Anti-KIF20B autoantibodies are associated with cranial neuropathy in systemic lupus erythematosus.

BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.

B cell depletion and inhibition in systemic lupus erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is characterized by autoantibody expression and aberrant autoreactive B cells contribute to disease progression; therefore, B cell inhibition has been an attractive target for novel therapies. However, after more than two decades of research and over 40 randomized clinical trials, only one such therapy, belimumab, has been approved for use in SLE. AREAS COVERED: In this review, we discuss the evidence for B cell-targeted therapies in SLE and lupus nephritis. Belimumab has been successful in several large clinical trials and is approved in several countries for use in SLE and lupus nephritis. Despite a lack of supporting phase III evidence, rituximab is used off-label in SLE. Several other B cell-targeted therapies have failed to meet their end points in late-stage clinical trials. Successful phase II trials have recently been reported for obinutuzumab and telitacicept with larger confirmatory trials currently underway. EXPERT OPINION: Refinements in pharmaceutical mechanisms of action, trial design, and patient selection have resulted in recent preliminary successes, offering renewed optimism for B-cell targeted therapeutics in SLE management.

Alpha-1-antitrypsin reduces inflammation and exerts chondroprotection in arthritis.

While new treatments have been developed to control joint disease in rheumatoid arthritis, they are partially effective and do not promote structural repair of cartilage. Following an initial identification of α-1-Antitrypsin (AAT) during the resolution phase of acute inflammation, we report here the properties of this protein in the context of cartilage protection, joint inflammation, and associated pain behavior. Intra-articular and systemic administration of AAT reversed joint inflammation, nociception, and cartilage degradation in the KBxN serum and neutrophil elastase models of arthritis. Ex vivo analyses of arthritic joints revealed that AAT promoted transcription of col2a1, acan, and sox9 and downregulated mmp13 and adamts5 gene expression. In vitro studies using human chondrocytes revealed that SERPINA1 transfection and rAAT protein promoted chondrogenic differentiation through activation of PKA-dependent CREB signaling and inhibition of Wnt/ß-catenin pathways. Thus, AAT is endowed with anti-inflammatory, analgesic, and chondroprotective properties that are partially inter-related. We propose that AAT could be developed for new therapeutic strategies to reduce arthritic pain and repair damaged cartilage.

Development and Implementation of a Three-dimensional Printed Knee Joint Simulation Model Using the Consolidated Framework for Implementation Research: Addressing Local Simulation Needs.

Background Knee joint injections and aspirations are essential procedures for medical students, residents, and primary care physicians to master. Simulation-based training has been shown to improve learner confidence and performance scores in knee joint injections. Current knee joint simulators are expensive, ranging from hundreds to thousands of dollars. Using three-dimensional (3D) printing and gel layering technology, we designed and manufactured an inexpensive simulator. The aim of this implementation study was to gather the opinions of local simulation specialists and administrators regarding the simulator's curricular implementation. Methods Using the Consolidated Framework for Implementation Research (CFIR), we developed a 31-item implementation survey. It was administered to local simulation specialists and administrators. The purpose of the survey was to identify the aspects of the simulator that they deemed important to the implementation process, as well as obtain their qualitative feedback about the design. Results In total, three participants completed the survey. There were 16 survey items that were rated as very important, including local manufacturing, appropriate planning, internal development, evidence-based development, and reasonable costs. Another nine items were deemed important, including the adaptability of the product and ability to test the product. The simulation specialists also expressed some concerns they had with the design of the simulator and made suggestions about how we could address these concerns. Conclusions Local development and manufacturing, coupled with appropriate pre-implementation planning and efficacy evidence, were selected as factors that would potentially contribute to the success of the implementation of the simulator in the local curriculum.

Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice.

BACKGROUND: A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA. METHODS: MIA (0.3 mg/10 µl) was injected into the right knee joint of male C57BL/6 mice (20-34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.) and serpinA1 (10 µg i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 µg i.p. days 0 to 1) and PAR2 knockout animals. RESULTS: MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control). CONCLUSIONS: Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets.

Early blockade of joint inflammation with a fatty acid amide hydrolase inhibitor decreases end-stage osteoarthritis pain and peripheral neuropathy in mice.

BACKGROUND: The endocannabinoid system has been shown to reduce inflammatory flares and pain in rodent models of arthritis. A limitation of endocannabinoids is that they are rapidly denatured by hydrolysing enzymes such as fatty acid amide hydrolase (FAAH) which renders them physiologically inert. Osteoarthritis (OA) is primarily a degenerative joint disease; however, it can incorporate mild inflammation and peripheral neuropathy. The aim of this study was to determine whether early blockade of FAAH bioactivity could reduce OA-associated inflammation and joint neuropathy. The ability of this treatment to prevent end-stage OA pain development was also tested. METHODS: Physiological saline or sodium monoiodoacetate (MIA; 0.3 mg) was injected into the right knee of male C57Bl/6 mice (20-42 g) and joint inflammation (oedema, blood flow and leukocyte trafficking) was measured over 14 days. Joint inflammation was also measured in a separate cohort of animals treated on day 1 with either saline or the FAAH inhibitor URB597 (0.03-0.3 mg/kg topical onto the knee joint). In other experiments, von Frey hair tactile sensitivity was determined on days 1 and 14 in MIA-injected mice treated prophylactically with URB597 (0.3 mg/kg s.c. over the knee joint on days 0-3). Saphenous nerve myelination was also assessed in these animals on day 14 by G-ratio analysis. RESULTS: Intra-articular injection of MIA caused an increase in joint oedema (P < 0.0001), blood flow (P < 0.05), leukocyte rolling (P < 0.05) and adherence (P < 0.001) on day 1 after treatment which subsequently resolved over later time points. This acute inflammatory response was ameliorated by local URB597 treatment. Prophylactic local administration of URB597 prevented MIA-induced saphenous nerve demyelination, and chronic joint pain was also attenuated. CONCLUSIONS: These data indicate that local inhibition of FAAH in MIA-injected knees can reduce acute inflammatory changes associated with the model. Prophylactic treatment of OA mice with the endocannabinoid hydrolysis inhibitor URB597 was also shown to be neuroprotective and prevented the development of joint pain at later time points.

