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Erik Lubberts - One of the best experts on this subject based on the ideXlab platform.
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interleukin 17 receptor deficiency results in impaired synovial expression of interleukin 1 and matrix metalloproteinases 3 9 and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall induced arthritis
Arthritis & Rheumatism, 2005Co-Authors: Marije I Koenders, Leo A B Joosten, Erik Lubberts, Jay K Kolls, Birgitte Opperswalgreen, Jill R Schurr, Paul Schwarzenberger, Liduine Van Den Bersselaar, Wim B Van Den BergAbstract:OBJECTIVE: To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)-induced arthritis. METHODS: SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R-deficient (IL-17R-/-) mice. At different time points, Joint inflammation was assessed by using calipers to measure Joint Swelling. On day 42, mice were killed, and knee Joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R-/- mice after 5 repeated injections of SCW fragments. RESULTS: IL-17R signaling did not play a significant role in acute Joint Swelling induced by a single injection of SCW fragments directly into the Joint. However, repeated local injections of SCW fragments into the knee Joints of IL-17R-/- mice resulted in fewer infiltrating cells in the Joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R-/- mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R-/- mice. CONCLUSION: These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven Joint inflammation to a chronic, cartilage-destructive, T cell-mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
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interleukin 17 receptor deficiency results in impaired synovial expression of interleukin 1 and matrix metalloproteinases 3 9 and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall induced arthritis
Arthritis & Rheumatism, 2005Co-Authors: Marije I Koenders, Leo A B Joosten, Erik Lubberts, Wim B Van Den Berg, Jay K Kolls, Birgitte Opperswalgreen, Liduine Van Den Bersselaar, Jill R Schurr, Paul SchwarzenbergerAbstract:Objective To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)–induced arthritis. Methods SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R–deficient (IL-17R–/–) mice. At different time points, Joint inflammation was assessed by using calipers to measure Joint Swelling. On day 42, mice were killed, and knee Joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R–/– mice after 5 repeated injections of SCW fragments. Results IL-17R signaling did not play a significant role in acute Joint Swelling induced by a single injection of SCW fragments directly into the Joint. However, repeated local injections of SCW fragments into the knee Joints of IL-17R–/– mice resulted in fewer infiltrating cells in the Joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R–/– mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R–/– mice. Conclusion These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven Joint inflammation to a chronic, cartilage-destructive, T cell–mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
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toll like receptor 2 pathway drives streptococcal cell wall induced Joint inflammation critical role of myeloid differentiation factor 88
Journal of Immunology, 2003Co-Authors: Leo A B Joosten, Kiyoshi Takeda, Shizuo Akira, Marije I Koenders, Ruben L Smeets, Marleen Heuvelmansjacobs, Monique M Helsen, Erik Lubberts, Fons A J Van De Loo, Wim B Van Den BergAbstract:The IL-1R/Toll-like receptor (TLR) superfamily of receptors has a key role in innate immunity and inflammation. In this study, we report that streptococcal cell wall (SCW)-induced Joint inflammation is predominantly dependent on TLR-2 signaling, since TLR-2-deficient mice were unable to develop either Joint Swelling or inhibition of cartilage matrix synthesis. Myeloid differentiation factor 88 (MyD88) is a Toll/IL-1R domain containing adaptor molecule known to have a central role in both IL-1R/IL-18R and TLR signaling. Mice deficient for MyD88 did not develop SCW-induced arthritis; both Joint Swelling and disturbance of cartilage chondrocyte anabolic function was completely abolished. Local levels of proinflammatory cytokines and chemokines in synovial tissue washouts were strongly reduced in MyD88-deficient mice. Histology confirmed the pivotal role of MyD88 in acute Joint inflammation. TLR-2-deficient mice still allow influx of inflammatory cells into the Joint cavity, although the number of cells was markedly reduced. No influx of inflammatory cells was seen in Joints of MyD88-deficient mice. In addition, cartilage matrix proteoglycan loss was completely absent in MyD88 knockout mice. These findings clearly demonstrated that MyD88 is a key component in SCW-induced Joint inflammation. Since agonists of the Toll-like pathway are abundantly involved in both septic and rheumatoid arthritis, targeting of MyD88 may be a novel therapy in inflammatory Joint diseases.
