Bisphosphonates may have chondroprotective effects that could be of relevance in osteoarthritis. Using data from a large fracture prevention trial, we evaluated the effect of alendronate on the progression of radiographic spinal osteophytes (OST) and disc-space narrowing (DSN).The Fracture Intervention Trial (FIT) evaluated the effectiveness of alendronate at 5 mg/day (first 2 years) followed by 10 mg/day (third year) vs placebo over 3-4 years in preventing osteoporotic fractures. In 200 randomly selected subjects from FIT, we read baseline and follow-up lateral x rays for anterior OST and DSN (both scored 0-3 at each vertebral level) in the thoracic and lumbar spine. We calculated the mean difference in change in the sum of OST and DSN scores at T4 to L5 from baseline to follow-up, respectively, in each treatment arm using linear regression.The participants' baseline characteristics were similar in the alendronate and placebo arms. The adjusted mean change in summary OST score was less in the alendronate group compared to placebo (3.2 vs 4.7, p = 0.04), indicating that OST progression was less in the alendronate group. The adjusted mean change in summary DSN score was less in the alendronate group vs placebo for the whole spine (0.4 vs 0.7, p = 0.2), particularly when limited to the lumbar spine (0.3 vs 0.6, p = 0.04).In this secondary analysis of data from a randomised controlled trial, alendronate was associated with less spinal OST and DSN progression than placebo. This suggests a role for bisphosphonates in altering the pathological processes seen in osteoarthritis.

T Neogi

M C Nevitt

K E Ensrud

D Bauer

D T Felson

Annals of the Rheumatic Diseases

The effect of alendronate on progression of spinal osteophytes and disc-space narrowing

Understanding the molecular mechanisms underlying human cartilage degeneration and regeneration is helpful for improving therapeutic strategies for treating osteoarthritis (OA). Here, we report the molecular programmes and lineage progression patterns controlling human OA pathogenesis using single-cell RNA sequencing (scRNA-seq).
We performed unbiased transcriptome-wide scRNA-seq analysis, computational analysis and histological assays on 1464 chondrocytes from 10 patients with OA undergoing knee arthroplasty surgery. We investigated the relationship between transcriptional programmes of the OA landscape and clinical outcome using severity index and correspondence analysis.
We identified seven molecularly defined populations of chondrocytes in the human OA cartilage, including three novel phenotypes with distinct functions. We presented gene expression profiles at different OA stages at single-cell resolution. We found a potential transition among proliferative chondrocytes, prehypertrophic chondrocytes and hypertrophic chondrocytes (HTCs) and defined a new subdivision within HTCs. We revealed novel markers for cartilage progenitor cells (CPCs) and demonstrated a relationship between CPCs and fibrocartilage chondrocytes using computational analysis. Notably, we derived predictive targets with respect to clinical outcomes and clarified the role of different cell types for the early diagnosis and treatment of OA.
Our results provide new insights into chondrocyte taxonomy and present potential clues for effective and functional manipulation of human OA cartilage regeneration that could lead to improved health.

Quanbo Ji

Yuxuan Zheng

Guoqiang Zhang

Yuqiong Hu

Xiaoying Fan

Yu Hou

Lu Wen

Li Li

Yameng Xu

Yan Wang

Fuchou Tang

Ann Rheum Dis

Single-cell RNA-seq analysis reveals the progression of human osteoarthritis

<h3>Objective:</h3> To assess the efficacy of anti-tumour necrosis factor (TNF) therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies. <h3>Methods:</h3> Retrospective single-centre study of 25 patients with refractory TAK. <h3>Results:</h3> Patients were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months (range 2–84)) and 9 with ETA (median 28 months (range 4–82)); 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50%) could taper or discontinue the additional agent. Major relapses occurred in four patients that initially achieved stable remission. Four patients suffered adverse events, including one with opportunistic infections and one with breast cancer. <h3>Conclusions:</h3> In this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conducting of a randomised controlled trial of anti-TNF therapy in TAK.

