madison, Alí Duarte‐García, Jason S. Knight, Yu Zuo","doi":"10.1002/art.70021","DOIUrl":"https://doi.org/10.1002/art.70021","url":null,"abstract":"Objective Antiphospholipid syndrome ( APS ) is a thrombo‐inflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody ( aPL )‐positive patients using whole‐blood transcriptomics. Methods Whole‐blood RNA sequencing was performed on 174 aPL‐positive patients, including those with primary APS (n=102), secondary APS (n=29), and aPL‐positivity without classifiable APS (n=43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes. Results Four transcriptionally distinct clusters were identified. At one end of the spectrum, Cluster 1 showed upregulation of ribosomal and metabolic pathways and downregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. In contrast, Cluster 4 exhibited the opposite pattern, with strong upregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. Cluster 2 demonstrated modest enrichment in mRNA processing and amino acid metabolism, and Cluster 3 showed biosynthetic suppression with mild Hippo/IL‐6 activation. Clinically, Cluster 4 stood out with higher aCL and aβ2GPI IgG positivity, elevated neutrophil counts, and increased urine protein‐to‐creatinine ratios. Immune deconvolution revealed distinct cell‐type profiles: Cluster 1 was lymphoid‐predominant; Cluster 2 had a balanced composition; Cluster 3 was enriched in regulatory T cells, NK cells, macrophages, mast cells, and memory B cells; and Cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features including white matter lesions, seizures, and cardiac valve disease. Conclusion This study reveals four endotypes of aPL‐positive patients, a step toward personalized medicine for APS through pathway‐informed stratification and therapy.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"1 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Klippel-Feil Syndrome in a Patient Referred for Axial Spondyloarthritis.","authors":"Zeyu Tang,Brian Buonocore,Abhijeet Danve","doi":"10.1002/art.70023","DOIUrl":"https://doi.org/10.1002/art.70023","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"230 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qi Zheng,Yejun Tan,Zhaoling Wang,Yanjie Qian,Qian Ma,Danping Shen,Meiping Lu
OBJECTIVEThis study aimed to investigate the mechanisms of immune dysregulation in a pediatric patient with monogenic lupus driven by IKZF1-haploinsufficiency.METHODSPeripheral immune cells from patient with IKZF1-haploinsufficiency, lupus cases with no currently known genetic mutations, and healthy controls were analyzed using single-cell RNA sequencing. Bioinformatic analyses, including pseudotime trajectory and network reconstruction were performed. Activation of type I interferon (IFN) pathway was evaluated by measuring serum cytokine levels, IFN signatures, and the phosphorylation status of Janus kinase (JAK) and signal transducer and activator of transcription (STAT).RESULTSThe patient with IKZF1-haploinsufficiency exhibited notable B cell and T cell dysregulation, with nearly total absence of regulatory B cells (Bregs) and increased percentage of naive CD4+ T cells. Pseudotime analysis in this patient suggested simplified B cell differentiation trajectories with arrested maturation and naïve-like cell resurgence. WGCNA identified a lupus-linked gene module (IKZF1, DUSP1, JUN, FOS), with inferred networks suggesting compensatory stress circuits (DUSP1, DDX17). Over-activation of IFN-JAK-STAT signaling pathway was observed in the patient with IKZF1-haploinsufficiency. Given persistent thrombocytopenia, baricitinib combined with mycophenolate mofetil was administered based on these findings. Her platelet count returned to normal in a month after combination therapy with baricitinib.CONCLUSIONIKZF1 haploinsufficiency disrupted lymphocyte homeostasis, especially Bregs and naive CD4+ T cells, highlighting these as key IKZF1-functional targets. A phenotype- and single-cell-based approach may offer a pathway toward more precise diagnosis and personalized treatment strategies for monogenic lupus.
