Géraldine Bart

Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease.

Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohns disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68+ macrophages, dendritic/Langerhans cells and CD79α+ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.

Distinct Expression of IL‐36α, β, γ, their antagonist IL‐36Ra and IL‐38 in psoriasis, rheumatoid arthritis and Crohn's disease

Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohns disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68+ macrophages, dendritic/Langerhans cells and CD79α+ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.

IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

Objectives Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro. Methods Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38. Results Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA. Conclusions This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.

Usefulness of a pre-procedure ultrasound scanning of the lumbar spine before epidural injection in patients with a presumed difficult puncture: A randomized controlled trial

UNLABELLED Ultrasound (US) is widely used in rheumatology to study and guide injection of peripheral joints. It can also provide useful information about the anatomy of the lumbar spine. Studies have shown that US examination of the spine was a useful tool to help perform epidural anaesthesia. The purpose of the study was to determine if the selection of the optimum puncture level by US may facilitate epidural steroid injection in case of presumed difficult puncture (BMI>30 kg/m(2), age>60 years or lumbar scoliosis). METHODS We performed a prospective randomized controlled study. Eighty patients were randomized in two groups: US group (n=40) which underwent a pre-procedure spinal US to determine the optimal lumbar level for injection or control group (n=40) for which the level of injection was determined by palpation. Primary endpoint was the pain during the procedure assessed using the Visual Analogue Scale (VAS). RESULTS We found a positive correlation between depth of the epidural space and BMI (P<0.001) and a negative correlation between size of the interspinous spaces and age (P<0.01). Visibility of the epidural space was not altered by obesity or age. We observed a trend toward a reduction in pain intensity during the procedure in the US group compared to the control group with a mean difference at -0.94 [-1.90; 0.02] but the difference was not significant (P=0.054). CONCLUSION US of the lumbar spine was feasible in patients with lumbar conditions even in obese and old ones and allowed the visualization of the epidural space. However, pre-procedure US examination did not reduce pain during the procedure.

Bilateral Pulmonary Embolism Following a Viper Envenomation in France: A Case Report and Review.

AbstractComplications following snake bites are not common in France. We report the case of a bilateral pulmonary embolism following a viper envenomation in France.A healthy 72-year-old female presented with a lower limb hematoma following a viper bite. She was admitted at the hospital 2 days later and received low-molecular-weight heparin because of bed rest. Seven days later, she complained of thoracic pain and respiratory failure, and a bilateral pulmonary was diagnosed, without biological sign of neither disseminated intravascular coagulation nor coagulation trouble. Repeated lower limbs Doppler ultrasound were normal.This case is particularly interesting because it is only the 7th reported case of pulmonary embolism following a snake envenomation; moreover, it happened in France where poisonous snakes are very rare.Several hypotheses have been made to explain this late localized coagulopathy: an increased level of unstable fibrin produced by thrombin-like glycoproteins from the venom is one of them.

Is There an Association Between Magnetic Resonance Imaging and Neurological Signs in Patients With Vertebral Osteomyelitis?: A Retrospective Observational Study on 121 Patients.

Abstract Neurological complications can occur in up to 51% of vertebral osteomyelitis (VO) in surgical series. The aim of our study was to estimate the frequency of neurological signs in a nonselected population of patients with VO and to assess clinical and MRI changes associated with these complications. We reviewed medical charts of patients with VO from 2007 to 2014 in our University Hospital and their MRIs were analyzed by a radiologist blinded from clinical data. Neurological status was defined as follow: normal, minor signs (radiculalgia or sensory loss), and major signs (motor deficit and/or sphincter dysfunction). A total of 121 patients were included. Mean age was 64.3 years. Overall, 50 patients (40%) had neurological signs, 26 were major signs (21.5%). Neurological signs were present at the time of admission in 37 patients and happened secondarily in 13 cases. MRI changes associated with major neurological signs were: Cervical involvement (P = 0.011), dural sac compression (P = 0.0012), ventral effacement of the subarachnoidal space (P < 0.001), compressive myelopathy (P = 0.006). More than 50% of the vertebral body destruction (P = 0.017), angular kyphosis (P = 0.016) partial or complete destruction of posterior arch (P = 0.032) were also associated with these signs. Neither epidural abscesses, multifocal lesions, loss of disk height, nor nerve roots compression were associated with major neurological signs. Neurological signs occurred in 40% of our patients with one half being major signs. Cervical involvement, vertebral destruction, angular kyphosis, dural compression, effacement of subarachnoid space and compressive myelopathy on MRI were risk factors associated with neurological complications.