E S Molloy

C A Langford

T M Clark

C E Gota

G S Hoffman

Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up

Introduction Recent advances in understanding the biology of ankylosing spondylitis (AS) using innovative genomic and proteomic approaches offer the opportunity to address current challenges in AS diagnosis and management. Altered expression of genes, microRNAs (miRNAs) or proteins may contribute to immune dysregulation and may play a significant role in the onset and persistence of inflammation in AS. The ability of exosomes to transport miRNAs across cells and alter the phenotype of recipient cells has implicated exosomes in perpetuating inflammation in AS. This study reports the first proteomic and miRNA profiling of plasma-derived exosomes in AS using comprehensive computational biology analysis. Methods Plasma samples from patients with AS and healthy controls (HC) were isolated via ultracentrifugation and subjected to extracellular vesicle flow cytometry analysis to characterise exosome surface markers by a multiplex immunocapture assay. Cytokine profiling of plasma-derived exosomes and cell culture supernatants was performed. Next-generation sequencing was used to identify miRNA populations in exosomes enriched from plasma fractions. CD4+ T cells were sorted, and the frequency and proliferation of CD4+ T-cell subsets were analysed after treatment with AS-exosomes using flow cytometry. Results The expression of exosome marker proteins CD63 and CD81 was elevated in the patients with AS compared with HC (q&lt;0.05). Cytokine profiling in plasma-derived AS-exosomes demonstrated downregulation of interleukin (IL)-8 and IL-10 (q&lt;0.05). AS-exosomes cocultured with HC CD4+ T cells induced significant upregulation of IFNα2 and IL-33 (q&lt;0.05). Exosomes from patients with AS inhibited the proliferation of regulatory T cells (Treg), suggesting a mechanism for chronically activated T cells in this disease. Culture of CD4+ T cells from healthy individuals in the presence of AS-exosomes reduced the proliferation of FOXP3+ Treg cells and decreased the frequency of FOXP3+IRF4+ Treg cells. miRNA sequencing identified 24 differentially expressed miRNAs found in circulating exosomes of patients with AS compared with HC; 22 of which were upregulated and 2 were downregulated. Conclusions Individuals with AS have different immunological and genetic profiles, as determined by evaluating the exosomes of these patients. The inhibitory effect of exosomes on Treg in AS suggests a mechanism contributing to chronically activated T cells in this disease.

Fataneh Tavasolian

Starlee Lively

Chiara Pastrello

Michael Tang

Melissa Lim

Addison Pacheco

Zoya Qaiyum

Enoch Yau

Zeynep Baskurt

Igor Jurisica

Mohit Kapoor

Robert D Inman

Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis

Background/objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. Methods We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. Results Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia &lt;4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement. Conclusions Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of &gt;80% for all items, explaining the higher overall specificity of the criteria set.

