Synovitis in osteoarthritis: current understanding with therapeutic implications

Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage, subchondral bone and (increasingly recognized) inflammation of the synovium. The synovium may show significant changes, even before visible cartilage degeneration has occurred, with infiltration of mononuclear cells, thickening of the synovial lining layer and production of inflammatory cytokines. The combination of sensitive imaging modalities and tissue examination has confirmed a high prevalence of synovial inflammation in all stages of OA, with a number of studies demonstrating that synovitis is related to pain, poor function and may even be an independent driver of radiographic OA onset and structural progression. Treating key aspects of synovial inflammation therefore holds great promise for analgesia and also for structure modification. This article will review current knowledge on the prevalence of synovitis in OA and its role in symptoms and structural progression, and explore lessons learnt from targeting synovitis therapeutically

Biomarkers of cardiovascular risk across phenotypes of osteoarthritis.

BACKGROUND: The objective of this study was to explore the associations between ultrasonographic and radiographic joint scores and levels of arterial CVD risk markers in patients with osteoarthritis (OA). Secondly, to compare the levels of arterial CVD risk markers between OA phenotypes and controls. METHOD: The "Musculoskeletal pain in Ullensaker" Study (MUST) invited residents of Ullensaker municipality with self-reported OA to a medical examination. OA was defined according to the American College of Rheumatology (ACR) criteria and phenotyped based on joint distribution. Joints of the hands, hips and knees were examined by ultrasonography and conventional radiography, and scored for osteosteophytes. Hands were also scored for inflammation by grey scale (GS) synovitis and power Doppler (PD) signal. Control populations were a cohort of inhabitants of Oslo (OCP), and for external validation, a UK community-based register (UKPC).Pulse pressure augmentation index (AIx) and pulse wave velocity (PWV) were measured using the Sphygmocor apparatus (Atcor®). Ankel-brachial index (ABI) was estimated in a subset of patients. In separate adjusted regression models we explored the associations between ultrasonography and radiograph joint scores and AIx, PWV and ABI. CVD risk markers were also compared between phenotypes of OA and controls in adjusted analyses. RESULTS: Three hundred and sixty six persons with OA were included (mean age (range); 63.0 (42.0-75.0)), (females (%); 264 (72)). Of these, 155 (42.3%) had isolated hand OA, 111 (30.3%) had isolated lower limb OA and 100 (27.3%) had generalized OA. 108 persons were included in the OCP and 963 persons in the UKPC; (mean age (range); OCP: 57.2 (40.4-70.4), UKPC: 63.9 (40.0-75.0), females (%); OCP: 47 (43.5), UKPC: 543 (56.4%). Hand osteophytes were associated with AIx while GS and PD scores were not related to CVD risk markers. All OA phenotypes had higher levels of AIx compared to OCP in adjusted analyses. External validation against UKPC confirmed these findings. CONCLUSIONS: Hand osteophytes might be related to higher risk of CVD. People with OA had higher augmented central pressure compared to controls.Words 330

Ultrasonography of Inflammatory and Structural Lesions in Hand Osteoarthritis: An OMERACT Agreement and Reliability Study

Objective To standardize and assess the reliability of ultrasonographic assessment of inflammatory and structural lesions in patients with hand osteoarthritis (OA). Methods The Outcome Measures in Rheumatology Ultrasound Working Group selected synovial hypertrophy (SH), joint effusion (JE), and power Doppler (PD) signals as the main inflammatory lesions in hand OA, and suggested osteophytes in the scapho-trapezio-trapezoid (STT) and cartilage defects in the proximal interphalangeal (PIP) joints as novel additions to previous structural scoring systems. A complementary imaging atlas provided detailed examples of the scores. A reliability exercise of static images was performed for the inflammatory features, followed by a patient-based exercise with 6 sonographers testing inflammatory and structural features in 12 hand OA patients. We used Cohen's kappa for intrareader and Light's kappa for interreader reliability for all features except PD, in which prevalence-adjusted bias-adjusted kappa (PABAK) was applied. Percentage agreement was also assessed. Results The web-based reliability exercise demonstrated substantial intra- and interreader reliability for all inflammatory features (kappa > 0.64). In the patient-based exercise, intra- and interreader reliability, respectively, varied: SH kappa = 0.73 and 0.45; JE kappa = 0.70 and 0.55; PD PABAK = 0.90 and 0.88; PIP joint cartilage kappa = 0.56 and 0.45; and STT osteophytes kappa = 0.62 and 0.36. Percentage close agreement was high for all features (>85%). Conclusion With ultrasound, substantial to excellent intrareader reliability was found for inflammatory features of hand OA. Interreader reliability was moderate, but overall high close agreement between readers suggests that better reliability is achievable after further training. Assessment of osteophytes in the STT joint and cartilage in the PIP joints achieved less reliability and the latter is not endorsed

Ultrasonography of Inflammatory and Structural Lesions in Hand Osteoarthritis: An OMERACT Agreement and Reliability Study