H B Hammer - One of the best experts on this subject based on the ideXlab platform.
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swollen but not tender Joints are independently associated with ultrasound synovitis results from a longitudinal observational study of patients with established rheumatoid arthritis
Annals of the Rheumatic Diseases, 2019Co-Authors: H B Hammer, Brigitte Michelsen, Joseph Sexton, I K Haugen, S A Provan, Espen A Haavardsholm, Till Uhlig, Tore K KvienAbstract:Objectives Joint Swelling and tenderness are considered a proxy for inflammation in patients with rheumatoid arthritis (RA). With ultrasound-detected inflammation as reference, our objectives were to explore on patient and Joint level the associations between ultrasound synovitis and Joint Swelling, tenderness and patient-reported Joint pain (PRJP). Methods 209 patients with established RA were examined six times during 12 months with assessment of 32 Joints in upper/lower extremities for Joint Swelling/tenderness and Grey scale (GS)/power Doppler (PD) synovitis. PRJP was assessed on a manikin. Correlations between different sum scores were at each examination calculated using Spearman’s rho (r), agreement at Joint level was examined by Cohen’s kappa and logistic regression models were used to explore the associations between Joint assessment and GS/PD scores. Results At patient level, swollen Joints were strongly correlated with GS/PD sum scores (r=0.64–0.88), while tender Joints were primarily associated with PRJP (r=0.54–0.68). At Joint level, GS/PD pathology had higher agreement with Swelling (kappa 0.54–0.57) than tenderness (kappa 0.20–0.21) or PRJP (0.23–0.25). Higher percentages of Joints were swollen according to increasing GS/PD scores, independently of Joint tenderness. However, Joints being tender, but not swollen, were not associated with GS/PD scores. Receiver operating curves showed swollen but not tender Joints to be associated with GS/PD scores. Conclusions Swollen Joints were strongly associated with ultrasound detected synovitis at both patient and Joint level, while this association was not found for tender Joints. These results may question if tender Joints reflect ongoing inflammation in established RA.
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what is metacarpophalangeal Joint Swelling in psoriatic arthritis ultrasound findings and reliability assessment
Clinical and Experimental Rheumatology, 2018Co-Authors: Cristina Maciavilla, H B Hammer, Sandra Falcao, M Gutierrez, J Medina, E De MiguelAbstract:OBJECTIVES To evaluate by ultrasound (US) the frequency and reliability of peritenon extensor tendon inflammation (PTI) and intra articular synovitis (IAS) in metacarpophalangeal Joints (MCPj) of psoriatic arthritis (PsA) patients. METHODS 27 PsA patients with clinical involvement of MCPj were consecutively included. Presence of PTI and IAS were evaluated by grey-scale (GS) and power Doppler (PD). Longitudinal and transverse 3-5 second videos of US examinations were recorded for reliability assessments by five readers. Consensus on positive US results was achieved when at least three readers agreed. RESULTS Clinical Swelling was present in 60 Joints whereas US detected IAS and/or PTI in 75 MCPj. GS PTI in at least one MCPj was found in 19 patients and 41 Joints, concurring with clinical Swelling in 30/41. GS IAS in at least one MCPj was found in 23 patients and 63 Joints, concurring with clinical Swelling in 37/63. The inter-reader reliability was good for PD PTI and moderate for GS PTI. CONCLUSIONS Our study identifies that both IAS and PTI cause MCPj Swelling, where PTI is almost as frequent as IAS as a cause of Swelling. The reliability of PTI is at least as good as for IAS.
