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1.  Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in vivo 
Annals of the rheumatic diseases  2015;75(6):1228-1235.
Objectives
Osteoarthritis is a leading cause of disability for which there is no cure. The identification of molecules supporting cartilage homeostasis and regeneration is therefore a major pursuit in musculoskeletal medicine. Agrin is a heparan sulphate proteoglycan which, through binding to LRP4, is required for neuromuscular synapse formation. In other tissues, it connects the cytoskeleton to the basement membrane through binding to α-dystroglycan. Prompted by an unexpected expression pattern, we investigated the role and receptor usage of Agrin in cartilage.
Methods
Agrin expression pattern was investigated in human osteoarthritic cartilage and following destabilization of the medial meniscus in mice. Extracellular matrix formation and chondrocyte differentiation was studied in gain and loss of function experiments in vitro in 3D cultures and gain of function in vivo, using an ectopic cartilage formation assay in nude mice. Receptor usage was investigated by disrupting LRP4 and α-dystroglycan by siRNA and blocking antibodies respectively.
Results
Agrin was detected in normal cartilage but was progressively lost in osteoarthritis. In vitro, Agrin knockdown resulted in reduced glycosaminoglycan content, downregulation of the cartilage transcription factor SOX9 and other cartilage-specific extracellular matrix molecules. Conversely, exogenous Agrin supported cartilage differentiation in vitro and ectopic cartilage formation in vivo. In the context of cartilage differentiation, Agrin utilised an unusual receptor repertoire requiring both LRP4 and α-dystroglycan.
Conclusions
We have discovered that Agrin strongly promotes chondrocyte differentiation and cartilage formation in vivo. Our results identify Agrin as a novel potent anabolic growth factor with strong therapeutic potential in cartilage regeneration.
doi:10.1136/annrheumdis-2015-207316
PMCID: PMC4760904  PMID: 26290588
Cartilage; Osteoarthritis; Agrin; LRP4; Dystroglycan
2.  A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet’s disease in HLA-B*51 carriers 
Annals of the rheumatic diseases  2016;75(12):2208-2211.
Introduction
Endoplasmic reticulum aminopeptidase 1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behçet’s disease.
Methods
Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes EUR super-population frequency greater than 1% were determined in 1,900 Behçet’s disease cases and 1,779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behçet’s disease risk were determined by haplotype identification and disease association analyses.
Results
One ERAP1 protein allotype with 5 non-ancestral amino acids was recessively associated with disease (P = 3.13 × 10−6, odds ratio 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B*51. Individuals who carry HLA-B*51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (P = 4.80 × 10−20, odds ratio 10.96, 95% CI 5.91 to 20.32).
Discussion
The Behçet’s disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behçet’s disease risk by altering the peptides available for binding to HLA-B*51.
doi:10.1136/annrheumdis-2015-209059
PMCID: PMC5106293  PMID: 27217550
3.  Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study 
Annals of the Rheumatic Diseases  2016;75(11):1909-1916.
Objectives
The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE).
Methods
431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52.
Results
Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment.
Conclusions
Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity.
Trial registration number
NCT01283139; Results.
doi:10.1136/annrheumdis-2015-208562
PMCID: PMC5099191  PMID: 27009916
Systemic Lupus Erythematosus; Treatment; Autoimmune Diseases
4.  Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials 
Annals of the Rheumatic Diseases  2016;75(11):1964-1970.
Objective
To examine the overall treatment effect and the proportion attributable to contextual effect (PCE) in randomised controlled trials (RCTs) of diverse treatments for osteoarthritis (OA).
Methods
We searched Medline, Embase, Central, Science Citation Index, AMED and CINAHL through October 2014, supplemented with manual search of reference lists, published meta-analyses and systematic reviews. Included were RCTs in OA comparing placebo with representative complementary, pharmacological, non-pharmacological and surgical treatments. The primary outcome was pain. Secondary outcomes were function and stiffness. The effect size (ES) of overall treatment effect and the PCE were pooled using random-effects model. Subgroup analyses and meta-regression were conducted to examine determinants of the PCE.
Results
In total, 215 trials (41 392 participants) were included. The overall treatment effect for pain ranged from the smallest with lavage (ES=0.46, 95% CI 0.24 to 0.68) to the largest with topical non-steroidal anti-inflammatory drugs (ES=1.37, 95% CI 1.19 to 1.55). On average, 75% (PCE=0.75, 95% CI 0.72 to 0.79) of pain reduction was attributable to contextual effect. It varied by treatment from 47% (PCE=0.47, 95% CI 0.32 to 0.70) for intra-articular corticosteroid to 91% (PCE=0.91, 95% CI 0.60 to 1.37) for joint lavage. Similar results were observed for function and stiffness. Treatment delivered by needle/injection and other means than oral medication, longer duration of treatment, large sample size (≥100 per arm) and public funding source were associated with increased PCE for pain reduction.