Isolation of Coxiella burnetii from an acromioclavicular infection with low serological titres

Coxiella burnetii acromioclavicular infection is a new infectious focus, evidenced here for the first time using the gold standard, culture. Positron emission tomography had a crucial role in identifying the deep infectious focus, even when C. burnetii serological titres were low.

A7.13 Distinct expression of IL-36α, β, γ and their antagonists IL-36RA and IL-38 in psoriasis, rheumatoid arthritis (RA) and crohn’s disease (CD)

Background and objectives The IL-36 family of cytokines comprises three agonists: IL-36α, IL-36β and IL-36γ, an antagonist: IL-36Ra, and IL-38: another potential IL-36 inhibitor. IL-36 agonists are highly expressed in skin and are involved in the pathogenesis of psoriasis, while antagonists limit uncontrolled inflammation. The expression and role of IL-36 cytokines in other chronic inflammatory diseases is currently debated. In this study, we compared the expression profile of IL-36 cytokines in psoriasis, RA and CD. Materials and methods Skin, joint and colon inflammation was induced in mice. Skin, synovial and colonic biopsies from patients respectively with psoriasis, RA or CD were collected. Synovial fluids from patients with RA were also collected. These samples were analysed for cytokines expression by RT-qPCR, ELISA, immunohistochemistry and confocal microscopy. The cell sources of IL-36 cytokines were confirmed in cell cultures after stimulation with inflammatory cytokines and TLR agonists by RT-qPCR. Results During imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36β and IL-38, was induced and correlated with Th17 cytokines (IL-17A, IL-22…). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, β, γ, IL-36Ra and IL-38 were all elevated and correlated with myeloid cytokines such as CCL3, CCL4 and MCSF, but not with Th17 cytokines. In mice with dextran sulfate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at a relatively low level. Only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By IHC and in cell cultures, the different IL-36 cytokines were produced at different levels by human keratinocytes, CD68+ inflammatory macrophages, dendritic/Langerhans cells, and CD79α+ plasmocytes. Conclusion Expression of the different IL-36 cytokines is differently regulated and their cell sources are distinct. This helps to explain the different expression profiles observed in three chronic inflammatory diseases and why only a minor subgroup of RA and CD patients have an elevated IL-36 agonists/antagonists ratio. Additional studies are necessary to better identify these patients and to investigate whether they would benefit from IL-36 neutralisation.

FRI0526 Quality of Ultrasound-Guided Synovial Biopsies Performed in Clinical Practice

Background Synovial tissue is the principal target and end organ involved in the pathogenesis of multiple articular disease processes. Histological and bacteriological analyses of synovial tissue (ST) are useful in clinical practice for the diagnosis of undifferentiated arthritis. Ultrasound (US) allows an evaluation of the synovial thickness and inflammation. It also helps to perform real-time synovial biopsy and detect nearby structures such as tendons, nerves and vessels. Objectives The aim of this study was to assess quantity and quality of synovial tissue obtained by ultrasound guided synovial biopsies, in clinical practice. Methods We retrospectively analysed all synovial biopsies performed between January 2007 and December 2014 in the Rheumatology Department of Nantes University Hospital. Synovial biopsies were performed under real-time US guidance (Philips HD11 XE) using a core biopsy needle with a 14 or 16G calibre semi-automatic Tru-cut needle. This technique allows to collect multiple synovial samples during a single procedure. Hematoxylin and eosin stained slides were analysed by one operator (AN), blindly from clinical data. Size, area, presence/absence of synovial tissue, presence/absence of lining layer, other types of tissues were assessed and compared to pathologists analysis (gold standard). Results 75 biopsy procedures were analysed (73 patients). 125 samples were available for analysis corresponding to a median number of samples taken per patient of 1 (IQR 1–3). Mean length and width of the biopsy samples were 6.34 millimetres (mm) (±3.60) and 1.70 mm (±0.77) respectively. The mean total area of the samples was 8.77 mm2. Biopsies showed synovial tissue at the histological examination in 102 samples (80.1%). The average area of synovial tissue in these samples was 6.36 mm2 corresponding to 72.5% of the total area of biopsied tissue. The other types of tissue present on these biopsies were connective tissue in 101 cases (80.8%), adipose tissue in 42 cases (33.6%), tendon in 14 cases (11.2%) and fibrin in 24 cases (19.2%). The 23 sample retrieving no synovial tissue were composed of fibrin in 15 cases (12%), conjunctive and adipose tissue in 17 cases (13.6%), tendon in 3 cases (3.15%), cartilage in 3 cases (3.15%) and muscle in one case (0.8%). Synovial lining layer was found in 92.6% of the successful biopsies. Interobserver reliability for presence/absence of synovial tissue between AN and the pathologist was high with a kappa coefficient of 0.90 (95%CI =0.763 to 1). Conclusions Our study is the first to assess quality and quantity of synovial tissue obtained by ultrasound guided biopsy, in the clinical setting. In 80% of the biopsy procedures, quantity and quality of the synovial tissue were high enough to allow a proper histological examination. Given the fact that conjunctive and adipose tissues as well as fibrin were frequently seen on histological examination, retrieving a minimal number of 2 samples per patient appears to be required for appropriate pathology assessment in the clinical setting. Disclosure of Interest None declared

