Annals of the Rheumatic Diseases

Journal Information
ISSN / EISSN : 0003-4967 / 1468-2060
Published by: BMJ (10.1136)
Total articles ≅ 43,491
Current Coverage
SCOPUS
LOCKSS
MEDICUS
MEDLINE
PUBMED
PMC
SCIE
Archived in
SHERPA/ROMEO
Filter:

Latest articles in this journal

Jun Wang, Qiao Ye, , Xiaomin Yu, Fang Luo, Ran Fang, Yaoyao Shangguan, Zhijun Du, , Taijie Jin, et al.
Published: 15 April 2022
by BMJ
Annals of the Rheumatic Diseases; https://doi.org/10.1136/annrheumdis-2021-221708

Abstract:
Objectives: We aim to investigate the genetic basis of a case of late-onset autoinflammatory disease characterised by arthritis, recurrent fever and skin rashes.Methods: We performed whole-exome/genome sequencing and digital droplet PCR (ddPCR) to identify the pathogenic somatic mutation. We used single-cell RNA sequencing (scRNA-seq), intracellular cytokine staining, quantitative PCR, immunohistochemistry and western blotting to define inflammatory signatures and to explore the pathogenic mechanism.Results: We identified a somatic mutation in NLRC4 (p.His443Gln) with the highest mosaicism ratio in the patient’s monocytes (5.69%). The somatic mutation resulted in constitutive NLRC4 activation, spontaneous apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) aggregation, caspase-1 hyperactivation and increased production of interleukin (IL)-1β and IL-18. Moreover, we demonstrated effective suppression of inflammatory cytokine production by targeting gasdermin D, an approach that could be considered as a novel treatment strategy for patients with NLRC4-associated autoinflammatory syndrome.Conclusions: We reported a case of a late-onset autoinflammatory disease caused by a somatic NLRC4 mutation in a small subset of leucocytes. We systemically analysed this condition at a single-cell transcriptomic level and revealed specific enhancement of inflammatory response in myeloid cells.
, Paula Isabel Burgos, Nicole Le Corre, Cinthya Ruiz Tagle, Constanza Martinez-Valdebenito, Mauricio Castro, Valentina Metcalfe, Paula Niemann, M Elvira Balcells
Published: 13 April 2022
by BMJ
Annals of the Rheumatic Diseases; https://doi.org/10.1136/annrheumdis-2022-222189

Anthony Rousselle, Janis Sonnemann, Kerstin Amann, Alexander Mildner, Dörte Lodka, Lovis Kling, Markus Bieringer, , Achim Leutz, , et al.
Published: 13 April 2022
by BMJ
Annals of the Rheumatic Diseases; https://doi.org/10.1136/annrheumdis-2021-221984

Abstract:
Objectives: Myeloid cell activation by antineutrophil cytoplasmic antibody (ANCA) is pivotal for necrotising vasculitis, including necrotising crescentic glomerulonephritis (NCGN). In contrast to neutrophils, the contribution of classical monocyte (CM) and non-classical monocyte (NCM) remains poorly defined. We tested the hypothesis that CMs contribute to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and that colony-stimulating factor-2 (CSF2, granulocyte-macrophage colony-stimulating factor (GM-CSF)) is an important monocyte-directed disease modifier.Methods: Myeloperoxidase (MPO)-immunised MPO−/− mice were transplanted with haematopoietic cells from wild-type (WT) mice, C–C chemokine receptor 2 (CCR2)−/− mice to abrogate CM, or transcription factor CCAAT–enhancer-binding protein beta (C/EBPβ)−/− mice to reduce NCM, respectively. Monocytes were stimulated with CSF2, and CSF2 receptor subunit beta (CSF2rb)-deficient mice were used. Urinary monocytes and CSF2 were quantified and kidney Csf2 expression was analysed. CSF2-blocking antibody was used in the nephrotoxic nephritis (NTN) model.Results: Compared with WT mice, CCR2−/− chimeric mice showed reduced circulating CM and were protected from NCGN. C/EBPβ−/− chimeric mice lacked NCM but developed NCGN similar to WT chimeric mice. Kidney and urinary CSF2 were upregulated in AAV mice. CSF2 increased the ability of ANCA-stimulated monocytes to generate interleukin-1β and to promote TH17 effector cell polarisation. CSF2rb−/− chimeric mice harboured reduced numbers of kidney TH17 cells and were protected from NCGN. CSF2 neutralisation reduced renal damage in the NTN model. Finally, patients with active AAV displayed increased urinary CM numbers, CSF2 levels and expression of GM-CSF in infiltrating renal cells.Conclusions: CMs but not NCMs are important for inducing kidney damage in AAV. CSF2 is a crucial pathological factor by modulating monocyte proinflammatory functions and thereby TH17 cell polarisation.
, Iftach Sagy, Lena Novack, Shay Brikman, Ran Abuhasira, Snait Ayalon, Irina Novofastovski, Mahmoud Abu-Shakra, Reuven Mader
Published: 13 April 2022
by BMJ
Annals of the Rheumatic Diseases; https://doi.org/10.1136/annrheumdis-2021-221824

