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

Effectiveness of a new model of primary care management on knee pain and function in patients with knee osteoarthritis: Protocol for THE PARTNER STUDY

© 2018 The Author(s). Background: To increase the uptake of key clinical recommendations for non-surgical management of knee osteoarthritis (OA) and improve patient outcomes, we developed a new model of service delivery (PARTNER model) and an intervention to implement the model in the Australian primary care setting. We will evaluate the effectiveness and cost-effectiveness of this model compared to usual general practice care. Methods: We will conduct a mixed-methods study, including a two-arm, cluster randomised controlled trial, with quantitative, qualitative and economic evaluations. We will recruit 44 general practices and 572 patients with knee OA in urban and regional practices in Victoria and New South Wales. The interventions will target both general practitioners (GPs) and their patients at the practice level. Practices will be randomised at a 1:1 ratio. Patients will be recruited if they are aged =45 years and have experienced knee pain =4/10 on a numerical rating scale for more than three months. Outcomes are self-reported, patient-level validated measures with the primary outcomes being change in pain and function at 12 months. Secondary outcomes will be assessed at 6 and 12 months. The implementation intervention will support and provide education to intervention group GPs to deliver effective management for patients with knee OA using tailored online training and electronic medical record support. Participants with knee OA will have an initial GP visit to confirm their diagnosis and receive management according to GP intervention or control group allocation. As part of the intervention group GP management, participants with knee OA will be referred to a centralised multidisciplinary service: the PARTNER Care Support Team (CST). The CST will be trained in behaviour change support and evidence-based knee OA management. They will work with patients to develop a collaborative action plan focussed on key self-management behaviours, and communicate with the patients' GPs. Patients receiving care by intervention group GPs will receive tailored OA educational materials, a leg muscle strengthening program, and access to a weight-loss program as appropriate and agreed. GPs in the control group will receive no additional training and their patients will receive usual care. Discussion: This project aims to address a major evidence-to-practice gap in primary care management of OA by evaluating a new service delivery model implemented with an intervention targeting GP practice behaviours to improve the health of people with knee OA. Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12617001595303, date of registration 1/12/2017

Complex Interactions between Soil-Transmitted Helminths and Malaria in Pregnant Women on the Thai-Burmese Border

Intestinal worms, particularly hookworm and whipworm, can cause anaemia, which is harmful for pregnant women. The WHO recommends deworming in pregnancy in areas where hookworm infections are frequent. Some studies indicate that coinfection with worms and malaria adversely affects pregnancy whereas other studies have shown that coinfection with worms might reduce the severity of malaria. On the Thai-Burmese border malaria in pregnancy has been an important cause of maternal death. We examined the relationship between intestinal helminth infections in pregnant women and their malaria risk in our antenatal care units. In total 70% of pregnant women had worm infections, mostly hookworm, but also roundworm and whipworm; hookworm was associated with mild anaemia although ova counts were not high. Women infected with hookworm had more malaria and their babies had a lower birth weight than women without hookworm. In contrast women with roundworm infections had the lowest rates of malaria in pregnancy. Deworming eliminates all worms. In this area it is unclear whether mass deworming would be beneficial

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

Association between age at disease onset of anti-neutrophil cytoplasmic antibody-associated vasculitis and clinical presentation and short-term outcomes

Objectives: ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- A nd older-onset patients are still incompletely understood. Methods: We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results: A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03]. Conclusion: Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients

Multiple ring-enhancing cerebral lesions in systemic lupus erythematosis: A case report

Introduction: Infectious disease in an immunosuppressed patient is a diagnostic challenge. The clinical presentation and the bodys immune response may be quite different from those seen in an immunocompetent patient with the same infection. It is also a race against time to diagnose, as many of these infections can be fatal without timely intervention. Case presentation: We present the case of a 39-year-old Sri Lankan woman who was on immunosuppressive treatment for systemic lupus erythematosis and who presented with multiple ring-enhancing lesions of the brain. The most likely diagnosis, given the clinical picture, available investigation results, and characteristics of magnetic resonance imaging, was central nervous system tuberculosis. Owing to the small size of the lesions, a tissue biopsy could not be performed. Our patient responded well to a trial of anti-tuberculosis therapy, and there was clinical and radiological evidence of recovery. A paradoxical reaction with the initiation of anti-tuberculosis therapy was observed and this had to be countered with a prolonged course of steroids. Conclusions: Our experience and previous evidence from case reports suggest that high-dose steroids for a prolonged period (up to eight weeks) should be administered to counter the initial deterioration after starting anti-tuberculous chemotherapy for central nervous system tuberculomas. © 2012 Chang et al.; licensee BioMed Central Ltd