Inflammatory Joint Pain Research Articles

Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol

Trial designWe present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis.MethodsThe study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study.ConclusionsThere is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the “at risk” state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA.Trial registrationCurrent Controlled Trials, ID: ISRCTN46017566. Registered on 4 July 2014.

Considerations for Optimal Trial Design for Rheumatoid Arthritis Prevention Studies

The field of rheumatology has made major contributions to medicine through the identification of cellular and molecular targets and with the development of therapies for the treatment of an impressive range of immune-mediated rheumatic diseases. In recent years new milestones have been achieved. These include the recognition of an “at risk” state, defined by distinct clusters of characteristics, including disease-specific autoantibodies in serum and symptom complexes that include inflammatory joint pain. Studies seeking to prevent high-risk individuals from progressing to a state of clinically apparent arthritis have been initiated. Here, exploiting the current evidence base, an experimental framework to inform trial design is described, taking into consideration study patient phenotypes and highlighting the impact of risk stratification and the options available for therapeutic intervention according to the different phases of the preclinical syndrome. Pragmatic primary end points and suggestions for a set of risk-focused trial outcome measures are proposed, including both clinical assessments and patient-reported outcome measures. Rheumatoid arthritis prevention studies provide an important experimental framework for generating deeper insights into risk stratification and for refining trial design in the future. To this end, a research agenda is suggested, together with some considerations for imaging and for biological sampling. This commentary concludes with some of the operational issues that arise from such studies and addresses some of the challenges associated with recruitment and retention of the at-risk trial participant.

Real benefits of ultrasound evaluation of hand and foot synovitis for better characterisation of the disease activity in rheumatoid arthritis

ObjectivesOptimal management of rheumatoid arthritis (RA) depends on accurate evaluation of disease activity. Foot synovitis is not included in the most used RA outcome measure (DAS-28 score). The aim of this study was to investigate how musculoskeletal ultrasound (MSK-US) examination of hand and feet correlate with the disease activity score (DAS-28 score). We also explored whether performing MSK-US assessments of hands alone compared with hands and feet underestimates the disease activity in RA.MethodsThis is a real-life cross-sectional study of 101 patients (51 with RA and 50 with other musculoskeletal conditions) with inflammatory small joint pain, who underwent MSK-US examination of hands and feet.ResultsMSK-US-detected hand synovitis was found in 18/51 (35.3%) RA patients and 16/50 (32%) of those with other musculoskeletal conditions (p = 0.96), while foot synovitis was detected in 18/51 (35.3%) and 12/50 (24%) patients, respectively (p = 0.78). DAS-28 did not correlate with any of the US outcome measures in patients with RA. Six out of 13 (46.1%) RA patients in remission, 7/14 (50%) with low disease activity and 18/32 (56.2%) with moderate disease activity (according to DAS-28 definition) had active synovitis as assessed by the MSK-US examination of their hands and feet. MSK-US-detected synovitis led to treatment escalation in 26/51 (51%) RA patients.ConclusionThis study emphasises that MSK-US examination of hands and feet has led to optimised management of the majority of RA patients, which would have not been possible otherwise, because of the lack of correlation between DAS-28 assessment and MSK-US outcomes.Key Points• The most used disease activity score in rheumatoid arthritis (DAS-28) did not correlate with US outcome measures derived from hands and feet examination.• DAS-28 did not differentiate between RA patients with subclinical active synovitis versus well-controlled disease on US.• As a result of US examination of the hands and feet, 51% RA patients had their immunosuppressive treatment optimised.

Effect of soluble epoxide hydrolase and cyclooxygenase inhibition on lameness and synovial fluid prostanoids in horses with experimentally induced radiocarpal synovitis