Abstract:
Introduction Emerging evidence supports the immunogenic response to mRNA COVID-19 vaccine in patients with autoimmune rheumatic diseases (ARD). However, large-scale data about the association between vaccination, and COVID-19 outcomes in patients with ARD is limited. Methods We used data from Clalit Health Services, which covers more than half of the population in Israel. Patients with ARD older than 18 were included between 20 December 2021 and 30 September 2021, when the BNT162b2 mRNA COVID-19 vaccine, and later a third booster dose, were available. The primary outcome was a documented positive SARS-CoV-2 PCR test. We used a Cox regression models with vaccination status as time-dependent covariate and calculated the HR for the study outcome. Results We included 127 928 patients with ARD, of whom, by the end of the study follow-up, there were 27 350 (21.3%) unvaccinated patients, 31 407 (24.5%) vaccinated patients and 69 171 (54.1%) patients who also received a third booster-dose. We identified 8470 (6.6%) patients with a positive SARS-CoV-2 PCR test during the study period. The HR for SARS-CoV-2 infection among the vaccination group was 0.143 (0.095 to 0.214, p<0.001), and among the booster group was 0.017 (0.009 to 0.035, p<0.001). Similar results were found regardless of the type of ARD group or antirheumatic therapy. Conclusion Our results indicate that both the BNT162b2 mRNA COVID-19 vaccine and the booster are associated with better COVID-19 outcomes in patients with ARD.
Vanessa Waltereit-Kracke, Corinna Wehmeyer, Denise Beckmann, Eugenie Werbenko, Julia Reinhardt, Fabienne Geers, Mike Dienstbier, Michelle Fennen, Johanna Intemann, Peter Paruzel, et al.
Published: 13 April 2022
by BMJ
Annals of the Rheumatic Diseases; https://doi.org/10.1136/annrheumdis-2021-221409

Abstract:
Objective: The aim of this study was to assess the extent and the mechanism by which activin A contributes to progressive joint destruction in experimental arthritis and which activin A-expressing cell type is important for disease progression.Methods: Levels of activin A in synovial tissues were evaluated by immunohistochemistry, cell-specific expression and secretion by PCR and ELISA, respectively. Osteoclast (OC) formation was assessed by tartrat-resistant acid phosphatase (TRAP) staining and activity by resorption assay. Quantitative assessment of joint inflammation and bone destruction was performed by histological and micro-CT analysis. Immunoblotting was applied for evaluation of signalling pathways.Results: In this study, we demonstrate that fibroblast-like synoviocytes (FLS) are the main producers of activin A in arthritic joints. Most significantly, we show for the first time that deficiency of activin A in arthritic FLS (ActβAd/d ColVI-Cre) but not in myeloid cells (ActβAd/d LysM-Cre) reduces OC development in vitro, indicating that activin A promotes osteoclastogenesis in a paracrine manner. Mechanistically, activin A enhanced OC formation and activity by promoting the interaction of activated Smad2 with NFATc1, the key transcription factor of osteoclastogenesis. Consistently, ActβAd/d LysM-Cre hTNFtg mice did not show reduced disease severity, whereas deficiency of activin A in ColVI-Cre-expressing cells such as FLS highly diminished joint destruction reflected by less inflammation and less bone destruction.Conclusions: The results highly suggest that FLS-derived activin A plays a crucial paracrine role in inflammatory joint destruction and may be a promising target for treating inflammatory disorders associated with OC formation and bone destruction like rheumatoid arthritis.
Zhenhuan Zhao, Bihua Xu, Shuang Wang, Mianjing Zhou, Yuefang Huang, Chaohuan Guo, Mengyuan Li, Jijun Zhao, Sun-Sang J Sung, Felicia Gaskin, et al.
Published: 12 April 2022
by BMJ
Annals of the Rheumatic Diseases; https://doi.org/10.1136/annrheumdis-2021-221985

Abstract:
Objective: NLRP3 inflammasome regulates T cell responses. This study examined the roles of NLRP3 inflammasome activation in the regulation of T follicular helper (Tfh) cells during humoral response to T dependent antigens and in systemic lupus erythematosus (SLE).Methods: NLRP3 inflammasome activation of Tfh cells was studied in B6, MRL/lpr and NZM2328 mice and in SLE patients and healthy controls using a fluorescence-labelled caspase-1 inhibitor probe. MCC950, a selective inhibitor of NLRP3, was used to investigate the relation between NLRP3 inflammasome activation and germinal centre (GC) reaction, Ab responses to immunisation, and autoantibody production.Results: NLRP3 inflammasome activation in Tfh cells after immunisation was identified in B6 mice. MCC950 inhibited humoral responses to sheep red blood cell and NP-CGG with reduction of the GC reaction. B6 mice with lymphoid cell-specific deletion of NLRP3 or Casp1 mounted suboptimal humoral responses with impaired GC formation and defective affinity maturation. In MRL/lpr and NZM2328 mice, inhibition of NLRP3 activation suppressed NLRP3 activated Tfh cell expansion as well as attenuated lupus-like phenotypes. Tfh cells with activated NLRP3 inflammasome exhibited increased expression of molecules for Tfh cell function and differentiation, and had greater ability to activate B cells. In SLE patients, disease activity was positively correlated with an increase in the activated NLRP3+ Tfh population and this population was markedly reduced in response to therapy.Conclusions: The activation of NLRP3 inflammasome in Tfh cells is an integral part of responses to immunisation. The activated NLRP3+ Tfh population is essential for optimal humoral responses, GC formation and autoimmunity.
Back to Top Top