Reorganization of functional brain network architecture in chronic osteoarthritis pain

Osteoarthritis (OA) manifests with chronic pain, motor impairment, and proprioceptive changes. However, the role of the brain in the disease is largely unknown. Here, we studied brain networks using the mathematical properties of graphs in a large sample of knee and hip OA (KOA, n = 91; HOA, n = 23) patients. We used a robust validation strategy by subdividing the KOA data into discovery and testing groups and tested the generalizability of our findings in HOA. Despite brain global topological properties being conserved in OA, we show there is a network wide pattern of reorganization that can be captured at the subject-level by a single measure, the hub disruption index. We localized reorganization patterns and uncovered a shift in the hierarchy of network hubs in OA: primary sensory and motor regions and parahippocampal gyrus behave as hubs and insular cortex loses its central placement. At an intermediate level of network structure, frontoparietal and cingulo-opercular modules showed preferential reorganization. We examined the association between network properties and clinical correlates: global disruption indices and isolated degree properties did not reflect clinical parameters; however, by modeling whole brain nodal degree properties, we identified a distributed set of regions that reliably predicted pain intensity in KOA and generalized to hip OA. Together, our findings reveal that while conserving global topological properties, brain network architecture reorganizes in OA, at both global and local scale. Network connectivity related to OA pain intensity is dissociated from the major hub disruptions, challenging the extent of dependence of OA pain on nociceptive signaling.CCDRN, Grant/Award Number: Norte‐08‐5369‐FSE‐000026; Unilabs Boavista and the Grünenthal Young Pain Researcher 2017 Grant; Luso‐American Development Foundation R&D@PhD Scholarship Grant; OARSI Collaborative Scholarship 201

A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

Objective: To assess the efficacy and safety of the anti–interleukin‐1α/β (anti–IL‐1α/β) dual variable domain immunoglobulin lutikizumab (ABT‐981) in patients with knee osteoarthritis (OA) and evidence of synovitis. Methods: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2–3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI‐assessed synovitis at week 26. Results: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab‐treated and placebo‐treated patients. Changes from baseline in MRI‐assessed synovitis at week 26 and other key symptom‐ and most structure‐related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high‐sensitivity C‐reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations. Conclusion: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL‐1 inhibitors, suggest that IL‐1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis

SAT0548 Plasma CGRP concentrations were not associated with patient OA symptoms or response to galcanezumab, a monoclonal antibody against CGRP

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Update on novel pharmacological therapies for osteoarthritis

Osteoarthritis (OA) is a chronic painful arthritis with increasing global prevalence. Current management involves non-pharmacological interventions and commonly used pharmacological treatments that generally have limited analgesic efficacy and multiple side-effects. New treatments are therefore required in order to relieve patient symptoms and disease impact. A number of existing pharmacological therapies have been recently trialled in OA. These include extended-release triamcinolone and conventional disease-modifying anti-rheumatic drugs (DMARDs) used in the management of rheumatoid arthritis; generally the DMARDs have not shown benefit in treating OA. Novel analgesic therapies are in development, including those targeting peripheral pain pathways. Disease-modifying osteoarthritis drugs (DMOADs) target key tissues in the OA pathophysiology process and aim to prevent structural progression; a number of putative DMOADs are in phase II development. There is preliminary evidence of structural improvement with some of these therapies but without concomitant symptom improvement, raising new considerations for future DMOAD trials

Weak coupling large-N transitions at finite baryon density

We study thermodynamics of free SU(N) gauge theory with a large number of colours and flavours on a three-sphere, in the presence of a baryon number chemical potential. Reducing the system to a holomorphic large-N matrix integral, paying specific attention to theories with scalar flavours (squarks), we identify novel third-order deconfining phase transitions as a function of the chemical potential. These transitions in the complex large-N saddle point configurations are interpreted as "melting" of baryons into (s)quarks. They are triggered by the exponentially large (~ exp(N)) degeneracy of light baryon-like states, which include ordinary baryons, adjoint-baryons and baryons made from different spherical harmonics of flavour fields on the three-sphere. The phase diagram of theories with scalar flavours terminates at a phase boundary where baryon number diverges, representing the onset of Bose condensation of squarks.Comment: 38 pages, 7 figure

A 6-week, multicentre, randomised, double-blind, double-dummy, active-controlled, clinical safety study of lumiracoxib and rofecoxib in osteoarthritis patients