Purpose: Concurrently, rather than separately, blocking production of pro-nociceptive and degradation of anti-nociceptive lipids might result in better control of inflammatory joint pain in horses. Methods: The effects cyclooxygenase (COX) and soluble epoxide hydrolase (sEH) inhibition on lameness and synovial fluid (SF) prostanoids were determined in horses with radiocarpal synovitis. Six healthy horses were administered the sEH inhibitor t-TUCB, the COX inhibitor phenylbutazone or their combination, all IV, concurrently with LPS (3 μg) into a radiocarpal joint in a randomized, crossover design. Investigators were blinded to treatment identity. Lameness was quantified as surrogate for joint pain using a validated wireless lameness sensor before and up to 48 hours after treatment. Concentrations of prostaglandin (PG)E2 and thromboxane (Tx)A2 in SF were determined with ELISA-based assays. Areas under the curves of lameness (AUC-lameness), PGE2 (AUC-PGE2) and TxA2 (AUC-TxA2) were calculated and analyzed with repeated measures ANOVA with p<0.05 considered significant. Data are mean±SD. Results: AUC-lameness with phenylbutazone (2 mg kg-1; 285±207 mm 48h-1) was significantly lower than with t-TUCB (1 mg kg-1; 498±82), but was lowest (91±35) with combined phenylbutazone (2 mg kg-1) and t-TUCB (0.3 mg kg-1). This combination was associated with significantly smaller AUC-PGE2 (3,609±2,311 pg ml-1 48h-1) in SF than phenylbutazone (20,614±10,023) or t-TUCB (13,911±7,380) separately. AUC-TxA2 was significantly smaller with inhibiting COX alone (17,375±5,476 pg ml-1 48h-1) or combined with sEH (22,645±15,112) compared to inhibiting sEH alone (103,066±75,407). Conclusions: Combined COX and sEH inhibition enhanced analgesia and better-controlled SF prostanoid response in horses with inflammatory joint pain than inhibiting each enzyme separately.

“The descending noradrenergic spinal modulation is impaired during prolonged joint inflammatory pain conditions.”

Event Abstract Back to Event “The descending noradrenergic spinal modulation is impaired during prolonged joint inflammatory pain conditions.” Raquel Pereira Da Silva1, 2*, José Tiago Da Costa Pereira1, 2, Raquel Alonso1, 2, Isabel Martins1, 2 and Fani Neto1, 2 1 Faculty of Medicine, University of Porto, Portugal 2 i3S, Instituto de Investigação e Inovação em Saúde, Portugal Chronic pain is a widespread condition responsible for a huge socioeconomic negative impact. Several monoaminergic systems, such as the noradrenergic system, are involved in descending modulation of pain (DMP) events, either through noxious stimuli facilitation or inhibition. Even though this is known, the pharmacologic approaches to treat severe chronic joint inflammatory pain (CJIP) are still mostly unsuccessful. To study the changes on descending noradrenergic pain modulation caused by CJIP, we performed spinal pharmacological studies, evaluated the expression levels of dopamine β-hydroxylase (DBH), the noradrenaline biosynthetic enzyme, and of the α2-adrenoreceptor (AR), and quantified the noradrenaline (NE) levels at the spinal cord of monoarthritic (MA) animals. MA was induced in adult male Wistar rats by complete Freund’s adjuvant injection (CFA) in the tibiotarsal joint. Control animals were injected with CFA vehicle. Movement-induced allodynia (ankle-bend test), mechanical hyperalgesia (Randall Selitto test) and signs of inflammation (inflammation score) were weekly evaluated in all animals during 6 weeks post-intraarticular injection. For the pharmacological studies (week 5), an intrathecal catheter was implanted above the L4-L5 spinal segments and one week later (week 6) cumulative doses (1, 5, 10µg) of clonidine, an α2-AR agonist, or saline were injected through the catheter. The effects of each dose were evaluated by the Randall Selitto test. DBH and α-2AR expression and NE levels were evaluated at L4 and 5 segments by immunohistochemistry and HPLC, respectively. MA animals showed typical movement-induced allodynia and mechanical hyperalgesia during the 6 weeks when compared to controls. Clonidine induced anti-hyperalgesia in MA animals, more significant at the highest dose, and produced no effects in controls. On MA rats, DBH labeling was significantly increased, no differences were found in α2-AR expression and NE spinal levels were lower, in comparison to controls In conclusion, chronic MA causes a loss of NE spinal input, triggered by the ongoing nociceptive input. However, a compensatory antinociceptive noradrenergic spinal mechanism to counteract this condition appears to be also developing, as indicated by DBH increase. Therapeutic strategies aiming at strengthening these antinociceptive noradrenergic spinal effects could represent new avenues when treating CJIP. Acknowledgements This work would not have been possible without the financial support of 2014–2020 North Portugal Regional Operational Programme. Keywords: monoarthritis, Noradrenalin (NA), descending modulation, Spinal Cord, nociception and pain Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019. Presentation Type: Oral presentation Topic: Sensory Processing Citation: Pereira Da Silva R, Da Costa Pereira J, Alonso R, Martins I and Neto F (2019). “The descending noradrenergic spinal modulation is impaired during prolonged joint inflammatory pain conditions.”. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00033 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Feb 2019; Published Online: 27 Sep 2019. * Correspondence: Dr. Raquel Pereira Da Silva, Faculty of Medicine, University of Porto, Porto, Portugal, raquel.silva.farm.86@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Raquel Pereira Da Silva José Tiago Da Costa Pereira Raquel Alonso Isabel Martins Fani Neto Google Raquel Pereira Da Silva José Tiago Da Costa Pereira Raquel Alonso Isabel Martins Fani Neto Google Scholar Raquel Pereira Da Silva José Tiago Da Costa Pereira Raquel Alonso Isabel Martins Fani Neto PubMed Raquel Pereira Da Silva José Tiago Da Costa Pereira Raquel Alonso Isabel Martins Fani Neto Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Animal models in the study and treatment of orofacial pain.