Conclusions
The majority (75%) of the overall treatment effect in OA RCTs is attributable to contextual effects rather than the specific effect of treatments. Reporting overall treatment effect and PCE, in addition to traditional ES, permits a more balanced, clinically meaningful interpretation of RCT results. This would help dispel the frequent discordance between conclusions from RCT evidence and clinical experience—the ‘efficacy paradox’.
doi:10.1136/annrheumdis-2015-208387
PMCID: PMC5099197  PMID: 26882927
Osteoarthritis; Treatment; Epidemiology
5.  Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis 
Annals of the Rheumatic Diseases  2016;75(11):2045-2052.
Objective
The zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis.
Methods
Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL).
Results
MTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA.
Conclusions
MTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.
doi:10.1136/annrheumdis-2015-208406
PMCID: PMC5099198  PMID: 26903440
Osteoarthritis; Chondrocytes; Arthritis
6.  Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology 
Annals of the Rheumatic Diseases  2015;75(11):1989-1997.
Objective
Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.
Methods
OA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain.
Results
Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone.
Conclusions
This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes.
doi:10.1136/annrheumdis-2015-208268
PMCID: PMC5099200  PMID: 26698846
Osteoarthritis; Synovitis; Chondrocytes; Inflammation
7.  Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study) 
Annals of the Rheumatic Diseases  2016;75(11):1917-1923.
Objective
To compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active rheumatoid arthritis (RA).
Methods
This is a 2-year randomised, controlled study. RA patients with moderate or high disease activity despite methotrexate were randomly assigned either to tocilizumab added to methotrexate (add-on) or tocilizumab switched from methotrexate (switch). The primary endpoint was the DAS28 remission rate at week 24. Secondary objectives included other clinical efficacy indices, radiological outcomes assessed with the van der Heijde-modified total Sharp scoring system (mTSS), and safety.
Results
Of 223 randomised patients, 83% completed 52 weeks. DAS28 remission rates at week 24 were 70% for add-on and 55% for switch (p=0.02), but they became comparable at week 52 (72% vs 70%, p=0.86). Structural remission rates (mTSS≤0.5) at week 52 were not different (66% vs 64%, p=0.92). However, clinically relevant radiographic progression rates (CRRP; mTSS≥3) tended to be higher with the switch than with the add-on (15% vs 7%, p=0.07). Radiographic progression in the CRRP patients was larger with the switch than with the add-on (9.0/year vs 5.0/year, p=0.04). The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24 weeks (1.56 vs 0.49, p=0.001) but not for the following 28 weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group.
Conclusions
In RA patients with inadequate response to methotrexate, tocilizumab added to methotrexate more rapidly suppressed inflammation than tocilizumab switched from methotrexate, leading to superior clinical efficacy and prevention of joint destruction.
Trial registration number
NCT01120366.
doi:10.1136/annrheumdis-2015-208426
PMCID: PMC5099201  PMID: 26733110
Rheumatoid Arthritis; DMARDs (biologic); Treatment; Disease Activity
8.  Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes 
Annals of the Rheumatic Diseases  2016;75(11):2029-2036.
Objectives
Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.
Methods
Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.
Results
We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.
Conclusions
Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.
doi:10.1136/annrheumdis-2015-208659
PMCID: PMC5099203  PMID: 26857698
Sjøgren's Syndrome; B cells; Autoimmunity; Gene Polymorphism
9.  Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study 
Annals of the rheumatic diseases  2014;74(11):1968-1975.
Objective
Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein which has a co-stimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis, and inflammatory bowel disease, associated with DPP4i in patients with T2DM.
Methods
Using U.S. insurance claims data (2005–2012), we conducted a population-based cohort study that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and non-DPP4i (non-DPP4i plus metformin). RA and other AD were identified with ≥2 diagnoses and ≥1 dispensing for AD-specific immunomodulating drugs or steroids. Composite AD includes RA or other AD. Propensity score (PS)-stratified Cox proportional hazards models compared the risk of AD in DPP4i initiators vs. non-DPP4i, controlling for potential confounders.
Results
After asymmetric trimming on the PS, 73,928 patients with T2DM starting DPP4i combination therapy and 163,062 starting non-DPP4i combination therapy were selected. Risks of incident RA and composite AD were lower in the DPP4i group vs. non-DPP4i with the PS-stratified hazard ratio of 0.66 (95% CI 0.44–0.99) for RA, 0.73 (0.51–1.03) for other AD, and 0.68 (95% CI 0.52–0.89) for composite AD.