<p>Abstract</p> <p>Background</p> <p>Lumiracoxib is a selective cyclooxygenase-2 inhibitor effective in the treatment of osteoarthritis (OA) with a superior gastrointestinal (GI) safety profile as compared to traditional non-steroidal anti-inflammatory drugs (NSAIDs, ibuprofen and naproxen). This safety study compared the GI tolerability, the blood pressure (BP) profile and the incidence of oedema with lumiracoxib and rofecoxib in the treatment of OA. Rofecoxib was withdrawn worldwide due to an associated increased risk of CV events and lumiracoxib has been withdrawn from Australia, Canada, Europe and a few other countries following reports of suspected adverse liver reactions.</p> <p>Methods</p> <p>This randomised, double-blind study enrolled 309 patients (aged greater than or equal to 50 years) with primary OA across 51 centres in Europe. Patients were randomly allocated to receive either lumiracoxib 400 mg od (four times the recommended dose in OA) (<it>n </it>= 154) or rofecoxib 25 mg od (<it>n </it>= 155). The study was conducted for 6 weeks and assessments were performed at Weeks 3 and 6. The primary safety measures were the incidence of predefined GI adverse events (AEs) and peripheral oedema. The secondary safety measures included effect of treatment on the mean sitting systolic and diastolic blood pressure (msSBP and msDBP). Tolerability of lumiracoxib 400 mg was assessed by the incidence of AEs.</p> <p>Results</p> <p>Lumiracoxib and rofecoxib displayed similar GI safety profiles with no statistically significant difference in predefined GI AEs between the two groups (43.5% <it>vs</it>. 37.4%, respectively). The incidence and severity of individual predefined GI AEs was comparable between the two groups. The incidence of peripheral oedema was low and identical in both the groups (<it>n </it>= 9, 5.8%). Only one patient in the lumiracoxib group and three patients in the rofecoxib group had a moderate or severe event. At Week 6 there was a significantly lower msSBP and msDBP in the lumiracoxib group compared to the rofecoxib group (<it>p </it>< 0.05). A similar percentage of patients in both groups showed an improvement in target joint pain and disease activity. The tolerability profile was similar in both the treatment groups.</p> <p>Conclusion</p> <p>Lumiracoxib 400 mg od (four times the recommended dose in OA) provided a comparable GI safety profile to rofecoxib 25 mg od (therapeutic dose). However, lumiracoxib was associated with a significantly better BP profile as compared to rofecoxib.</p> <p>Trial registration number -</p> <p>NCT00637949</p

Chinese herbal recipe versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial [ISRCTN70292892]

BACKGROUND: Duhuo Jisheng Wan (DJW) is perhaps the best known and most widely used Chinese herbal recipe for arthralgia, but the clinical study to verify its efficacy is lacking. The purpose of this study was to compare the efficacy of DJW versus diclofenac in symptomatic treatment of osteoarthritis (OA) of the knee. METHODS: This study was a randomized, double-blind, double-dummy, controlled trial. The 200 patients suffering from OA of the knee, were randomized into the DJW and diclofenac group. The patients were evaluated after a run-in period of one week (week 0) and then weekly during 4 weeks of treatment. The clinical assessments included visual analog scale (VAS) score that assessed pain and stiffness, Lequesne's functional index, time for climbing up 10 steps, as well as physician's and patients' overall opinions on improvement. RESULTS: Ninety four patients in each group completed the study. In the first few weeks of treatment, the mean changes in some variables (VAS, which assessed walking pain, standing pain and stiffness, as well as Lequesne's functional index) of the DJW group were significantly lower than those of the diclofenac group. Afterwards, these mean changes became no different throughout the study. Most of the physician's and patients' overall opinions on improvement at each time point did not significantly differ between the two groups. Approximately 30% of patients in both groups experienced mild adverse events. CONCLUSION: DJW demonstrates clinically comparable efficacy to diclofenac after 4 weeks of treatment. However, the slow onset of action as well as approximately equal rate of adverse events to diclofenac might limit its alternative role in treatment of OA of the knee

Nonsteroidal anti-inflammatory drugs (NSAIDs), cyxlooxygenase-2 selective inhibitors (coxibs) and gastrointestinal harm: review of clinical trials and clinical practice

BACKGROUND: Gastrointestinal harm, known to occur with NSAIDs, is thought to be lower with NSAID and gastroprotective agent, and with inhibitors selective to cyclooxygenase-2 (coxibs) at usual plasma concentrations. We examine competing strategies for available evidence of reduced gastrointestinal bleeding in clinical trials and combine this evidence with evidence from clinical practice on whether the strategies work in the real world, whether guidance on appropriate prescribing is followed, and whether patients adhere to the strategies. METHODS: We used a series of systematic literature searches to find full publications of relevant studies for evidence about the efficacy of these different gastroprotection strategies in clinical trials, and for evidence that they worked and were adhered to in clinical practice – whether they were effective. We chose to use good quality systematic reviews and meta-analyses when they were available. RESULTS: Evidence of efficacy of coxibs compared to NSAIDs for upper gastrointestinal bleeding was strong, with consistent reductions in events of about 50% in large randomised trials (34,460 patients), meta-analyses of randomised trials (52,474 patients), and large observational studies in clinical practice (3,093 bleeding events). Evidence on the efficacy of NSAID plus gastroprotection with acid suppressants (proton pump inhibitors, PPIs, and histamine antagonists, H2As) was based mainly on the surrogate measure of endoscopic ulcers. The limited information on damage to the bowel suggested that NSAID plus PPI was more damaging than coxibs. Eleven observational studies studied 1.6 million patients, of whom 911,000 were NSAID users, and showed that 76% (range 65% to 90%) of patients with at least one gastrointestinal risk factor received no prescription for gastroprotective agent with an NSAID. The exception was a cohort of US veterans with previous gastrointestinal bleeding, where 75% had gastroprotection with an NSAID. When gastroprotection was prescribed, it was often described as inadequate. A single study suggested that patient adherence to prescribed gastroprotection was low. CONCLUSION: Evidence for efficacy of gastroprotection strategies with NSAIDs is limited. In clinical practice few patients who need gastroprotection get it, and those who get it may not take it. For coxibs, gastroprotection is inherent, although probably not complete