BackgroundPain is one of the first causes of medical consultation in the world and by extension of dental consultation too. Orofacial pain comprehends the oral and facial regions including teeth, oral mucosa, gingiva, tongue and lips, but also the muscles of the jaw and neck, the temporomandibular joint, face, head and neck. Despite its highly estimated prevalence, it appears controversial and hard to quantify given the lack of common criteria to select the population under study and the difficulties to classify the different types of pain. Although for many patients the problem eventually fades after tissue healing, certain sub-chronic and chronic pain conditions remain notoriously undertreated. In this respect, animal models can be of great help.Material and MethodsA systematic search was conducted in PubMed-Medline with appropriate keywords: orofacial pain, prevalence and dentist. Seven groups were generated and a second search based on each of these groups and on animal models was made. Search was restricted to English and Spanish, but no time restriction was applied.ResultsThere are as yet few experimental models of orofacial pain: there hardly exists no other than trigeminal nerve injury for neuropathic pain, a bunch of oral squamous cell carcinoma models (mainly referred to the tongue) for cancer pain and none for the painful swelling of salivary glands. Similarly occurs for the burning mouth syndrome. A few more exist for inflammatory odontalgiae, aphthae, joint, myofascial and muscle inflammatory pains, although scarcely diverse as regards the nature of the noxious stimulus.ConclusionsGiven the relevance of envisaging the mechanistic of the various types of orofacial pain, new experimental models are needed on the basis of the dentist’s perspective for their correct management. Key words:Orofacial pain, neuralgia, odontalgia, oral cancer, animal models.

Effect of Electroacupuncture on Pain Transition and Content of Protein Kinase Cε in Dorsal Root Ganglia in Hyperalgesia Rats

To observe the effect of electroacupuncture (EA)on mechanical pain transition and content of protein kinase C epsilon(PKCε)in dorsal root ganglia (DRG) in inflammatory articular pain rats，so as to explore its peripheral mechanism underlying relieving transition from acute to chronic pain. 1)In the first part of the present study，male SD rats were equally randomized into blank control，sham hyperalgesic priming(HP), and real HP groups(n＝6 in each). The HP model was established by subcutaneous injection of 1% carrageenan (100 µL) into the left hind paw (the first injection)，followed by injection of PGE 2 (100 ng/25 µL, the second injection) into the dorsum pedis of the same hind paw 7 days after the first injection. The mechanical withdrawal threshold (MWT) of the ipsilateral paw was detected before and 4, 24, 48, 72 h, and 7 d after the first injection，and 1, 4, 24 and 48 h after the second injection. 2) In the second part，SD rats were randomly divided into sham-HP，real HP，sham-EA and EA groups(n＝6 in each). The sham-HP and HP models were made in the same way as those in the first part. Bilateral "Zusanli"(ST 36)and "Kunlun"(BL 60)were punctured with filiform needles and also stimulated with electrical current：2 Hz/100 Hz，0.5－1.5 mA(0.5 mA increase per 10 min)for 30 min，1 time/d from the 1st carrageenan injection on till the end of the experiments. PKCε protein expression in the L 4－L 6 DRGs was assayed by Western blot 48 h after the second injection. 1)In the first part of the study，compared with the sham-HP group，the MWT at 4, 24、48 h after carrageenan injection and 4, 24 and 48 h after PGE 2 injection were significantly decreased in the HP model group(P<0.01). 2)In the second part，compared with the HP group，the MWT at 24、48 and 72 h after carrageenan injection, and 24 and 48 h after PGE 2 injection were significantly up-regulated in the EA group(P<0.05，P<0.01). 3)The relative content of PKCε in the DRGs(L 4－L 6)was significantly higher in the HP group than in the sham-HP group(P<0.01)，but considerably lower in the EA group than in the HP group (P<0.01)．. EA has a good effect on pain conversion in inflammatory joint pain rats，which may be related to its effect in down-regulating the PKCε level in the ipsilateral lumbar DRGs.

