Biochemical investigation of rheumatic diseases, Patrick Twomey Auto-immune serology, Neil McHugh Complement, Matthew Pickering Limb anatomy and medical imaging, Mike Benjamin Radiographic imaging, Andrew Grainger Ultrasound, Phil Platt Magnetic resonance imaging, Phil O'Connor Computed tomography, Geoff Hide Nuclear medicine, Adil Al-Nahhas Imaging in children, Karl Johnson Assessment of synovial joint fluid, Tony Freemont Cardiopulmonary investigation, Benjamin Schreiber Electrophysiology, Julian Blake Section 8 Management of rheumatic disease Patient education, David Walker Multidisciplinary treatment, Sarah Ryan Cyclooxygenase inhibitors, Kay Brune Analgesics, Philip Conaghan Glucocorticoids, Frank Buttgereit Immunosuppressants, Joanna Ledingham Signalling pathway inhibitors, Roy Fleischmann Anti-cytokine biologics, Andrew Ostor Cellular therapies, John Isaacs Biologics in paediatric rheumatic diseases, Daniel Lovell Stem cell therapies, Alan Tyndall Tissue engineering, Andrew McCaskie Injection therapy, Phil Platt Diet and obesity, Dorothy Pattison Alternative therapies, Edzard Ernst Principles of upper limb surgery, Ian McNab Principles of lower limb surgery, Damien Griffin Principles of spine surgery, Jeremy Fairbank Perioperative management of immunosuppression, Loreto Carmona Vaccination in immunocompromised adults, Van Assen Vaccination in immunocompromised children, Nico Wulffraat Anti-rheumatic drugs in pregnancy and lactation, Tarnya Marshall Section 9 Infection in rheumatic disease Septic arthritis in adults, Max Field Bone and joint infections in children, Julia Clark Osteomyelitis, Jeremy Field Lyme disease, Andreas Krause Viral arthritis, Stanley J.
Naides Mycobacterial diseases, Rita Abdulkader Brucellar arthritis, Eliseo Pascual Parasitic involvement, Yusuf Patel Fungal arthritis, Richard Watts Opportunistic infection, Susan Hopkins Rheumatic fever, Andrew C. Steer Section 10 Rheumatoid arthritis Pathogenesis of rheumatoid arthritis, Andy Cope Rheumatoid arthritis - diagnosis, Daniel Aletaha Rheumatoid arthritis - clinical features, Gerd Burmester Rheumatoid arthritis - management, Chris Deighton Section 11 Spondyloarthropathies Ankylosing spondylitis, Joachim Sieper Psoriatic arthritis, Philip Helliwell Reactive arthritis and enteropathic arthropathy, J.
Hill Gaston Section 12 Arthropathies primarily occuring in childhood Juvenile idiopathic arthritis, Eileen Baildam Section 13 Systemic lupus erythematosus Systemic lupus erythematosus - clinical features and aetiopathogenesis, Caroline Gordon Systemic lupus erythematosus - management, David Isenberg Paediatric onset systemic lupus erythematosus, Michael Beresford The antiphospholipid antibody syndrome, Munther A.
Khamashta Section 14 Scleroderma Systemic sclerosis, Chris Denton Paediatric scleroderma and related disorders, Francesco Zulian Nephrogenic systemic fibrosis, Cate Orteu Section 15 Myositis Polymyositis and dermatomyositis in adults, Hector Chinoy Paediatric polymyositis and dermatomyositis, Clarissa Pilkington Non-inflammatory myopathies, Mark Roberts Section 16 Sjogren's syndrome Sjogren's syndrome: clinical features, Simon Bowman Classification and diagnosis, Richard A.
Watts Large vessel vasculitis, Carlo Salvarani Polymyalgia rheumatica, Bhaskar Dasgupta Behcet's syndrome, Hasan Yazici Paediatric vasculitis, Paul Brogan Miscellaneous vasculitides, Richard A. Watts Section 19 Osteoarthritis Pathogenesis of osteoarthritis, Tonia Vincent Clinical features of osteoarthritis, Mike Doherty Osteoarthritis management, Phil Conaghan Section 20 Crystal arthropathies Gout, Nicola Dalbeth Osteoporosis, David Reid Paget's disease of bone, Stuart Ralston Paediatric metabolic bone disease, Nick Bishop Disorders of bone mineralisation: Osteomalacia, Ashok Bhalla Bone Tumours, Craig Gerrand Avascular necrosis, Stefan Rehart Renal osteodystrophy, Thomas Bardin Skeletal dysplasias, Paul Wordsworth Section 22 Regional rheumatic disease Shoulder, Andrew Ostor Elbow, Karen Walker-Bone Forearm, hand and wrist, Karen Walker-Bone Pelvis, groin and thigh, Cathy Speed Knee, Roger Wolman Foot and ankle, Tony Redmond Cervical and lumbar spine, David Walsh Additional boosts were necessary to maintain antibody levels figure 1C.