Conclusions
In this large cohort of diabetic patients, those initiating DPP4i combination therapy appear to have a decreased risk of incident AD including RA compared to those initiating non-DPP4i combination therapy. These results may suggest possible pharmacologic pathways for prevention or treatment of AD.
doi:10.1136/annrheumdis-2014-205216
PMCID: PMC4263684  PMID: 24919467
dipeptidyl peptidase-4 inhibitors; autoimmune disease; rheumatoid arthritis; inflammatory bowel disease; psoriasis; multiple sclerosis; systemic lupus erythematosus; type 2 diabetes
10.  Defining the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in rheumatoid arthritis through the study of PPAD biology 
Annals of the rheumatic diseases  2014;74(11):2054-2061.
Background
Antibodies to citrullinated proteins (ACPAs) are a hallmark of rheumatoid arthritis (RA). Porphyromonas gingivalis peptidylarginine deiminase (PPAD) has been implicated in the initiation of RA by generating citrullinated neoantigens and due to its ability to autocitrullinate.
Objectives
To define the citrullination status and biology of PPAD in P gingivalis and to characterize the anti-PPAD antibody response in RA and associated periodontal disease (PD).
Methods
PPAD in P gingivalis cells and culture supernatant was analyzed by immunoblotting and mass spectrometry to detect citrullination. Recombinant PPAD (rPPAD), inactive mutant PPAD (rPPADC351S), and N-terminal truncated PPAD (rPPADNtx) were cloned and expressed inE coli. Patients with RA and healthy controls were assayed for IgG antibodies to citrullinated rPPAD and unmodified rPPADC351S by ELISA. Anti-PPAD antibodies were correlated with anti-CCP3 antibody levels, RA disease activity, and PD status.
Results
PPAD from P gingivalis is truncated at the N- and C-terminal domains and not citrullinated. Only when artificially expressed in E coli, full-length rPPAD, but not truncated (fully active) rPPADNtx, is autocitrullinated. Anti-PPAD antibodies show no heightened reactivity to citrullinated rPPAD, but are exclusively directed against the unmodified enzyme. Antibodies against PPAD do not correlate with anti-CCP levels and disease activity in RA. By contrast, anti-PPAD antibody levels are significantly decreased in RA patients with PD.
Conclusions
PPAD autocitrullination is not the underlying mechanism linking PD and RA. N-terminal processing protects PPAD from autocitrullination and enhances enzyme activity. Anti-PPAD antibodies may have a protective role for the development of PD in RA patients.
doi:10.1136/annrheumdis-2014-205385
PMCID: PMC4368502  PMID: 24864075
Rheumatoid arthritis; periodontal disease; Porphyromonas gingivalis peptidylarginine deiminase; anti-PPAD antibodies; ACPA
11.  Gadolinium-based Compounds Induce NLRP3-dependent IL-1β Production and Peritoneal Inflammation 
Annals of the rheumatic diseases  2014;74(11):2062-2069.
Objective
Nephrogenic systemic fibrosis (NSF) is a progressive fibrosing disorder that may develop in patients with chronic kidney disease (CKD) after administration of gadolinium-based contrast agents (GBCAs). In the setting of impaired renal clearance of GBCAs, gadolinium (Gd) deposits in various tissues and fibrosis subsequently develops. However, the precise mechanism by which fibrosis occurs in NSF is incompletely understood. Because other profibrotic agents, such silica or asbestos, activate the NOD-like receptor protein 3 (NLRP3) inflammasome and initiate IL-1β release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation.
Methods
Bone marrow derived macrophages (BMDM) from C57BL/6, Nlrp3−/− and Asc−/− mice were incubated with three Gd-containing compounds and IL-1β activation and secretion was detected by ELISA and Western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and IFNγ-polarized macrophages by ELISA, qRT-PCR and NanoString nCounter analysis. Furthermore, C57BL/6 and Nlrp3−/− mice were injected i.p. with GBCA and recruitment of inflammatory cells to the peritoneum was analyzed by FACS.
Results
Both free Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1β secretion in vitro. Gd-DTPA also induces the recruitment of neutrophils and inflammatory monocytes to the peritoneum in vivo. Gd activated IL-4-polarized macrophages more effectively than IFNγ-polarized macrophages, which preferentially expressed genes known to downregulate inflammasome activity.