Effect of soluble epoxide hydrolase and cyclooxygenase inhibition on lameness and synovial fluid prostanoids in horses with experimentally induced radiocarpal synovitis

Introduction: Concurrently, rather than separately, blocking production of pronociceptive and degradation of antinociceptive lipids might result in better control of inflammatory joint pain in horses.

Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner

Ongoing, spontaneous pain is characteristic of inflammatory joint pain and reduces an individual's quality of life. To understand the neural basis of inflammatory joint pain, we made a unilateral knee injection of complete Freund's adjuvant (CFA) in mice, which reduced their natural digging behavior. We hypothesized that sensitization of knee-innervating dorsal root ganglion (DRG) neurons underlies this altered behavior. To test this hypothesis, we performed electrophysiological recordings on retrograde labeled knee-innervating primary DRG neuron cultures and measured their responses to a number of electrical and chemical stimuli. We found that 24-h after CFA-induced knee inflammation, knee neurons show a decreased action potential generation threshold, as well as increased GABA and capsaicin sensitivity, but have unaltered acid sensitivity. The inflammation-induced sensitization of knee neurons persisted for 24-h in culture, but was not observed after 48-h in culture. Through immunohistochemistry, we showed that the increased knee neuron capsaicin sensitivity correlated with enhanced expression of the capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1) in knee-innervating neurons of the CFA-injected side. We also observed an increase in the co-expression of TRPV1 with tropomyosin receptor kinase A (TrkA), which is the receptor for nerve growth factor (NGF), suggesting that NGF partially induces the increased TRPV1 expression. Lastly, we found that systemic administration of the TRPV1 antagonist, A-425619, reversed the decrease in digging behavior induced by CFA injection, further confirming the role of TRPV1, expressed by knee neurons, in acute inflammatory joint pain.

Sustained intra-articular release of celecoxib in an equine repeated LPS synovitis model

Synovial inflammation is an important characteristic of arthritic disorders like osteoarthritis and rheumatoid arthritis. Orally administered non-steroidal anti-inflammatory drugs (NSAIDs) such as celecoxib are among the most widely prescribed drugs to manage these debilitating diseases. Intra-articular delivery in biodegradable in situ forming hydrogels overcomes adverse systemic effects and prolongs drug retention in the joint.In this study two formulations of celecoxib (40 mg/g and 120 mg/g) in a propyl-capped PCLA-PEG-PCLA triblock copolymer were sequentially evaluated in a multiple LPS challenge equine synovitis model. Intra-articular release and systemic exposure to celecoxib and local changes at joint level were evaluated longitudinally.A single intra-articular injection of the high dose (HCLB)-gel or low dose (LCLB)-gel showed a sustained and controlled intra-articular release in both inflamed and healthy joints together with very low systemic exposure. Synovitis and lameness were moderate respectively very mild in this model due to the low concentration LPS (0.25 ng/joint). Both celecoxib formulations had a mild, transient effect on inflammatory and structural synovial fluid biomarkers but these returned to baseline within one week of administration. The HCLB-gel showed a significant inhibition in peak white blood cell concentration at 8 h after LPS induction.Elevated levels of celecoxib were observed in the joint for up to 30 days but no overall anti-inflammatory effects could be observed, which was thought to be due to the moderate synovitis. As there were no long-term adverse effects, sustained intra-articular release of celecoxib from in situ forming hydrogels should be evaluated further for its effects on longer-term relief of inflammatory joint pain in humans and animals.

Analgesic effect of S (+)-flurbiprofen plaster in a rat model of knee arthritis: analysis of gait and synovial fluid prostaglandin E2 levels.

