ObjectivesRheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) might contribute to bone loss and arthralgia before the onset of joint inflammation. We aimed to dissect additional mechanisms by which ACPAs might contribute to development of joint pathology.MethodsFibroblast-like synoviocytes (FLS) were isolated from the synovial membrane of patients with RA. The FLS cultures were stimulated with polyclonal ACPAs (anti-CCP-2 antibodies) purified from the peripheral blood of patients with RA or with monoclonal ACPAs derived from single synovial fluid B cells. We analysed how ACPAs modulate FLS by measuring cell adhesion and mobility as well as cytokine production. Expression of protein arginine deiminase (PAD) enzymes and protein citrullination were analysed by immunofluorescence, and signal transduction was studied using immunoblotting.ResultsChallenge of FLS by starvation-induced stress or by exposure to the chemokine interleukin-8 was essential to sensitise the cells to ACPAs. These challenges led to an increased PAD expression and protein citrullination and an ACPA-mediated induction of FLS migration through a mechanism involving phosphoinositide 3-kinase activation. Inhibition of the PAD enzymes or competition with soluble citrullinated proteins or peptides completely abolished the ACPA-induced FLS migration. Different monoclonal ACPAs triggered distinct cellular effects in either fibroblasts or osteoclasts, suggesting unique roles for individual ACPA clones in disease pathogenesis.ConclusionWe propose that transient synovial insults in the presence of a certain pre-existing ACPA repertoire might result in an ACPA-mediated increase of FLS migration.
Objective. The appearance of anti-citrullinated protein antibodies (ACPAs) in the circulation represents a major risk factor for developing rheumatoid arthritis (RA). Patient-derived ACPAs have been shown to induce pain and bone erosion in mice, suggesting an active role in the pathogenicity of RA. We undertook this study to investigate whether ACPAs can induce tenosynovitis, an early sign of RA, in addition to pain and bone loss and whether these symptoms are dependent on peptidyl arginine deiminase 4 (PAD4).Methods. Monoclonal ACPAs generated from plasma cells of RA patients were transferred to wild-type and PAD4-deficient mice. Pain-like behavior and macroscopic inflammation were monitored for a period of 4 weeks, followed by the analyses of tenosynovitis in the ankle joints using magnetic resonance imaging (MRI) and bone microarchitecture in the tibia using an X-ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections.Results. The combination of 2 monoclonal ACPAs (1325:04C03 and 1325:01B09) induced long-lasting pain-like behavior and trabecular bone loss in mice. Although no synovitis was observed macroscopically, we detected tenosynovitis in the ACPA-injected mice by MRI. Microscopic analyses of the joints revealed a cellular hyperplasia and a consequent enlargement of the tendon sheath in the ACPA-treated group. In PAD4 −/− mice, the effects of ACPAs on pain-like behavior, tenosynovitis, and bone loss were significantly reduced.Conclusion. Monoclonal ACPAs can induce tenosynovitis in addition to pain and bone loss via mechanisms dependent on PAD4-mediated citrullination.
Background:Retrospective studies have shown that anti-citrullinated protein antibodies (ACPA) are a risk factor for the development of clinical arthritis.Objectives:We aimed to investigate in a prospective setting if ACPA and other biomarkers could predict development of ultrasound detected arthritis.Methods:Subjects with positive ACPA-test referred from primary care to the Rheumatology clinic that lacked arthritis in hands, feet and any other symptomatic joints by clinical and ultrasound examination (according to EULAR-OMERACT definition), were recruited into the Risk-RA research program during 2015-2016 and were followed up to the end of 2017. At inclusion a detailed clinical examination was performed and blood samples were analyzed for 13 specific ACPA reactivities (using a custom made peptide microarray) as well as 92 inflammation-associated protein biomarkers (using a multiplex immunoassay with Olink proximity extension technology). Presence of HLA-SE was analyzed using DR low-resolution kit. Univariate and multivariate analysis were used to investigate the association between clinical and laboratory parameters and development of ultrasound detected arthritis adjusting for the follow-up time.Results:42% (27 out of 65) of the Risk RA subjects developed ultrasound detectable arthritis during a median follow up of 8 months. The remaining 58% (38 out of 65) were followed for a median of 25 months (range 12-44) without any signs of ultrasound detectable arthritis. Subjects developing arthritis had higher prevalence of HLA-SE (89% vs 56%) and increased occurrence of ultrasound detected tenosynovitis (44% vs 5%), as compared to those not developing arthritis. ACPA reactivities to citrullinated vimentin peptides (cit vim 2-17: 22% vs 6%; and cit vim 60-75: 70% vs 43%) and citrullinated histone peptides (cit H4 31-50: 89% vs 49%; and cit H3 21-44: 48% vs 23%) were a more common occurrence in subjects developing ultrasound detectable arthritis. Backward selection in a Cox regression model showed that ultrasound detectable arthritis could be predicted in a model including HLA-SE, tenosynovitis and ACPA reactivity to cit H4 31-50. Hazard ratio (HR) for arthritis development were 3.4 (95% CI 1.0-12, p 0.06) for HLA-SE carriers, 2.9 (95% CI 1.3-6.7, p 0.01) for tenosynovitis and 4.1 (95% CI 1.2-14, p 0.02) for Anti-citrullinated H4 31-50 positivity. Only modest differences were observed for few of the tested inflammatory markers in those developing as compared to those not developing ultrasound detectable arthritis: Interleukin- 6 (3.9 vs 3.3 AU/ML), Programmed death-ligand 1 (4.9 vs 5.2 AU/ML) and Chemokine (C-X-C motif) ligand 6 (9.2 vs 9.5 AU/ML).Conclusion:Certain ACPA fine specificities, HLA-SE and tenosynovitis predict the development of ultrasound detectable arthritis in seropositive individuals with musculoskeletal symptom who are at risk for RA. Disclosure of Interests:Aase Hensvold: None declared, Yogan Kisten: None declared, Alexandra Circiumaru: None declared, Monika Hansson: None declared, Meng Sun Grant/resea...
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