Conclusion
These data suggest that Gd released from GBCAs triggers a NLRP3 inflammasome-dependent inflammatory response that leads to fibrosis in an appropriate clinical setting. The preferential activation of IL-4-differentiated macrophages is consistent with the predominantly fibrotic presentation of NSF.
doi:10.1136/annrheumdis-2013-204900
PMCID: PMC4428954  PMID: 24914072
gadolinium; nephrogenic systemic fibrosis; inflammasome; NLRP3; macrophages
12.  Quantitative measurement of syndesmophyte volume and height in ankylosing spondylitis using CT 
Annals of the rheumatic diseases  2013;73(3):544-550.
Objective
Syndesmophyte growth in ankylosing spondylitis can be difficult to measure using radiographs because of poor visualisation and semiquantitative scoring methods. We developed and tested the reliability and validity of a new computer-based method that fully quantifies syndesmophyte volumes and heights on CT scans.
Methods
In this developmental study, we performed lumbar spine CT scans on 38 patients and used our algorithm to compute syndesmophyte volume and height in four intervertebral disk spaces. To assess reliability, we compared results between two scans performed on the same day in nine patients. To assess validity, we compared computed measures to visual ratings of syndesmophyte volume and height on both CT scans and radiographs by two physician readers.
Results
Coefficients of variation for syndesmophyte volume and height, based on repeat scans, were 2.05% and 2.40%, respectively. Based on Bland–Altman analysis, an increase in syndesmophyte volume of more than 4% or in height of more than 0.20 mm represented a change greater than measurement error. Computed volumes and heights were strongly associated with physician ratings of syndesmophyte volume and height on visual examination of both the CT scans (p<0.0001) and plain radiographs (p<0.002). Syndesmophyte volumes correlated with the Schober test (r=−0.48) and lateral thoracolumbar flexion (r=−0.60).
Conclusions
This new CT-based method that fully quantifies syndesmophytes in three-dimensional space had excellent reliability and face and construct validity. Given its high precision, this method shows promise for longitudinal clinical studies of syndesmophyte development and growth.
doi:10.1136/annrheumdis-2012-202661
PMCID: PMC5071781  PMID: 23345598
13.  Quantitative syndesmophyte measurement in ankylosing spondylitis using CT: longitudinal validity and sensitivity to change over 2 years 
Annals of the rheumatic diseases  2013;74(2):437-443.
Objectives
Accurate measurement of syndesmophyte development and growth in ankylosing spondylitis (AS) is needed for studies of biomarkers and of treatments to slow spinal fusion. We tested the longitudinal validity and sensitivity to change of quantitative measurement of syndesmophytes using CT.
Methods
We performed lumbar spine CT scans on 33 patients with AS at baseline, 1 year and 2 years. Volumes and heights of syndesmophytes were computed in four intervertebral disk spaces. We compared the computed changes to a physicians ratings of change ‘ based on CT scan inspection. Sensitivity to change of the computed measures was compared with that of the modified Stoke AS Spinal Score (radiography) and a scoring method based on MRI.
Results
At years 1 and 2, respectively 24 (73%) and 26 (79%) patients had syndesmophyte volume increases by CT. At years 1 and 2, the mean (SD) computed volume increases per patient were, respectively 87 (186) and 201 (366) mm3. Computed volume changes were strongly associated with the physicians visual ratings of ‘ change (p<0.0002 and p<0.0001 for changes at years 1 and 2, respectively). The sensitivity to change over 1 year was higher for the CT volume measure (1.84) and the CT height measure (1.22) than either the MRI measure (0.50) or radiography (0.29).
Conclusions
CT-based syndesmophytes measurements had very good longitudinal validity and better sensitivity to change than radiography or MRI. This method shows promise for longitudinal clinical studies of syndesmophyte development and growth.
doi:10.1136/annrheumdis-2013-203946
PMCID: PMC5069457  PMID: 24297375
14.  The Effects of Colchicine on Risk of Cardiovascular Events and Mortality Among Patients with Gout: A Cohort Study Using Electronic Medical Records Linked with Medicare Claims 
Annals of the rheumatic diseases  2015;75(9):1674-1679.
Background
Colchicine may have beneficial effects on cardiovascular (CV) disease, but there are sparse data on its CV effect among patients with gout. We examined the potential association between colchicine and CV risk and all-cause mortality in gout.
Methods
The analyses used data from an electronic medical record (EMR) database linked with Medicare claims (2006–2011). To be eligible for the study cohort, subjects must have had a diagnosis of gout in the EMR and Medicare claims. New users of colchicine were identified and followed-up from the first colchicine dispensing date. Non-users had no evidence of colchicine prescriptions during the study period and were matched to users on the start of follow-up, age, and gender. Both groups were followed for the primary outcome, a composite of myocardial infarction (MI), stroke or transient ischemic attack (TIA). We calculated hazard ratios (HRs) in Cox regression, adjusting for potential confounders.