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op0150 ultrasound power doppler activity predicts clinical Joint Swelling in early rheumatoid arthritis patients secondary analyses from the arctic trial
Annals of the Rheumatic Diseases, 2018Co-Authors: L B Nordberg, D Van Der Heijde, Siri Lillegraven, A B Aga, Joseph O Sexton, E Lie, H B Hammer, I C Olsen, T Uhlig, T K KvienAbstract:Background Ultrasound is increasingly applied in the management of rheumatoid arthritis (RA). It is important to detect synovitis early to prevent future Joint damage and disability. It is not known whether subclinical ultrasound inflammation in a Joint precedes clinical Joint Swelling. Objectives We aimed to investigate whether ultrasound power Doppler (PD) activity in a Joint is associated with subsequent clinical Joint Swelling in early RA patients. Methods In the treat-to-target ARCTIC trial, DMARD naive early RA patients were randomised to follow-up with or without ultrasound, with the same treatment algorithm applied in both arms. Patients were assessed by 44 swollen Joint count at all visits (13 visits over two years). Ultrasound examinations were performed using a validated 0–3 semi-quantitative scoring system. 1 with assessments at all visits in the ultrasound arm and at baseline, 12 and 24 months in the conventional arm. We calculated the risk of next-visit clinical Joint Swelling according to ultrasound inflammation status in clinically non-swollen Joints at the preceding visit. We estimated the odds ratio of a Joint being swollen at next visit in Joints with different PD activity (PD score: 1, 2 or 3), compared to non-swollen Joints with no PD activity (PD score=0). These calculations were performed in a logistic mixed-effects model with random intercepts for patient and Joint in order to account for within-patient and -Joint dependencies, and were adjusted for age, gender, ACPA status, DMARD treatment and strategy arm. Joints injected with corticosteroids were excluded. Data from the two strategy arms were pooled and analysed together, as clinical and radiographic outcomes were similar in the two arms after two years. 2 Results 230 patients were included (118 in the ultrasound strategy arm, 112 in the conventional strategy arm). Mean (SD) age was 51.4 (13.7) years, 61% were female and mean baseline DAS was 3.46 (1.17). The risk of clinical Joint Swelling at the next visit increased with grade of PD activity (table 1). PD=Power Doppler. Odds ratios are adjusted for within-patient and within-Joint dependencies, gender, age, DMARD treatment, ACPA status and strategy arm. Conclusions We found PD activity in non-swollen Joints to be strongly associated with development of clinical Joint Swelling at the next visit, and the risk increased with higher power Doppler activity. This study supports the use of ultrasound as a tool to detect Joints at risk for developing clinical synovitis. References [1] Hammer HB, et al. ARD 2011. [2] Haavardsholm EA, et al. BMJ2016. Disclosure of Interest L. Nordberg: None declared, S. Lillegraven: None declared, A.-B. Aga: None declared, J. Sexton: None declared, E. Lie: None declared, H. Hammer: None declared, I. Olsen: None declared, T. Uhlig: None declared, D. van der Heijde: None declared, T. Kvien: None declared, E. Haavardsholm Grant/research support from: Pfizer, UCB, Roche, MSD, and AbbVie
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sat0626 metacarpophalangeal Joint Swelling in psoriatic arthritis what does it mean
Annals of the Rheumatic Diseases, 2017Co-Authors: C Macia, H B Hammer, Sandra Falcao, M Gutierrez, J Medina, E De MiguelAbstract:Background Clinical metacarpophalangeal Joint (MCPj) Swelling is a frequent finding in psoriatic arthritis (PsA). It is assumed to be caused by intra-articular synovitis (IAS). However, ultrasound (US) have also demonstrated in PsA peritenon inflammation of the extensor digitorum tendon (PTI).To date the data about the significance of this two lesions (IAS and PTI) in MCPj Swelling are sparse. Objectives Our objective was to explore PTI and IAS as the cause of clinical MCPj Swelling in PsA patients. Methods 27 consecutive non selected PsA patients, fulfilling CASPAR criteria, with clinical involvement of at least one 2nd to 5th MCPj were included. A MyLab 70 XVG machine, Esaote, Genova, Italy, with a greyscale (GS) 13 MHz probe, and a 7.1 MHz power Doppler (PD) frequency (PRF 750 Hz, Gain 60) was used. Videos (3–5 sec) of each MCPj 2nd to 5th of both hands in transversal and longitudinal views were obtained for central reader analysis, scoring US as presence or absence in GS and PD of: 1) PTI (defined as an hypoechoic Swelling of the soft tissue surrounding the extensor tendon at MCPj level with or without PD) and 