{"title":"Single-cell RNA sequencing informs precision targeting of monogenic lupus associated with IKZF1 haploinsufficiency.","authors":"Qi Zheng,Yejun Tan,Zhaoling Wang,Yanjie Qian,Qian Ma,Danping Shen,Meiping Lu","doi":"10.1002/art.70017","DOIUrl":"https://doi.org/10.1002/art.70017","url":null,"abstract":"OBJECTIVEThis study aimed to investigate the mechanisms of immune dysregulation in a pediatric patient with monogenic lupus driven by IKZF1-haploinsufficiency.METHODSPeripheral immune cells from patient with IKZF1-haploinsufficiency, lupus cases with no currently known genetic mutations, and healthy controls were analyzed using single-cell RNA sequencing. Bioinformatic analyses, including pseudotime trajectory and network reconstruction were performed. Activation of type I interferon (IFN) pathway was evaluated by measuring serum cytokine levels, IFN signatures, and the phosphorylation status of Janus kinase (JAK) and signal transducer and activator of transcription (STAT).RESULTSThe patient with IKZF1-haploinsufficiency exhibited notable B cell and T cell dysregulation, with nearly total absence of regulatory B cells (Bregs) and increased percentage of naive CD4+ T cells. Pseudotime analysis in this patient suggested simplified B cell differentiation trajectories with arrested maturation and naïve-like cell resurgence. WGCNA identified a lupus-linked gene module (IKZF1, DUSP1, JUN, FOS), with inferred networks suggesting compensatory stress circuits (DUSP1, DDX17). Over-activation of IFN-JAK-STAT signaling pathway was observed in the patient with IKZF1-haploinsufficiency. Given persistent thrombocytopenia, baricitinib combined with mycophenolate mofetil was administered based on these findings. Her platelet count returned to normal in a month after combination therapy with baricitinib.CONCLUSIONIKZF1 haploinsufficiency disrupted lymphocyte homeostasis, especially Bregs and naive CD4+ T cells, highlighting these as key IKZF1-functional targets. A phenotype- and single-cell-based approach may offer a pathway toward more precise diagnosis and personalized treatment strategies for monogenic lupus.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"27 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Refining the Interpretation of Drug Survival and Safety in VEXAS Syndrome: The Importance of Competing Risks and Exposure Time","authors":"Yi Pei, Runze Jiang, Shenglong Li","doi":"10.1002/art.70012","DOIUrl":"https://doi.org/10.1002/art.70012","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"26 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dafne Capelusnik, Tali Eviatar, Corrado Campochiaro, Iftach Sagy, Arsene Mekinian
{"title":"Response to “Refining the Interpretation of Drug Survival and Safety in VEXAS Syndrome: The Importance of Competing Risks and Exposure Time” by Pei Y. et al. and “Reinterpreting the Efficacy of IL ‐1 Inhibitors in VEXAS Syndrome: A Matter of Superiority or Sequencing?” by Ding Z. et al","authors":"Dafne Capelusnik, Tali Eviatar, Corrado Campochiaro, Iftach Sagy, Arsene Mekinian","doi":"10.1002/art.70011","DOIUrl":"https://doi.org/10.1002/art.70011","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"3 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amber De Visscher,Jarne Beliën,Bert Malengier-Devlies,Eline Bernaerts,Leana De Vuyst,Jessica Filtjens,Kourosh Ahmadzadeh,Tania Mitera,Nele Berghmans,Katerina Laskari,Yvan Jamilloux,Paul Regnier,David Saadoun,Charlotte Girard-Guyonvarc'h,Cem Gabay,Mieke Gouwy,Paul Proost,Stephanie Humblet-Baron,Yvonne M Mueller,Stefan J Erkland,Harmen J G van de Werken,Dwin G B Grashof,Peter D Katsikis,Immunome Project Consortium, ,Carine Wouters,Carine Wouters,Patrick Matthys