Results
We matched 501 users with an equal number of non-users with a median follow-up of 16.5 months. During follow-up, 28 primary CV events were observed among users and 82 among non-users. Incidence rates per 1,000 person-years were 35.6 for users and 81.8 for non-users. After full adjustment, colchicine use was associated with a 49% lower risk (HR 0.51, 95% CI 0.30 – 0.88) in the primary CV outcome as well as a 73% reduction in all-cause mortality (HR 0.27, 95% CI 017 – 0.43).
Conclusion
Colchicine use was associated with a reduced risk of a CV event among patients with gout.
doi:10.1136/annrheumdis-2015-207984
PMCID: PMC5049504  PMID: 26582823
Gout; Colchicine; Cardiovascular Disease; Epidemiology
15.  Characterizing the expression and function of CCL28 and its corresponding receptor CCR10 in RA pathogenesis 
Annals of the rheumatic diseases  2014;74(10):1898-1906.
Objective
This study was conducted to determine the expression pattern, regulation and function of CCL28 and CCR10 in rheumatoid arthritis (RA) pathogenesis.
Methods
Expression of CCL28 and CCR10 was assessed in RA compared to other arthritis synovial tissues (ST)s or fluids (SF)s by histology or ELISA. The factors modulating CCL28 and CCR10 expression were identified in RA myeloid and endothelial cells by ELISA, FACS and Western blotting. The mechanism by which CCL28 ligation promotes RA angiogenesis was examined in control or CCR10 knockdown endothelial cell chemotaxis and capillary formation.
Results
CCL28 and/or CCR10 expression levels were accentuated in STs or SFs of patients with joint disease compared to normal controls and they were predominately coexpressed in RA myeloid and endothelial cells. We show that protein expression of CCL28 and CCR10 was modulated by TNF-α and TLR4 ligation in RA monocytes and endothelial cells and by IL-6 stimulation in RA macrophages. Neutralization of CCL28 in RA SF or blockade of CCR10 on human endothelial progenitor cells (EPC)s significantly reduced SF induced endothelial migration and capillary formation, demonstrating that ligation of joint CCL28 to endothelial CCR10+ cells participates in RA angiogenesis. We uncovered that angiogenesis driven by ligation of CCL28 to CCR10 is linked to the ERK cascade as CCR10 knockdown cells exhibit dysfunctional CCL28 induced ERK signaling, chemotaxis and capillary formation.
Conclusions
The overexpression of CCL28 and CCR10 in RA ST and their contribution to EPC migration into the RA joints support CCL28/CCR10 cascade as a potential therapeutic target for RA.
doi:10.1136/annrheumdis-2013-204530
PMCID: PMC4282625  PMID: 24833787
RA; CCL28; CCR10; angiogenesis; macrophages; endothelial cells
16.  Genome-wide Association and Functional Studies Identify a Role for IGFBP3 in Hip Osteoarthritis 
Annals of the rheumatic diseases  2014;74(10):1861-1867.
Objectives
To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.
Methods
The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (P-value ≤ 5x10−8) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.
Results
The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR = 0.71, P-value = 2x10−8). The association replicated in five studies (OR = 0.92, P-value = 0.020), but the joint analysis of discovery and replication results was not genome-wide significant (P-value = 1x10−6). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (P-value = 4x10−13), suggesting that this SNP or a variant in linkage disequilibrium (LD) could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.
Conclusions
Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.
doi:10.1136/annrheumdis-2013-205020
PMCID: PMC4449305  PMID: 24928840
Osteoarthritis of hip; genome-wide association study; functional study; chondrogenesis; IGFBP3
17.  Disease-specificity of autoantibodies to cytosolic 5’-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases 
Annals of the rheumatic diseases  2015;75(4):696-701.
Objectives
The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5’-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease-specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls.
Methods
Serum samples obtained from patients with IBM (n=238), polymyositis (PM) and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide enzyme-linked immunosorbent assays (ELISAs).
Results
Autoantibodies directed against major epitopes of cN-1A were frequent in IBM patients (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (<5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sjögren’s syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%).
Conclusions
In summary, we found frequent anti-cN-1A autoantibodies in sera from IBM patients. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist.
doi:10.1136/annrheumdis-2014-206691
PMCID: PMC4699257  PMID: 25714931
Autoantibodies; Cytosolic 5’-nucleotidase 1A (cN-1A); Disease-specificity; ELISA; Idiopathic inflammatory myopathy
18.  Imaging Modalities for the Classification of Gout: Systematic Literature Review and Meta-Analysis 
Annals of the rheumatic diseases  2014;74(10):1868-1874.