No difference in pain behaviour was detected in NGF immunised animals 24 hours postoperatively postop , but CuMVtt NGF vaccinated animals recovered from pain behaviour faster than mock-vaccinated animals within 48 hours figure 1D. As expected mice were pain free for several weeks, but pain behaviour started to develop from 8 weeks postsurgery. Following a boost at 10 weeks postop, and in keeping with a concomitant rise in the serum levels of anti-NGF antibody, a reversal of pain behaviour was observed.
This was maintained for 3 weeks until anti-NGF titres fell and pain behaviour resumed. At termination of the experiment, joints were harvested and scored for OA severity. No difference in disease severity between mock and vaccinated groups was observed figure 1E,F. Sera were also collected from experimental mice at the end of the study week 18 to measure general antibody responses.
Anti-CuMV IgG levels were elevated in both vaccinated and mock-vaccinated groups compared with non-vaccinated control animals. Total IgG and IgM levels were largely consistent across all groups.
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There was no evidence of induction of autoantibodies such as rheumatoid factor in any of the groups online supplementary figure 3. A second experiment was carried out to establish whether analgesia could be induced by immunisation after induction of pain behaviour i. When pain behaviour was established 10 weeks postop mice were randomised into two groups: vaccinated and mock-vaccinated.
Vaccine boosts were delivered at weeks 12 and 15 postop to maintain titres. Higher titre anti-NGF levels at the end of the experiment around OD50 10 3 appeared to be associated with an analgesic response between weeks 14 and 18 postop figure 2B,C. A subsequent spontaneous reduction in titres was associated with resumption of pain behaviour.revtalici.gq
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Direct correlation between antibody levels and pain behaviour during the experiment was not possible as titres were only measured in the sentinel and not the experimental group. The sentinel cohort was maintained to follow the fall in antibody titres over the following 10 weeks, which was similar to that observed in previous studies. A Therapeutic vaccination protocol. Mice were randomised to receive mock or NGF vaccine at 10 weeks postsurgery.
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E Neurite outgrowth inhibition with increasing concentrations of IgG isolated from serum of vaccinated animals and F their normalised difference compared with mock-vaccinated animals. Vaccines to self-antigens have been developed for other non-communicable diseases over the years. Early studies showed preclinical success but with limited clinical efficacy, which may have been due to poor immunogenicity of the vaccine platform, requiring the use of codelivery of adjuvant in preclinical models. Recent studies using refined vaccine platforms have demonstrated translatable efficacy from mouse to large animals including humans.
A unique aspect of this study is to combine a novel VLP-based therapeutic vaccine with measures of spontaneous pain behaviour in murine OA; its success confirming NGF as a valid target for OA related pain. Implementation of this type of strategy to treat OA pain has additional benefits. It induces a polyclonal response that might be more effective than a recombinant monoclonal antibody as it will stimulate antigen removal mediated by Fc-dependent clearance mechanisms.
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However, safety is also a concern. While we did not observe accelerated disease in our NGF-vaccinated cohort, we recognise that safety remains a significant issue, and this would need to be monitored carefully in any future clinical development. This proof of concept study has significant translational potential; in the first instance within veterinary practice where activity measures are validated pain outcomes. MFB originated the concept of the vaccine. AZ provided VLP constructs and developed purification strategies. AET performed the vaccinations and immunological assays.
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IP performed the histological preparation and in conjunction with ISvL conducted the histological analysis. LJ conducted and approved of the statistical analysis. Provenance and peer review Not commissioned; externally peer reviewed. Data sharing statement All data supporting this study are available on reasonable request from the corresponding authors. You will be able to get a quick price and instant permission to reuse the content in many different ways.
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Email alerts. Article Text. Article menu. Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis. Statistics from Altmetric. What does this study add? How might this impact on clinical practice or future developments? The prevalence and burden of arthritis. Rheumatology ; 41 Suppl 1 : 3 — 6. Care A. Oa arthritis nation report. Arthritis Care ; : 1 — Lane NE , Corr M. Osteoarthritis in Anti-NGF treatments for pain - two steps forward, one step back?
Nat Rev Rheumatol ; 13 : 76 — 8. Tanezumab for the treatment of pain from osteoarthritis of the knee.