OBJECTIVEStill's disease (SD) is a rare systemic inflammatory disorder of unknown origin, characterized by episodes of uncontrolled inflammation. While natural killer (NK) cells have been implicated in SD pathogenesis, their precise role remains elusive.METHODSWithin the framework of the ImmunAID consortium, we performed a comprehensive NK cell phenotyping in an international cohort comprising 121 patients with distinct systemic autoinflammatory diseases (53 SD, 23 chronic recurrent multifocal osteomyelitis, 23 Familial Mediterranean fever, and 22 inflammation of unknown origin) and 32 healthy controls.RESULTSOur analysis revealed a unique NK cell signature in SD, characterized by a reduction in NK cell frequency and elevated Fas expression, rendering them more susceptible to in vitro Fas ligand-induced apoptosis. Fas ligand was expressed by SD monocytes and CD38+HLA-DR+ cycling lymphocytes. SD NK cells displayed a hyperactivated but exhausted phenotype, including cytokine unresponsiveness, all features not observed in the other groups. This NK cell dysfunctional profile normalized during clinical remission. Exposure of healthy NK cells to IL-12, IL-15 and IL-18 recapitulates the SD-associated phenotype, suggesting an inflammation-driven mechanism. Transcriptomic profiling identified microRNA miR-146a as a potential regulator of this NK cell dysfunction.CONCLUSIONOur findings establish NK cell apoptosis, exhaustion, and cytokine unresponsiveness as defining immunological features of SD, distinguishing it from other inflammatory diseases in this cohort. This dysfunctional NK cell state may underlie the heightened risk of macrophage activation syndrome in SD and highlights inflammatory cytokines and miR-146a as promising therapeutic targets to mitigate disease severity and prevent life-threatening complications.
{"title":"Distinct natural killer cell signature in still's disease: Insights from a multinational immunome project consortium for autoinflammatory disorders.","authors":"Amber De Visscher,Jarne Beliën,Bert Malengier-Devlies,Eline Bernaerts,Leana De Vuyst,Jessica Filtjens,Kourosh Ahmadzadeh,Tania Mitera,Nele Berghmans,Katerina Laskari,Yvan Jamilloux,Paul Regnier,David Saadoun,Charlotte Girard-Guyonvarc'h,Cem Gabay,Mieke Gouwy,Paul Proost,Stephanie Humblet-Baron,Yvonne M Mueller,Stefan J Erkland,Harmen J G van de Werken,Dwin G B Grashof,Peter D Katsikis,Immunome Project Consortium, ,Carine Wouters,Carine Wouters,Patrick Matthys","doi":"10.1002/art.70008","DOIUrl":"https://doi.org/10.1002/art.70008","url":null,"abstract":"OBJECTIVEStill's disease (SD) is a rare systemic inflammatory disorder of unknown origin, characterized by episodes of uncontrolled inflammation. While natural killer (NK) cells have been implicated in SD pathogenesis, their precise role remains elusive.METHODSWithin the framework of the ImmunAID consortium, we performed a comprehensive NK cell phenotyping in an international cohort comprising 121 patients with distinct systemic autoinflammatory diseases (53 SD, 23 chronic recurrent multifocal osteomyelitis, 23 Familial Mediterranean fever, and 22 inflammation of unknown origin) and 32 healthy controls.RESULTSOur analysis revealed a unique NK cell signature in SD, characterized by a reduction in NK cell frequency and elevated Fas expression, rendering them more susceptible to in vitro Fas ligand-induced apoptosis. Fas ligand was expressed by SD monocytes and CD38+HLA-DR+ cycling lymphocytes. SD NK cells displayed a hyperactivated but exhausted phenotype, including cytokine unresponsiveness, all features not observed in the other groups. This NK cell dysfunctional profile normalized during clinical remission. Exposure of healthy NK cells to IL-12, IL-15 and IL-18 recapitulates the SD-associated phenotype, suggesting an inflammation-driven mechanism. Transcriptomic profiling identified microRNA miR-146a as a potential regulator of this NK cell dysfunction.CONCLUSIONOur findings establish NK cell apoptosis, exhaustion, and cytokine unresponsiveness as defining immunological features of SD, distinguishing it from other inflammatory diseases in this cohort. This dysfunctional NK cell state may underlie the heightened risk of macrophage activation syndrome in SD and highlights inflammatory cytokines and miR-146a as promising therapeutic targets to mitigate disease severity and prevent life-threatening complications.