Objective
Although there has been major progress in gout imaging, no gout classification criteria currently include advanced imaging techniques. The objective of this study was to examine the usefulness of imaging modalities in the classification of gout when compared to monosodium urate (MSU) crystal confirmation as the gold standard, in order to inform development of new gout classification criteria.
Methods
We systematically reviewed the published literature concerning the diagnostic performance of plain film radiography, magnetic resonance imaging, ultrasound (US), conventional computed tomography, and dual energy computed tomography (DECT). Only studies with MSU crystal confirmation as the gold standard were included. When more than one study examined the same imaging feature, the data were pooled and summary test characteristics were calculated.
Results
Eleven studies (9 manuscripts and 2 meeting abstracts) satisfied the inclusion criteria. All were set in secondary care, with mean gout disease duration of at least 7 years. Three features were examined in more than one study: the double contour sign (DCS) on US, tophus on US, and MSU crystal deposition on DECT. The pooled (95% CI) sensitivity and specificity of US DCS were 0.83 (0.72–0.91) and 0.76 (0.68–0.83) respectively, of US tophus were 0.65 (0.34–0.87) and 0.80 (0.38–0.96) respectively, and of DECT were 0.87 (0.79–0.93) and 0.84 (0.75–0.90) respectively.
Conclusions
US and DECT show promise for gout classification but the few studies to date have mostly been in patients with longstanding, established disease. The contribution of imaging over clinical features for gout classification criteria requires further examination.
doi:10.1136/annrheumdis-2014-205431
PMCID: PMC4869978  PMID: 24915980
gout; classification criteria; ultrasound; dual energy computed tomography; imaging
19.  THE PRINTO CRITERIA FOR CLINICALLY INACTIVE DISEASE IN JUVENILE DERMATOMYOSITIS 
Annals of the rheumatic diseases  2012;72(5):686-693.
Objectives
To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM).
Methods
The PRINTO database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physician's and parent's global disease activity/damage evaluations, inactive disease criteria derived from literature, and other ad hoc criteria, were evaluated for sensitivity, specificity, and Cohen's kappa agreement.
Results
The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohen's K>0.8) were manual muscle testing (MMT)≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, the Childhood Myositis Assessment Scale (CMAS) ≥48, the Disease Activity Score (DAS) ≤3 and the Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT) ≤0.2. The best combination of variables to classify a patient as being in a status of inactive disease on or off therapy is at least 3 out of 4 of the following criteria: creatine kinase ≤150, CMAS≥48, MMT≥78, and PhyGloVAS≤0.2. After 24 months, 30/31 (96.8%) patients were inactive off therapy and 69/145 (47.6%) were inactive on-therapy.
Conclusion
PRINTO established data-driven criteria, with clearly evidence-based cut off values, to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.
doi:10.1136/annrheumdis-2012-201483
PMCID: PMC5040631  PMID: 22736096
juvenile dermatomyositis; core set measures; inactive disease; disease activity; Dermatomyositis; Outcomes research
20.  Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis 
Annals of the Rheumatic Diseases  2016;75(10):1743-1748.
Objectives
Improvement of skin fibrosis is part of the natural course of diffuse cutaneous systemic sclerosis (dcSSc). Recognising those patients most likely to improve could help tailoring clinical management and cohort enrichment for clinical trials. In this study, we aimed to identify predictors for improvement of skin fibrosis in patients with dcSSc.
Methods
We performed a longitudinal analysis of the European Scleroderma Trials And Research (EUSTAR) registry including patients with dcSSc, fulfilling American College of Rheumatology criteria, baseline modified Rodnan skin score (mRSS) ≥7 and follow-up mRSS at 12±2 months. The primary outcome was skin improvement (decrease in mRSS of >5 points and ≥25%) at 1 year follow-up. A respective increase in mRSS was considered progression. Candidate predictors for skin improvement were selected by expert opinion and logistic regression with bootstrap validation was applied.
Results
From the 919 patients included, 218 (24%) improved and 95 (10%) progressed. Eleven candidate predictors for skin improvement were analysed. The final model identified high baseline mRSS and absence of tendon friction rubs as independent predictors of skin improvement. The baseline mRSS was the strongest predictor of skin improvement, independent of disease duration. An upper threshold between 18 and 25 performed best in enriching for progressors over regressors.