Martin Aringer

Ralph Brinks

Thomas Dörner

David Daikh

Marta Mosca

Rosalind Ramsey-Goldman

Josef S Smolen

David Wofsy

Dimitrios T Boumpas

Diane L Kamen

David Jayne

R Cervera

Nathalie Costedoat-Chalumeau

Betty Diamond

Dafna D Gladman

Bevra Hahn

Falk Hiepe

Søren Jacobsen

Dinesh Khanna

Kirsten Lerstrøm

Elena Massarotti

Joseph McCune

Guillermo Ruiz-Irastorza

Jorge Sanchez-Guerrero

Matthias Schneider

Murray Urowitz

George Bertsias

Bimba F Hoyer

Nicolai Leuchten

Gabriela Schmajuk

Chiara Tani

Sara K Tedeschi

Zahi Touma

Branimir Anic

Florence Assan

Tak Mao Chan

Ann Elaine Clarke

Mary K Crow

László Czirják

Andrea Doria

Winfried Graninger

Bernadett Halda-Kiss

Sarfaraz Hasni

Peter M Izmirly

Michelle Jung

Gábor Kumánovics

Xavier Mariette

Ivan Padjen

José M Pego-Reigosa

Juanita Romero-Diaz

Íñigo Rúa-Figueroa

Raphaèle Seror

Georg H Stummvoll

Yoshiya Tanaka

Maria G Tektonidou

Carlos Vasconcelos

Edward M Vital

Daniel J Wallace

Sule Yavuz

Pier Luigi Meroni

Marvin J Fritzler

Ray Naden

Karen Costenbader

Sindhu R Johnson

European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance

Objective Syndecan-4 (sdc4) is a cell-anchored proteoglycan that consists of a transmembrane core protein and glucosaminoglycan (GAG) side chains. Binding of soluble factors to the GAG chains of sdc4 may result in the dimerisation of sdc4 and the initiation of downstream signalling cascades. However, the question of how sdc4 dimerisation and signalling affects the response of cells to inflammatory stimuli is unknown. Methods Sdc4 immunostaining was performed on rheumatoid arthritis (RA) tissue sections. Interleukin (IL)-1 induced extracellular signal-regulated kinases (ERK) phosphorylation and matrix metalloproteinase-3 production was investigated. Il-1 binding to sdc4 was investigated using immunoprecipitation. IL-1 receptor (IL1R1) staining on wild-type, sdc4 and IL1R1 knockout fibroblasts was performed in fluorescence-activated cell sorting analyses. A blocking sdc4 antibody was used to investigate sdc4 dimerisation, IL1R1 expression and the histological paw destruction in the human tumour necrosis factor-alpha transgenic mouse. Results We show that in fibroblasts, the loss of sdc4 or the antibody-mediated inhibition of sdc4 dimerisation reduces the cell surface expression of the IL-1R and regulates the sensitivity of fibroblasts to IL-1. We demonstrate that IL-1 directly binds to sdc4 and in an IL-1R-independent manner leads to its dimerisation. IL-1-induced dimerisation of sdc4 regulates caveolin vesicle-mediated trafficking of the IL1R1, which in turn determines the responsiveness to IL-1. Administration of antibodies (Ab) against the dimerisation domain of sdc4, thus, strongly reduces the expression IL1R1 on arthritic fibroblasts both in vitro and an animal model of human RA. Conclusion Collectively, our data suggest that Ab that specifically inhibit sdc4 dimerisation may support anti-IL-1 strategies in diseases such as inflammatory arthritis.

Lars Godmann

Miriam Bollmann

Adelheid Korb-Pap

Ulrich König

Joanna Sherwood

Denise Beckmann

Katja Mühlenberg

Frank Echtermeyer

James Whiteford

Giulia De Rossi

Thomas Pap

Jessica Bertrand

Antibody-mediated inhibition of syndecan-4 dimerisation reduces interleukin (IL)-1 receptor trafficking and signalling

Objectives To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT). Methods Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking. Results In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks. Conclusions Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice. Trial registration number EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815 .

Kristina Lend

Jon Lampa

Leonid Padyukov

Merete Lund Hetland

Marte Schrumpf Heiberg

Dan C Nordström

Michael T Nurmohamed

Anna Rudin

Mikkel Østergaard

Espen A Haavardsholm

Kim Hørslev-Petersen

Till Uhlig

Tuulikki Sokka-Isler

Bjorn Gudbjornsson

Gerdur Grondal

Giulia Frazzei

Jeroen Christiaans

Gertjan Wolbink

Theo Rispens

Jos W R Twisk

Ronald F van Vollenhoven

Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial

类风湿因子、抗瓜氨酸化蛋白抗体和共享表位与早期类风湿关节炎患者初始治疗临床反应的关联：来自随机对照试验的数据

Helicobacter pyloriinfection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism ofH. pyloriinfection in the progression of RA.
The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared betweenH. pylori-negative andH. pylori-positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism ofH. pyloriinfection in RA progression.
The DAS-28 and ACPA levels of patients with RA in theH. pylori-positive group were significantly higher than those in theH. pylori-negative group. Polyclonal ACPA derived fromH. pylori-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found thatH. pyloriinfection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on thePADI4gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased inH. pylori-infected patients with RA.
Our findings reveal a novel mechanism by whichH. pyloriinfection contributes to RA progression. Therapeutic interventions targetingH. pylorimay be a viable strategy for the management of RA.