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"6 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shivani Garg,Benoît Blanchet,Yann Nguyen,Fauzia Hollnagel,Ada Clarke,Michelle Petri,Murray B Urowitz,John G Hanly,Caroline Gordon,Sang-Cheol Bae,Juanita Romero-Diaz,Jorge Sanchez-Guerrero,Ann E Clarke,Sasha Bernatsky,Daniel J Wallace,David A Isenberg,Anisur Rahman,Joan T Merrill,Paul R Fortin,Dafna D Gladman,Ian N Bruce,Ellen M Ginzler,Mary Anne Dooley,Rosalind Ramsey-Goldman,Susan Manzi,Andreas Jönsen,Graciela S Alarcón,Ronald F Van Vollenhoven,Cynthia Aranow,Véronique Le Guern,Meggan Mackay,Guillermo Ruiz-Irastorza,S Sam Lim,Murat Inanc,Kenneth C Kalunian,Søren Jacobsen,Christine A Peschken,Diane L Kamen,Anca Askanase,Jill Buyon,Julie Chezel,Alicja Puszkiel,Nathalie Costedoat-Chalumeau
BACKGROUNDUsing hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring.METHODSThis observational study included patients (n=2010) across the Systemic Lupus International Collaborating Clinics (SLICC), Wisconsin, International, and French studies, who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified a HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for SLE Disease Activity Index 2000 (SLEDAI-2K ≥6). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels.RESULTSAmong 1842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1150 ng/mL, and 1.7-fold higher with cumulative HCQ dose per 1000g increase. Blood levels ≥1150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1150 ng/mL).CONCLUSIONThe therapeutic reference range for HCQ blood level monitoring is 750-<1150 ng/ml. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.
{"title":"Defining Optimally Safe and Effective Blood Levels of Hydroxychloroquine in Lupus: An Important Step toward Precision Drug Monitoring.","authors":"Shivani Garg,Benoît Blanchet,Yann Nguyen,Fauzia Hollnagel,Ada Clarke,Michelle Petri,Murray B Urowitz,John G Hanly,Caroline Gordon,Sang-Cheol Bae,Juanita Romero-Diaz,Jorge Sanchez-Guerrero,Ann E Clarke,Sasha Bernatsky,Daniel J Wallace,David A Isenberg,Anisur Rahman,Joan T Merrill,Paul R Fortin,Dafna D Gladman,Ian N Bruce,Ellen M Ginzler,Mary Anne Dooley,Rosalind Ramsey-Goldman,Susan Manzi,Andreas Jönsen,Graciela S Alarcón,Ronald F Van Vollenhoven,Cynthia Aranow,Véronique Le Guern,Meggan Mackay,Guillermo Ruiz-Irastorza,S Sam Lim,Murat Inanc,Kenneth C Kalunian,Søren Jacobsen,Christine A Peschken,Diane L Kamen,Anca Askanase,Jill Buyon,Julie Chezel,Alicja Puszkiel,Nathalie Costedoat-Chalumeau","doi":"10.1002/art.70010","DOIUrl":"https://doi.org/10.1002/art.70010","url":null,"abstract":"BACKGROUNDUsing hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring.METHODSThis observational study included patients (n=2010) across the Systemic Lupus International Collaborating Clinics (SLICC), Wisconsin, International, and French studies, who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified a HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for SLE Disease Activity Index 2000 (SLEDAI-2K ≥6). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels.RESULTSAmong 1842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1150 ng/mL, and 1.7-fold higher with cumulative HCQ dose per 1000g increase. Blood levels ≥1150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1150 ng/mL).CONCLUSIONThe therapeutic reference range for HCQ blood level monitoring is 750-<1150 ng/ml. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"13 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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