Conclusions
Patients with advanced skin fibrosis at baseline and absence of tendon friction rubs are more likely to regress in the next year than patients with milder skin fibrosis. These evidence-based data can be implemented in clinical trial design to minimise the inclusion of patients who would regress under standard of care.
doi:10.1136/annrheumdis-2015-208024
PMCID: PMC5036205  PMID: 27016052
Systemic Sclerosis; Outcomes research; Epidemiology
21.  Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry 
Annals of the Rheumatic Diseases  2015;75(10):1770-1776.
Objectives
Digital ulcers (DUs) occur in up to half of patients with systemic sclerosis (SSc) and may lead to infection, gangrene and amputation with functional disability and reduced quality of life. This study has elucidated the burden of SSc-associated DUs through identification of four patient categories based on the pattern of DU recurrence over a 2-year observation period.
Methods
Patients with SSc-associated DUs enrolled in the Digital Ulcers Outcome Registry between 1 April 2008 and 19 November 2013, and with ≥2 years of observation and ≥3 follow-up visits during the observation period were analysed. Incident DU-associated complications were recorded during follow-up. Work and daily activity impairment were measured using a functional assessment questionnaire completed by patients after the observation period. Potential factors that could predict incident complications were identified in patients with chronic DUs.
Results
From 1459 patients, four DU occurrence categories were identified: 33.2% no-DU; 9.4% episodic; 46.2% recurrent; 11.2% chronic. During the observation period, patients from the chronic category had the highest rate of incident complications, highest work impairment and greatest need for help compared with the other categories. Independent factors associated with incident complications included gastrointestinal manifestations (OR 3.73, p=0.03) and previous soft tissue infection (OR 5.86, p=0.01).
Conclusions
This proposed novel categorisation of patients with SSc-associated DUs based on the occurrence of DUs over time may help to identify patients in the clinic with a heavier DU burden who could benefit from more complex management to improve their functioning and quality of life.
doi:10.1136/annrheumdis-2015-208121
PMCID: PMC5036212  PMID: 26612339
Autoimmune Diseases; Epidemiology; Systemic Sclerosis
22.  Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2015;75(10):1806-1812.
Objective
Compare changes in lipids and lipid-associated cardiovascular (CV) risk markers in patients with rheumatoid arthritis (RA) treated with tocilizumab or adalimumab.
Methods
Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4 weeks or adalimumab subcutaneously every 2 weeks for 24 weeks in the ADACTA trial. Lipid and lipid-associated CV risk biomarkers, including high-density lipoprotein-associated serum amyloid-A (HDL-SAA), secretory phospholipase A2 IIA (sPLA2 IIA) and lipoprotein(a) (Lp(a)), were measured at baseline and at week 8.
Results
The study included 162 patients treated with tocilizumab and 162 patients treated with adalimumab; HDL-SAA and sPLA2 IIA were measured in a subpopulation of 87 and 97 patients, respectively. Greater increases in mean low-density lipoprotein cholesterol (LDL-C) (0.46 mmol/L (95% CI 0.30 to 0.62)), high-density lipoprotein cholesterol (HDL-C) (0.07 mmol/L (0.001 to 0.14)), total cholesterol (TC) (0.67 mmol/L (0.47 to 0.86)), triglycerides (0.24 mmol/L (0.10 to 0.38)) and TC:HDL ratio (0.27 (0.12 to 0.42)) occurred with tocilizumab from baseline to 8 weeks. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab than adalimumab. Median changes from baseline to week 8 were –3.2 and –1.1 mg/L (p=0.0077) for HDL-SAA and –4.1 and –1.3 ng/mL (p<0.0001) for sPLA2 IIA; difference in adjusted means was –7.12 mg/dL (p<0.0001) for Lp(a). Similar results were observed in efficacy responders and non-responders per American College of Rheumatology and European League against Rheumatism criteria.
Conclusion
LDL-C and HDL-C increased more with tocilizumab than adalimumab. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab. Lipid change effects of interleukin-6 and tumour necrosis factor (TNF) inhibition, manifest by their net impact on lipids and lipoproteins, are not synonymous; the clinical significance is unclear and requires further study.
Trial registration number
NCT01119859.; post-results
doi:10.1136/annrheumdis-2015-207872
PMCID: PMC5036214  PMID: 26613768
Lipids; Cardiovascular Disease; Inflammation; Rheumatoid Arthritis
23.  Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study 
Annals of the Rheumatic Diseases  2015;75(10):1763-1769.
Objectives
To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX).
Methods
In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy.
Results
Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8.
Conclusions
In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment.