Objective: To standardize and assess the reliability of ultrasonographic assessment of inflammatory and structural lesions in patients with hand osteoarthritis (OA). Methods: The Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group selected synovial hypertrophy (SH), joint effusion (JE), and power Doppler (PD) signals as the main inflammatory lesions in hand OA, and suggested osteophytes in the scapho-trapezio-trapezoid (STT) and cartilage defects in the proximal interphalangeal (PIP) joints as novel additions to previous structural scoring systems. A complementary imaging atlas provided detailed examples of the scores. A reliability exercise of static images was performed for the inflammatory features, followed by a patient-based exercise with six sonographers testing inflammatory and structural features in twelve hand OA patients. We used Cohen's kappa (\u3ba) for intra-reader and Light's \u3ba for inter-reader reliability for all features except PD, in which Prevalence-Adjusted Bias-Adjusted Kappa (PABAK) was applied. Percentage agreement was also assessed. Results: The web-based reliability exercise demonstrated substantial intra- and inter-reader reliability for all inflammatory features (\u3ba>0.64). In the patient-based exercise, intra- and inter-reader reliability varied: SH \u3ba=0.73 and 0.45; JE \u3ba=0.70 and 0.55; PD PABAK=0.90 and 0.88; PIP cartilage \u3ba=0.56 and 0.45; STT osteophytes \u3ba=0.62 and 0.36. Percentage close agreement was high for all features (>85%). Conclusion: With ultrasound, substantial to excellent intra-reader reliability was found for inflammatory features of hand OA. Inter-reader reliability was moderate, but overall high close agreement between readers suggest that better reliability is achievable after further training. Assessment of osteophytes in the STT joint and cartilage in the PIP joints achieved less good reliability and the latter is not endorsed. Keywords: Hand osteoarthritis; outcome measures; ultrasonography

Biomarkers of cardiovascular risk across phenotypes of osteoarthritis

Abstract: Background: The objective of this study was to explore the associations between ultrasonographic and radiographic joint scores and levels of arterial CVD risk markers in patients with osteoarthritis (OA). Secondly, to compare the levels of arterial CVD risk markers between OA phenotypes and controls. Method: The “Musculoskeletal pain in Ullensaker” Study (MUST) invited residents of Ullensaker municipality with self-reported OA to a medical examination. OA was defined according to the American College of Rheumatology (ACR) criteria and phenotyped based on joint distribution. Joints of the hands, hips and knees were examined by ultrasonography and conventional radiography, and scored for osteosteophytes. Hands were also scored for inflammation by grey scale (GS) synovitis and power Doppler (PD) signal. Control populations were a cohort of inhabitants of Oslo (OCP), and for external validation, a UK community-based register (UKPC). Pulse pressure augmentation index (AIx) and pulse wave velocity (PWV) were measured using the Sphygmocor apparatus (Atcor®). Ankel-brachial index (ABI) was estimated in a subset of patients. In separate adjusted regression models we explored the associations between ultrasonography and radiograph joint scores and AIx, PWV and ABI. CVD risk markers were also compared between phenotypes of OA and controls in adjusted analyses. Results: Three hundred and sixty six persons with OA were included (mean age (range); 63.0 (42.0–75.0)), (females (%); 264 (72)). Of these, 155 (42.3%) had isolated hand OA, 111 (30.3%) had isolated lower limb OA and 100 (27.3%) had generalized OA. 108 persons were included in the OCP and 963 persons in the UKPC; (mean age (range); OCP: 57.2 (40.4–70.4), UKPC: 63.9 (40.0–75.0), females (%); OCP: 47 (43.5), UKPC: 543 (56.4%). Hand osteophytes were associated with AIx while GS and PD scores were not related to CVD risk markers. All OA phenotypes had higher levels of AIx compared to OCP in adjusted analyses. External validation against UKPC confirmed these findings. Conclusions: Hand osteophytes might be related to higher risk of CVD. People with OA had higher augmented central pressure compared to controls. Words 330

Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

Background: Synovial tissue fibrosis is common in advanced OA with features including the presence of stress fiber-positive myofibroblasts and deposition of cross-linked collagen type-I. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. PRG4 is a ligand of the CD44 receptor. Our objective was to examine the role of PRG4-CD44 interaction in regulating synovial tissue fibrosis in vitro and in vivo. Methods: OA synoviocytes were treated with TGF-β ± PRG4 for 24h and α-SMA content was determined using immunofluorescence. Rhodamine-labeled rhPRG4 was incubated with OA synoviocytes ± anti-CD44 or isotype control antibodies and cellular uptake of rhPRG4 was determined following a 30-min incubation and α-SMA expression following a 24-h incubation. HEK-TGF-β cells were treated with TGF-β ± rhPRG4 and Smad3 phosphorylation was determined using immunofluorescence and TGF-β/Smad pathway activation was determined colorimetrically. We probed for stress fibers and focal adhesions (FAs) in TGF-β-treated murine fibroblasts and fibroblast migration was quantified ± rhPRG4. Synovial expression of fibrotic markers: α-SMA, collagen type-I, and PLOD2 in Prg4 gene-trap (Prg4GT) and recombined Prg4GTR animals were studied at 2 and 9 months of age. Synovial expression of α-SMA and PLOD2 was determined in 2-month-old Prg4GT/GT&Cd44−/− and Prg4GTR/GTR&Cd44−/− animals. Results: PRG4 reduced α-SMA content in OA synoviocytes (p \u3c 0.001). rhPRG4 was internalized by OA synoviocytes via CD44 and CD44 neutralization attenuated rhPRG4’s antifibrotic effect (p \u3c 0.05). rhPRG4 reduced pSmad3 signal in HEKTGF- β cells (p \u3c 0.001) and TGF-β/Smad pathway activation (p \u3c 0.001). rhPRG4 reduced the number of stress fiberpositive myofibroblasts, FAs mean size, and cell migration in TGF-β-treated NIH3T3 fibroblasts (p \u3c 0.05). rhPRG4 inhibited fibroblast migration in a macrophage and fibroblast co-culture model without altering active or total TGF-β levels. Synovial tissues of 9-month-old Prg4GT/GT animals had higher α-SMA, collagen type-I, and PLOD2 (p \u3c 0.001) content and Prg4 re-expression reduced these markers (p \u3c 0.01). Prg4 re-expression also reduced α-SMA and PLOD2 staining in CD44-deficient mice. Conclusion: PRG4 is an endogenous antifibrotic modulator in the joint and its effect on myofibroblast formation is partially mediated by CD44, but CD44 is not required to demonstrate an antifibrotic effect in vivo

Organotin pollution at Arraial do Cabo, Rio de Janeiro State, Brazil: increasing levels after the TBT ban

Imposex, an endocrine disruption phenomenon, is a biomarker of tributyltin (TBT) exposure in marine gastropod populations. The occurrence and intensity of the syndrome in populations of the neogastropod Stramonita haemastoma were ascertained at nine sampling stations in October 2008 at Arraial do Cabo, a very important tourist resort in Rio de Janeiro state (Brazil) and part of the Marine Extractive Reserve of Arraial do Cabo. The results obtained made it possible to evaluate the changes which had occurred since the last biomonitoring campaign, undertaken in 2001, at these same stations. Despite the ban on the use of TBT imposed by the Brazilian Navy in 2003, the controls on the use of this agent in Brazil resulting from the establishment of NORMAM 23 by the Navy in 2007 and the complete ban of organotin compounds in antifouling paint formulae by the IMO on a global scale in 2008, imposex was still detected. Instead of the expected reduction, an increase was observed in the areas affected by imposex. Furthermore, populations in the areas seriously affected by imposex in 2001 were absent in the 2008 sampling campaign. These results suggest an increase in TBT pollution in the study area, indicating the inefficacy of legislative measures.O imposex, um fenômeno de desregulação endócrina, é um biomarcador da exposição ao tributilestanho (TBT) em populações de gastrópodes marinhos. A ocorrência e intensidade dessa síndrome nas populações do neogastrópode Stramonita haemastoma foram verificadas em nove estações amostrais em outubro de 2008 em Arraial do Cabo, uma área de grande importância turística no Rio de Janeiro (Brasil) e integrante da Reserva Extrativista Marinha de Arraial do Cabo. Com os resultados obtidos foi possível avaliar as alterações ocorridas desde o último biomonitoramento realizado em 2001, nessas mesmas estações. Mesmo após o banimento do TBT pela Marinha do Brasil em 2003, a entrada em vigor dos controles ao uso deste agente com o estabelecimento da NORMAM 23, no Brasil em 2007 pela Marinha, e o banimento completo do TBT nas fórmulas de tintas antiincrustantes pela IMO em escala global, em 2008, o imposex continua a ser detectado. Ao invés de um declínio esperado, observou-se um aumento da extensão das áreas afetadas pelo imposex. Além disso, observou-se a ausência de populações em áreas que em 2001 estavam gravemente afetadas pelo imposex. Esses resultados sugerem um aumento da poluição por TBT na área de estudo, indicando a ineficácia das medidas legislativas

Microplanning with Communicative Intentions: The SPUD System

The process of microplanning in Natural Language Generation (NLG) encompasses a range of problems in which a generator must bridge underlying domain-specific representations and general linguistic representations. These problems include constructing linguistic referring expressions to identify domain objects, selecting lexical items to express domain concepts, and using complex linguistic constructions to concisely convey related domain facts. In this paper, we argue that such problems are best solved through a uniform, comprehensive, declarative process. In our approach, the generator directly explores a search space for utterances described by a linguistic grammar. At each stage of search, the generator uses a model of interpretation, which characterizes the potential links between the utterance and the domain and context, to assess its progress in conveying domain-specific representations. We further address the challenges for implementation and knowledge representation in this approach. We show how to implement this approach effectively by using the lexicalized tree-adjoining grammar formalism (LTAG) to connect structure to meaning and using modal logic programming to connect meaning to context. We articulate a detailed methodology for designing grammatical and conceptua