SAT0502 Tolerance and Acceptability of US Guided Epidural Injections via The Sacral Hiatus

Background Epidural injection with corticosteroids is a common treatment option for patients with lower back pain or sciatica. It can be performed via the interlaminar/interspinous routes or via the sacral hiatus. US has shown its interest to guide steroid injection via the sacral hiatus with a high rate of injection success. However, it is thought that this route might be less well tolerated and more painful for the patient than the interspinous one. It has also been demonstrated that the shape of the sacral hiatus could lead to more difficult injections. Objectives The goal of our study was to evaluate the pain during the injection, the acceptability of the procedure and to find clinical or anatomical factors associated with a painful procedure. We compared the pain during sacral hiatus epidural and interspinous injections. Methods We performed a cross-sectional study. Patients undergoing an epidural steroid injection for the treatment of radicular pain due to a disc herniation were included. Epidural injection was performed under US guidance via the sacral hiatus. After a local anesthesia with 5 mL lidocaine, 1.5 mL of cortivazol followed by 18.5 mL sterile serum were slowly injected. Pain during the procedure was evaluated using VAS pain scale. US characteristics of the sacral hiatus was recorded. Acceptability was assessed by the question “If needed, would you accept to have the procedure again”. Association between pain and any clinical or anatomical characteristics of the hiatus were assessed by linear regression analysis. Pain during the procedure was compared to the pain during interspinous injection evaluated in one of our previous study (1). Results There were 52 patients, 28 male (53%), with a mean age 52.5 years (±15). Mean BMI was 26.5 (±5). Radicular VAS pain before the procedure was 5.2 (±2.1). On US, sacral hiatus mean depth was 7.4 mm (±5.4). Intercornual distance was a mean 12.3 mm (±4) and the mean length of the sacrococcygien ligament was 22.8 mm (±7). Mean VAS pain during the procedure was 3 (±2.4) with no significant difference when compared to the interspinous route (mean VAS = 2.8±2.1; p=NS). No immediate complication was recorded. Forty-height patients (92%) would either be very likely or somewhat likely to a repeat procedure. Only one patient would be somewhat unlikely to have a new injection. Thirty-six (69%) patients would surely recommend this procedure to one of their friends. We found no significant association between the pain during the procedure and any of the clinical or anatomical parameters. Importantly, no association was found between the pain and the US shape of the sacral hiatus. Conclusions US guided epidural injections through the sacral hiatus is a simple and well tolerated procedure. We found no difference of pain between the interspinous or the sacral hiatus routes. Most of the patients would accept to have this procedure again. We did not find any clinical or anatomical characteristic associated with a painful procedure. References Darrieutort-Laffite C, Bart G, Planche L, Glemarec J, Maugars Y, Le Goff B. Usefulness of a pre-procedure ultrasound scanning of the lumbar spine before epidural injection in patients with a presumed difficult puncture: A randomized controlled trial. Joint Bone Spine. 2015 Oct;82(5):356–61. Disclosure of Interest None declared