2) IAS (OMERACT definition). US pathology for each Joint and lesion was defined as at least three of five central readers having the same score. SPSS analysis was performed for frequencies, percentage of agreement and Cohen9s Kappa test. Results 27 PsA patients with a mean (SD) age of 56 (11) years and disease duration 109 (101) months were included. Isolated peripheral involvement was present in 21 patients (78%) and 6 (22%) had both axial and peripheral affection. Mean (SD) CRP level was 8.3 (8.2) mg/l and ESR 21.9 (19.3) mm. The mean DAS28 ESR was 3.88 (1.23). Psoriasis involvement included skin and nails in 15 (55.5%) of the patients. A total of 216 MCPj were examined, with 60 (27,7%) being clinically swollen. The figure illustrates the agreement between clinical and US assessments, and the table shows the kappa values for the agreements. PTI in at least one MCPj was found in 19/27 patients (70%) with a total of 41/216 locations (19%) in GS. For IAS, there was GS in at least one MCPj in 23/27 patients (85%) with a total of 63/216 locations (29%). 28 of 41 (68.3%) Joints had both PTI and IAS. Conclusions Our study identifies two different US lesions (IAS and PTI) causing clinical Joint Swelling. PTI is near as frequent as IAS as a cause of MCPj Swelling, and future studies are necessary to explore the added value of assessing PTI for prognosis or treatment. Disclosure of Interest None declared
Marije I Koenders - One of the best experts on this subject based on the ideXlab platform.
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inflammatory arthritis in caspase 1 gene deficient mice contribution of proteinase 3 to caspase 1 independent production of bioactive interleukin 1beta
Arthritis & Rheumatism, 2009Co-Authors: Leo A B Joosten, Marije I Koenders, Monique M Helsen, Mihai G Netea, Giamila Fantuzzi, Helmut Sparrer, Christine T N Pham, Jos W M Van Der Meer, Charles A Dinarello, Wim B Van Den BergAbstract:OBJECTIVE: Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro-interleukin-1beta (proIL-1beta), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. METHODS: Acute and chronic arthritis were induced in caspase 1-/- mice, and the lack of caspase 1 was investigated for its effects on Joint Swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. RESULTS: Surprisingly, caspase 1-/- mice, in a model of acute (neutrophil-dominated) arthritis, developed Joint Swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1beta were comparable in caspase 1-/- mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1-/- mice led to reduced Joint inflammation and less cartilage damage, implying a caspase 1-dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1beta concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. CONCLUSION: Caspase 1 deficiency does not affect neutrophil-dominated Joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced Joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1beta production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.
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interleukin 17 receptor deficiency results in impaired synovial expression of interleukin 1 and matrix metalloproteinases 3 9 and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall induced arthritis
Arthritis & Rheumatism, 2005Co-Authors: Marije I Koenders, Leo A B Joosten, Erik Lubberts, Jay K Kolls, Birgitte Opperswalgreen, Jill R Schurr, Paul Schwarzenberger, Liduine Van Den Bersselaar, Wim B Van Den BergAbstract:OBJECTIVE: To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)-induced arthritis. METHODS: SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R-deficient (IL-17R-/-) mice. At different time points, Joint inflammation was assessed by using calipers to measure Joint Swelling. On day 42, mice were killed, and knee Joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R-/- mice after 5 repeated injections of SCW fragments. RESULTS: IL-17R signaling did not play a significant role in acute Joint Swelling induced by a single injection of SCW fragments directly into the Joint. However, repeated local injections of SCW fragments into the knee Joints of IL-17R-/- mice resulted in fewer infiltrating cells in the Joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R-/- mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R-/- mice. CONCLUSION: These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven Joint inflammation to a chronic, cartilage-destructive, T cell-mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
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interleukin 17 receptor deficiency results in impaired synovial expression of interleukin 1 and matrix metalloproteinases 3 9 and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall induced arthritis
Arthritis & Rheumatism, 2005Co-Authors: Marije I Koenders, Leo A B Joosten, Erik Lubberts, Wim B Van Den Berg, Jay K Kolls, Birgitte Opperswalgreen, Liduine Van Den Bersselaar, Jill R Schurr, Paul SchwarzenbergerAbstract:Objective To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)–induced arthritis. Methods SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R–deficient (IL-17R–/–) mice. At different time points, Joint inflammation was assessed by using calipers to measure Joint Swelling. On day 42, mice were killed, and knee Joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R–/– mice after 5 repeated injections of SCW fragments. Results IL-17R signaling did not play a significant role in acute Joint Swelling induced by a single injection of SCW fragments directly into the Joint. However, repeated local injections of SCW fragments into the knee Joints of IL-17R–/– mice resulted in fewer infiltrating cells in the Joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R–/– mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R–/– mice. Conclusion These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven Joint inflammation to a chronic, cartilage-destructive, T cell–mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
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toll like receptor 2 pathway drives streptococcal cell wall induced Joint inflammation critical role of myeloid differentiation factor 88
Journal of Immunology, 2003Co-Authors: Leo A B Joosten, Kiyoshi Takeda, Shizuo Akira, Marije I Koenders, Ruben L Smeets, Marleen Heuvelmansjacobs, Monique M Helsen, Erik Lubberts, Fons A J Van De Loo, Wim B Van Den BergAbstract:The IL-1R/Toll-like receptor (TLR) superfamily of receptors has a key role in innate immunity and inflammation. In this study, we report that streptococcal cell wall (SCW)-induced Joint inflammation is predominantly dependent on TLR-2 signaling, since TLR-2-deficient mice were unable to develop either Joint Swelling or inhibition of cartilage matrix synthesis. Myeloid differentiation factor 88 (MyD88) is a Toll/IL-1R domain containing adaptor molecule known to have a central role in both IL-1R/IL-18R and TLR signaling. Mice deficient for MyD88 did not develop SCW-induced arthritis; both Joint Swelling and disturbance of cartilage chondrocyte anabolic function was completely abolished. Local levels of proinflammatory cytokines and chemokines in synovial tissue washouts were strongly reduced in MyD88-deficient mice. Histology confirmed the pivotal role of MyD88 in acute Joint inflammation. TLR-2-deficient mice still allow influx of inflammatory cells into the Joint cavity, although the number of cells was markedly reduced. No influx of inflammatory cells was seen in Joints of MyD88-deficient mice. In addition, cartilage matrix proteoglycan loss was completely absent in MyD88 knockout mice. These findings clearly demonstrated that MyD88 is a key component in SCW-induced Joint inflammation. Since agonists of the Toll-like pathway are abundantly involved in both septic and rheumatoid arthritis, targeting of MyD88 may be a novel therapy in inflammatory Joint diseases.
Leo A B Joosten - One of the best experts on this subject based on the ideXlab platform.
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inflammatory arthritis in caspase 1 gene deficient mice contribution of proteinase 3 to caspase 1 independent production of bioactive interleukin 1beta
Arthritis & Rheumatism, 2009Co-Authors: Leo A B Joosten, Marije I Koenders, Monique M Helsen, Mihai G Netea, Giamila Fantuzzi, Helmut Sparrer, Christine T N Pham, Jos W M Van Der Meer, Charles A Dinarello, Wim B Van Den BergAbstract:OBJECTIVE: Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro-interleukin-1beta (proIL-1beta), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. METHODS: Acute and chronic arthritis were induced in caspase 1-/- mice, and the lack of caspase 1 was investigated for its effects on Joint Swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. RESULTS: Surprisingly, caspase 1-/- mice, in a model of acute (neutrophil-dominated) arthritis, developed Joint Swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1beta were comparable in caspase 1-/- mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1-/- mice led to reduced Joint inflammation and less cartilage damage, implying a caspase 1-dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1beta concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. CONCLUSION: Caspase 1 deficiency does not affect neutrophil-dominated Joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced Joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1beta production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.
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interleukin 17 receptor deficiency results in impaired synovial expression of interleukin 1 and matrix metalloproteinases 3 9 and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall induced arthritis
Arthritis & Rheumatism, 2005Co-Authors: Marije I Koenders, Leo A B Joosten, Erik Lubberts, Jay K Kolls, Birgitte Opperswalgreen, Jill R Schurr, Paul Schwarzenberger, Liduine Van Den Bersselaar, Wim B Van Den BergAbstract:OBJECTIVE: To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)-induced arthritis. METHODS: SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R-deficient (IL-17R-/-) mice. At different time points, Joint inflammation was assessed by using calipers to measure Joint Swelling. On day 42, mice were killed, and knee Joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R-/- mice after 5 repeated injections of SCW fragments. RESULTS: IL-17R signaling did not play a significant role in acute Joint Swelling induced by a single injection of SCW fragments directly into the Joint. However, repeated local injections of SCW fragments into the knee Joints of IL-17R-/- mice resulted in fewer infiltrating cells in the Joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R-/- mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R-/- mice. CONCLUSION: These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven Joint inflammation to a chronic, cartilage-destructive, T cell-mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
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interleukin 17 receptor deficiency results in impaired synovial expression of interleukin 1 and matrix metalloproteinases 3 9 and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall induced arthritis
Arthritis & Rheumatism, 2005Co-Authors: Marije I Koenders, Leo A B Joosten, Erik Lubberts, Wim B Van Den Berg, Jay K Kolls, Birgitte Opperswalgreen, Liduine Van Den Bersselaar, Jill R Schurr, Paul SchwarzenbergerAbstract:Objective To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)–induced arthritis. Methods SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R–deficient (IL-17R–/–) mice. At different time points, Joint inflammation was assessed by using calipers to measure Joint Swelling. On day 42, mice were killed, and knee Joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R–/– mice after 5 repeated injections of SCW fragments. Results IL-17R signaling did not play a significant role in acute Joint Swelling induced by a single injection of SCW fragments directly into the Joint. However, repeated local injections of SCW fragments into the knee Joints of IL-17R–/– mice resulted in fewer infiltrating cells in the Joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R–/– mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R–/– mice. Conclusion These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven Joint inflammation to a chronic, cartilage-destructive, T cell–mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
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toll like receptor 2 pathway drives streptococcal cell wall induced Joint inflammation critical role of myeloid differentiation factor 88
Journal of Immunology, 2003Co-Authors: Leo A B Joosten, Kiyoshi Takeda, Shizuo Akira, Marije I Koenders, Ruben L Smeets, Marleen Heuvelmansjacobs, Monique M Helsen, Erik Lubberts, Fons A J Van De Loo, Wim B Van Den BergAbstract:The IL-1R/Toll-like receptor (TLR) superfamily of receptors has a key role in innate immunity and inflammation. In this study, we report that streptococcal cell wall (SCW)-induced Joint inflammation is predominantly dependent on TLR-2 signaling, since TLR-2-deficient mice were unable to develop either Joint Swelling or inhibition of cartilage matrix synthesis. Myeloid differentiation factor 88 (MyD88) is a Toll/IL-1R domain containing adaptor molecule known to have a central role in both IL-1R/IL-18R and TLR signaling. Mice deficient for MyD88 did not develop SCW-induced arthritis; both Joint Swelling and disturbance of cartilage chondrocyte anabolic function was completely abolished. Local levels of proinflammatory cytokines and chemokines in synovial tissue washouts were strongly reduced in MyD88-deficient mice. Histology confirmed the pivotal role of MyD88 in acute Joint inflammation. TLR-2-deficient mice still allow influx of inflammatory cells into the Joint cavity, although the number of cells was markedly reduced. No influx of inflammatory cells was seen in Joints of MyD88-deficient mice. In addition, cartilage matrix proteoglycan loss was completely absent in MyD88 knockout mice. These findings clearly demonstrated that MyD88 is a key component in SCW-induced Joint inflammation. Since agonists of the Toll-like pathway are abundantly involved in both septic and rheumatoid arthritis, targeting of MyD88 may be a novel therapy in inflammatory Joint diseases.
Tore K Kvien - One of the best experts on this subject based on the ideXlab platform.