ObjectivesWe developed S (+)‐flurbiprofen plaster (SFPP), a novel NSAID patch containing S (+)‐flurbiprofen (SFP), a potent cyclooxygenase (COX) inhibitor. The purpose of this study was to assess efficacy of SFPP by analysing its effect on the gait disturbance and measuring the prostaglandin E2 (PGE 2) production in synovial fluid in a rat model of knee arthritis.MethodsKnee inflammation was induced in rats by intra‐articular injection of a yeast suspension. Subsequently, an NSAID patch containing SFP, ketoprofen or loxoprofen was applied over the affected knee. Gait was assessed at 2, 4 and 6 h after application of the patch. The PGE 2 concentration in the synovial fluid was measured after the gait assessment.Key findingsApplication of SFPP (0.125, 0.25, 0.5 or 1 mg/sheet) was followed by a decrease in the visual gait score at all the doses examined. In the case of the other two NSAID patches, only the ketoprofen patch (1 or 2 mg/sheet) and loxoprofen patch (5 mg/sheet) produced a decrease in the visual gait score. All of the NSAID patches decreased the PGE 2 production in the synovial fluid.ConclusionsThese results suggest the potential usefulness of SFPP as an analgesic patch in patients with inflammatory joint pain.

Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis.

This study determined the pharmacokinetics, antinociceptive, and anti-inflammatory effects of the soluble epoxide hydrolase (sEH) inhibitor t-TUCB (trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) in horses with lipopolysaccharide (LPS)-induced radiocarpal synovitis. A total of seven adult healthy mares (n=4-6/treatment) were administered 3μg LPS into one radiocarpal joint and t-TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1mg/kg in a blinded, randomized, crossover design with at least 3weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48hr after t-TUCB/LPS. Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF) t-TUCB concentrations were determined before and up to 48hr after t-TUCB/LPS. Blood and SF were collected for clinical laboratory evaluations before and up to 48hr after t-TUCB/LPS. Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post-test. p<.05 was considered significant. Data are mean±SEM. Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1mg/kg t-TUCB, but not the other doses. For 0.1, 0.3, and 1mg/kg t-TUCB treatments, plasma terminal half-lives were 13±3, 13±0.5, and 24±5hr, and clearances were 68±15, 48±5, and 14±1 mlhr-1 kg-1 . The 1 mg/kg t-TUCB reached the SF at high concentrations. There were no important anti-inflammatory effects. In conclusion, sEH inhibition with t-TUCB may provide analgesia in horses with inflammatory joint pain.

Effects of Red or Black Ginseng Extract in a Rat Model of Inflammatory Temporomandibular Joint Pain

Effects of Red or Black Ginseng Extract in a Rat Model of Inflammatory Temporomandibular Joint Pain

Emerging therapies for pre-RA.

The field of rheumatology has made major contributions to medicine through the identification of cellular and molecular targets and the development of therapies for the treatment of an impressive range of immune-mediated inflammatory diseases such as rheumatoid arthritis. In recent years, new milestones have been achieved. These include the recognition of an at-risk state, characterized by disease specific autoantibodies in serum and inflammatory joint pain, and the initiation of studies seeking to prevent high-risk individuals from progressing to a state of clinically apparent arthritis. Here, the current state of the art of rheumatoid arthritis prevention is described, highlighting the importance of risk stratification and reporting on a growing portfolio of therapeutic interventions targeting different stages of the preclinical syndrome.

Mechanisms underlying the hyperalgesic responses triggered by joint activation of TLR4.

Toll-like receptors (TLRs) including TLR4 and their signal pathways contribute to the pathogenesis of arthritis. Herein, we evaluated the mechanisms underlying the hyperalgesic response caused by TLR4 activation in the tibio-tarsal joint in mice. Joint inflammatory hyperalgesia was induced by intra-articular (ia) injection of LPS (lipopolysaccharide- TLR4 agonist) in C57BL/6, TLR4, TLR2, MyD88, TRIF, TNFR1/2 and IL-1R1 knockout (-/-) mice. Joint hyperalgesia was evaluated using an electronic von Frey. Neutrophil recruitment was assessed by MPO activity. Joint levels of cytokines were measured by ELISA. Firstly, it was shown that LPS injected into the joints causes a dose- and time-dependent reduction in the mechanical nociceptive threshold. The TLR4 activation in the joint triggers mechanical hyperalgesia and neutrophil migration, which was abolished in TLR4 -/- and MyD88-/-, but not in TLR2-/- and TRIF-/- mice. Besides, joint administration of LPS increased the release of TNF-α, IL-1β, and KC/CXCL1, which were reduced in TLR4-/- and MyD88-/-, but not in TRIF-/- mice. In agreement, the LPS-induced joint nociceptive effect was decreased in TNFR1/2-/- and IL-1R1-/- mice or in mice pre-treated with a CXCR1/2 selective antagonist (DF2156A). These results suggest that TLR4 activation in the joint produces articular hyperalgesia via MyD88 signaling pathway. Moreover, this pathway is involved in the cascade of events of articular hyperalgesia through mechanisms dependent on cytokines and chemokines production. Thus, TLR4/MyD88 signaling pathway inhibitors might be useful for the treatment of inflammatory joint pain.

JUVENILE IDIOPATHIC ARTHRITIS ASSOCIATED WITH INCOMPLETE PRIMARY HYPERTROPHIC OSTEOARTHROPATHY (PACHYDERMOPERIOSTOSIS)

Introduction. Hypertrophic osteoarthropathy (HOA) is a rare, hereditary disease characterized by clubbing and new bone formation in the periosteal region that may be associated with joint pain, cutaneous abnormalities, seborrhea or hyperhydrosis. Juvenile idiopathic arthritis (JIA) is one of the most frequent chronic diseases with childhood onset, patients develop inflammatory joint pain and extra-articular manifestations with imunologic substrate. The association of the two diseases is very rare. 24 years old patient related disease onset at the age of 14 with arthritis of proximal interphalangeal joints (PIP), knees and right ankle. He is diagnosed with oligoarticular form of juvenile idiopathic arthritis. He receives Methotrexate, Suphasalazyne and association of the two, but after 5 years biological therapy with Etanercept is started. Later on, repeated physical examination revealed digital clubbing, non-painful enlargment of hands and feet with sweaty teguments. Radiological examination with subperiosteal new bone formation of the distal tibia, the fibula, the radius, the ulna, the metacarpals and the phalanges confirms the suspicion of HOA – pachydermoperiostosis (PDP). Conclusion. Final diagnosis considers both entities. The incomplete form of PDP included hands and feet enlargement with extensive periostitis, palmoplantar hyperhydrosis, but no significant facial changes. The specific treatment for JIA did not influence the evolution of PDP.

260. A Beta-Binominal Regression Model to Predict Doppler Score on Ultrasound Examination in Patients with Inflammatory Hand Joint Pain

260. A Beta-Binominal Regression Model to Predict Doppler Score on Ultrasound Examination in Patients with Inflammatory Hand Joint Pain

Using gait analysis to assess weight bearing in rats with Freund׳s complete adjuvant-induced monoarthritis to improve predictivity: Interfering with the cyclooxygenase and nerve growth factor pathways

Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund׳s complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches.Male rats injected intra-articularly into one ankle joint with FCA (1.0mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitors≥anti-NGF antibody>COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain.

Infusion of Gabrα6 siRNA into the trigeminal ganglia increased the myogenic orofacial nociceptive response of ovariectomized rats treated with 17β-estradiol

High levels of 17β-estradiol (E2) have been found to reduce inflammatory temporomandibular joint (TMJ) pain. A search for genes effected by a high concentration of estradiol showed an increase in GABAA receptor subunit alpha 6 (Gabrα6) in the trigeminal ganglia (TG). Blockade of Gabrα6 expression in the TG increases masseter muscle nociception in male rats, but the relationship between estradiol’s effect on nociception and Gabrα6 expression remains unclear in females. To address this knowledge gap we hypothesized that reducing Gabrα6 expression in the TG will increase the orofacial nociceptive response of ovariectomized female rats treated with estradiol. To administer hormone osmotic pumps were placed in rats that dispensed a low diestrus plasma concentration of 17β-estradiol, in addition, 17β-estradiol was injected to produce a high proestrus plasma concentration of estradiol. A ligature was then placed around the masseter tendon to induce a nociceptive response; a model for TMJ muscle pain. Gabrα6 small interfering RNA (siRNA) was later infused into the TG and the nociceptive response was measured using von Frey filaments and a meal duration assay. GABAA receptor expression was measured in the TG and trigeminal nucleus caudalis and upper cervical region (Vc-C1). Ligature significantly increased the nociceptive response but a high proestrus concentration of 17β-estradiol attenuated this response. Gabrα6 siRNA infusion decreased Gabrα6 expression in the TG and Vc-C1 but increased the nociceptive response after 17β-estradiol treatment. The results suggest estradiol decreased the orofacial nociceptive response, in part, by causing an increase in Gabrα6 expression.

THU0101 The Incidence of DE Novo Joint Symptoms in A Cohort of IBD Patients during Anti-TNF Treatment

BackgroundIncidence of de novo joint symptoms in patients with inflammatory bowel disease (IBD) treated with anti-TNF has not been well defined.ObjectivesWe aimed to evaluate the incidence and characteristics of joint...