Hui Wu

Hanmei Yuan

Jin Zhang

Taojun He

Yilin Deng

Ying Chen

Yunqi Zhang

Weisan Chen

Chao Wu

<i>Helicobacter pylori</i>upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis

幽门螺杆菌通过稳定HIF-1α上调PAD4表达以加重类风湿性关节炎

For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.

Ann-Kathrin Eiers

Sabine Vettorazzi

Jan P Tuckermann

Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases

75年糖皮质激素的发现之旅：我们对风湿病中糖皮质激素受体机制认识的演变

Objective Considering the diverse aetiologies and immunodysregulatory statuses observed in each patient with rheumatoid arthritis (RA), stratification based on peripheral blood immunophenotyping holds the potential to enhance therapeutic responses to molecular targeted therapies, biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Methods Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA. Results Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4 + effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as ‘expected’ whereas the ‘non-expected’ group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p&lt;0.0001). Trajectory analysis showed the non-expected group’s 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend. Conclusion Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.

Satoshi Kubo

Yusuke Miyazaki

Takahiro Nishino

Yuya Fujita

Michihiro Kono

Tsugumi Kawashima

Kazuyoshi Ishigaki

Katsuhide Kusaka

Hiroaki Tanaka

Masanobu Ueno

Yurie Satoh-Kanda

Yoshino Inoue

Yasuyuki Todoroki

Ippei Miyagawa

Kentaro Hanami

Shingo Nakayamada

Peripheral blood immunophenotypic diversity in patients with rheumatoid arthritis and its impact on therapeutic responsiveness

类风湿关节炎患者外周血免疫表型多样性及其对治疗反应的影响

风湿病年鉴 (ARD) 是一份国际同行评审期刊，致力于促进最高标准的科学交流和教育。它涵盖了风湿病学的所有方面，包括肌肉骨骼疾病、关节炎疾病和结缔组织疾病的谱系。 ARD 发表基础、临床和转化科学研究。鼓励简明的科学交流，并以同行评审的国际会议论文集为特色。教育论文包括最先进的评论、“如何”文章和教育案例，重点关注临床实践中面临的问题。该杂志于 1939 年首次出版，拥有权威的全球编辑委员会和不断增长的国际读者群。

The Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal dedicated to promoting the highest standards of scientific communication and education. It covers all aspects of rheumatology, including musculoskeletal disorders, arthritic diseases, and connective tissue diseases. ARD publishes basic, clinical, and translational scientific research, encouraging concise scientific communication and featuring peer-reviewed conference proceedings. Educational papers include cutting-edge reviews, 'how-to' articles, and educational cases, focusing on issues faced in clinical practice. Since its first publication in 1939, the journal has maintained a prestigious global editorial board and a growing international readership.

《Annals of the Rheumatic Diseases》（风湿病年鉴，ARD）是一份国际同行评审的学术期刊，旨在促进高标准的科学交流与教育。期刊涵盖风湿病学的各个方面，包括肌肉骨骼疾病、关节炎和结缔组织疾病等。ARD发表基础研究、临床研究和转化科学研究，鼓励简洁明了的科学交流，并定期刊登国际会议的同行评审论文。教育类论文包括前沿评论、实用指南和教育案例，重点关注临床实践中遇到的问题。该杂志自1939年创刊以来，拥有权威的全球编辑委员会和不断扩大的国际读者群。

Journals	Annals of the Rheumatic Diseases
ISSN	0003-4967, 1468-2060
h-index	288
Journal Impact	20.18
Quartiles(Global)	RHEUMATOLOGY(Q1)
Quartiles(China)	医学(1区)医学风湿病学(1区)