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swollen but not tender Joints are independently associated with ultrasound synovitis results from a longitudinal observational study of patients with established rheumatoid arthritis
Annals of the Rheumatic Diseases, 2019Co-Authors: H B Hammer, Brigitte Michelsen, Joseph Sexton, I K Haugen, S A Provan, Espen A Haavardsholm, Till Uhlig, Tore K KvienAbstract:Objectives Joint Swelling and tenderness are considered a proxy for inflammation in patients with rheumatoid arthritis (RA). With ultrasound-detected inflammation as reference, our objectives were to explore on patient and Joint level the associations between ultrasound synovitis and Joint Swelling, tenderness and patient-reported Joint pain (PRJP). Methods 209 patients with established RA were examined six times during 12 months with assessment of 32 Joints in upper/lower extremities for Joint Swelling/tenderness and Grey scale (GS)/power Doppler (PD) synovitis. PRJP was assessed on a manikin. Correlations between different sum scores were at each examination calculated using Spearman’s rho (r), agreement at Joint level was examined by Cohen’s kappa and logistic regression models were used to explore the associations between Joint assessment and GS/PD scores. Results At patient level, swollen Joints were strongly correlated with GS/PD sum scores (r=0.64–0.88), while tender Joints were primarily associated with PRJP (r=0.54–0.68). At Joint level, GS/PD pathology had higher agreement with Swelling (kappa 0.54–0.57) than tenderness (kappa 0.20–0.21) or PRJP (0.23–0.25). Higher percentages of Joints were swollen according to increasing GS/PD scores, independently of Joint tenderness. However, Joints being tender, but not swollen, were not associated with GS/PD scores. Receiver operating curves showed swollen but not tender Joints to be associated with GS/PD scores. Conclusions Swollen Joints were strongly associated with ultrasound detected synovitis at both patient and Joint level, while this association was not found for tender Joints. These results may question if tender Joints reflect ongoing inflammation in established RA.
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sat0040 remission without dmards in patients fulfilling the 2010 classification criteria for rheumatoid arthritis the impact of duration of Joint Swelling
Annals of the Rheumatic Diseases, 2014Co-Authors: E S Norli, E Lie, G H Brinkmann, Tore K Kvien, O Bjorneboe, Halvor Nygaard, Anne Julsrud Haugen, Patrik Stolt, Cathrine Thunem, M D MjaavattenAbstract:Background In 2010 the new ACR/EULAR classification criteria for rheumatoid arthritis (RA criteria) were published. The prospects for early diagnosis and treatment have increased over the past decades, partly driven by the theory of a window of opportunity. This theory even implies the possibility of preventing development of RA if aggressive treatment is started early. Objectives We wanted to study the 2-year outcome of patients with arthritis of less than 16 weeks duration, who fulfilled the RA criteria at baseline with a special focus on the impact of duration of Joint Swelling at baseline. Methods 1084 patients (age 18-75 years) were included in the NOR-VEAC (Norwegian Very Early Arthritis Clinic) study from 2004 to 2010, i.e. before the RA criteria were implemented. Patients with crystal arthritis, septic arthritis, osteoarthritis and arthritis due to trauma were excluded. 234 patients (21.6%) fulfilled the RA criteria at baseline. 202 of these had information about DMARD use and were included in the current study. The relationship between resolved arthritis (defined as no swollen Joints at last visit and never used DMARDs) and duration of Joint Swelling, as well as other factors, was examined. Duration was treated as a non-linear continuous variable as well as divided into categories. Mann-Whitney U, Fisher9s exact and Chi-Square tests were used for the statistical analyses. Results Duration of Joint Swelling [median (25-75 percentile)] was 64 (38-83) days, mean (SD) age 52 (14) years, 62% were females, 60% anti-CCP positive, and 69% anti-CCP and/or RF positive. Tventy-three out of 202 (11.4%) patients had resolved arthritis. A statistically significant relationship was found between duration of arthritis at baseline and resolution of arthritis without exposure to DMARDs (Mann-Whitney U p=0.01). In cases with very short (0-2 weeks) duration, the arthritis resolved without DMARDs in 9/23 patients (39.1%). The corresponding proportion for 2-6 weeks duration was 5/36 (13.9%), and for >6 weeks duration 9/143 (6.3%). The patients with resolved arthritis less often had positive anti-CCP (p Conclusions Among patients who fulfilled the RA criteria at baseline, the arthritis resolved without initiation of DMARD treatment in a considerable proportion of patients in whom baseline duration of Joint Swelling was very short. Patients with arthritis of more than 6 weeks duration experienced resolution of arthritis less frequently. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1377