Trial registration number
NCT00767325.
doi:10.1136/annrheumdis-2015-207709
PMCID: PMC5036216  PMID: 26590174
Rheumatoid Arthritis; Ultrasonography; Disease Activity; DMARDs (biologic)
24.  T cell subsets: an immunological biomarker to predict progression to clinical arthritis in ACPA-positive individuals 
Annals of the Rheumatic Diseases  2015;75(10):1884-1889.
Objectives
Anticitrullinated protein antibody (ACPA)+ individuals with non-specific musculoskeletal symptoms are at risk of inflammatory arthritis (IA). This study aims to demonstrate the predictive value of T cell subset quantification for progression towards IA and compare it with previously identified clinical predictors of progression.
Methods
103 ACPA+ individuals without clinical synovitis were observed 3-monthly for 12 months and then as clinically indicated. The end point was the development of IA. Naïve, regulatory T cells (Treg) and inflammation related cells (IRCs) were quantified by flow cytometry. Areas under the ROC curve (AUC) were calculated. Adjusted logistic regressions and Cox proportional hazards models for time to progression to IA were constructed.
Results
Compared with healthy controls (age adjusted where appropriate), ACPA+ individuals demonstrated reduced naïve (22.1% of subjects) and Treg (35.8%) frequencies and elevated IRC (29.5%). Of the 103 subjects, 48(46.6%) progressed. Individually, T cell subsets were weakly predictive (AUC between 0.63 and 0.66), although the presence of 2 T cell abnormalities had high specificity. Three models were compared: model-1 used T cell subsets only, model-2 used previously published clinical parameters, model-3 combined clinical data and T cell data. Model-3 performed the best (AUC 0.79 (95% CI 0.70 to 0.89)) compared with model-1 (0.75 (0.65 to 0.86)) and particularly with model-2 (0.62 (0.54 to 0.76)) demonstrating the added value of T cell subsets. Time to progression differed significantly between high-risk, moderate-risk and low-risk groups from model-3 (p=0.001, median 15.4 months, 25.8 months and 63.4 months, respectively).
Conclusions
T cell subset dysregulation in ACPA+ individuals predates the onset of IA, predicts the risk and faster progression to IA, with added value over previously published clinical predictors of progression.
doi:10.1136/annrheumdis-2015-207991
PMCID: PMC5036223  PMID: 27613874
Arthritis; Synovitis; T Cells
25.  Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs 
Annals of the Rheumatic Diseases  2015;75(10):1866-1875.
Objectives
Rheumatoid arthritis (RA) is characterised by breach of self-tolerance towards citrullinated antigens with generation of anti-citrullinated peptide/proteins antibodies (ACPA). Currently, the nature and source of citrullinated antigens driving the humoral autoimmune response within synovial ectopic lymphoid structures (ELS) is a crucial unknown aspect of RA pathogenesis. Here we characterised the autoreactive B-cell response of lesional B cells isolated from ELS+RA synovium.
Methods
Single synovial tissue CD19+cells were Fluorescence Activated Cell Sorting (FACS)-sorted and VH/VL Ig genes cloned to generate recombinant monoclonal antibodies (rmAbs) from patients with ELS+/ACPA+RA.
Results
RA-rmAbs immunoreactivity analysis provided the following key findings: (1) in a chIP-based array containing 300 autoantigens and in a ‘citrullinome’ multiplex assay, a strong reactivity against citrullinated histones H2A/H2B (citH2A/H2B) was observed in ∼40% of RA-rmAbs, followed by cit-fibrinogen and cit-vimentin; (2) anti-citH2A/H2B-reactive RA-rmAbs (but not anti-citH2A/H2B negative) selectively recognised neutrophil extracellular traps (NETs) from peripheral blood and/or RA joint neutrophils; (3) anti-citH2A/citH2B and anti-NET immunobinding was dependent on affinity maturation and was completely abrogated following reversion of hypermutated IgVH/VL genes to germline sequences; (4) ELS+ (not ELS−) RA synovial tissues engrafted into Severe Combined ImmunoDeficiency (SCID) mice released human anti-citH2A/citH2B and anti-NET antibodies in association with the intra-graft expression of CXCL13 and lymphotoxin (LT)-β, two master regulators of ELS.
Conclusion
We provided novel evidence that B cells differentiated within synovial ELS in the RA joints frequent target deiminated proteins which could be generated during NETosis of RA synovial neutrophils including histones. Thus, NETs could represent a source of citrullinated antigens fuelling the ACPA autoimmune response within the RA synovium.
doi:10.1136/annrheumdis-2015-208356
PMCID: PMC5036240  PMID: 26659717
Rheumatoid Arthritis; B cells; Autoantibodies

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