Endocannabinoids inhibit neurogenic inflammation in murine joints by a non-canonical cannabinoid receptor mechanism.

Neurogenic inflammation is a local inflammatory response that is driven by the peripheral release of neuropeptides from small diameter afferents which occurs in many organs including joints. The knee joint has a rich endocannabinoid system which has been shown to decrease acute synovitis. The aim of this study was to investigate the influence of joint afferents on leukocyte-endothelial interactions within the synovial microcirculation of mice and determine the role of endocannabinoids on this inflammatory response. Electrical, antidromic stimulation of the saphenous nerve decreased leukocyte rolling at the lowest frequency tested (0.5Hz), while increasing leukocyte rolling at higher frequencies (2.0 and 5.0Hz). The leukocyte rolling effect of nerve stimulation was completely abolished by pre-treating the knee with the vasoactive intestinal peptide antagonist VIP6-28; however, neither calcitonin gene related peptide nor substance P antagonism had an effect on this neurogenic inflammatory response. Treating knees with the endocannabinoid breakdown inhibitor URB597 completely blocked leukocyte rolling and this effect could be reversed with the non-canonical cannabinoid antagonist O-1918. These results provide evidence that antidromic stimulation of the mouse saphenous nerve promotes leukocyte rolling within the synovial microcirculation, and that endocannabinoids can attenuate this neurogenic inflammatory response.

Smoke Inhalation in a Rural Emergency Setting: A Simulation Session.

Smoke inhalation-associated lung injuries (SI-ALI) present multiple challenges to the rural emergency department, and they require timely and appropriate management to prevent significant mortality and morbidity. In this report, we outline an adaptable simulation of an SI-ALI patient that is designed for use in a rural emergency department. The aim of this simulation is to better equip clinicians and emergency department staff who may encounter SI-ALI in rural settings. The case is suitable for resident doctors and emergency department staff.

Preclinical Assessment of Inflammatory Pain.

While acute inflammation is a natural physiological response to tissue injury or infection, chronic inflammation is maladaptive and engenders a considerable amount of adverse pain. The chemical mediators responsible for tissue inflammation act on nociceptive nerve endings to lower neuronal excitation threshold and sensitize afferent firing rate leading to the development of allodynia and hyperalgesia, respectively. Animal models have aided in our understanding of the pathophysiological mechanisms responsible for the generation of chronic inflammatory pain and allowed us to identify and validate numerous analgesic drug candidates. Here we review some of the commonly used models of skin, joint, and gut inflammatory pain along with their relative benefits and limitations. In addition, we describe and discuss several behavioral and electrophysiological approaches used to assess the inflammatory pain in these preclinical models. Despite significant advances having been made in this area, a gap still exists between fundamental research and the implementation of these findings into a clinical setting. As such we need to characterize inherent pathophysiological pathways and develop new endpoints in these animal models to improve their predictive value of human inflammatory diseases in order to design safer and more effective analgesics.

Mechanisms and Mediators That Drive Arthritis Pain.

There are over 100 different types of arthritis and each can differ greatly in their aetiology and pathophysiology; however, one characteristic that is common to all arthritic conditions is joint pain. Musculoskeletal pain is the leading cause of disability in the world, and the number one reason arthritis patients visit their primary care physician. Despite the prevalence and burden of arthritis pain, current analgesics lack sufficient efficacy and are plagued by multiple adverse side effects. In this review, we outline the current landscape of research concerning joint pain, drawing from both preclinical and clinical studies. Specifically, this review is a discussion of the different neurophysiological processes that occur during joint disease and how inflammatory and neuropathic aspects contribute to the development of arthritis pain.

Tapping into the endocannabinoid system to ameliorate acute inflammatory flares and associated pain in mouse knee joints.

INTRODUCTION: During the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful. Although a number of drug therapies are currently used to treat RA, their effectiveness is variable and side effects are common. Endocannabinoids have the potential to ameliorate joint pain and inflammation, but these beneficial effects are limited by their rapid degradation. One enzyme responsible for endocannabinoid breakdown is fatty acid amide hydrolase (FAAH). The present study examined whether URB597, a potent and selective FAAH inhibitor, could alter inflammation and pain in a mouse model of acute synovitis. METHODS: Acute joint inflammation was induced in male C57BL/6 mice by intra-articular injection of 2% kaolin/2% carrageenan. After 24 hr, articular leukocyte kinetics and blood flow were used as measures of inflammation, while hindlimb weight bearing and von Frey hair algesiometry were used as measures of joint pain. The effects of local URB597 administration were then determined in the presence or absence of either the cannabinoid (CB)1 receptor antagonist AM251, or the CB2 receptor antagonist AM630. RESULTS: URB597 decreased leukocyte rolling and adhesion, as well as inflammation-induced hyperaemia. However, these effects were only apparent at low doses and the effects of URB597 were absent at higher doses. In addition to the anti-inflammatory effects of URB597, fatty acid amide hydrolase (FAAH) inhibition improved both hindlimb weight bearing and von Frey hair withdrawal thresholds. The anti-inflammatory effects of URB597 on leukocyte rolling and vascular perfusion were blocked by both CB1 and CB2 antagonism, while the effect on leukocyte adherence was independent of cannabinoid receptor activation. The analgesic effects of URB597 were CB1 mediated. CONCLUSIONS: These results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes.