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Clinical use of glucocorticoids Abi Karam Ghada. Pathophysiology and management of glucocorticoid induced osteoporosis. Bianchi, Genoa, Italy Biphasic.

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Présentation au sujet: "Clinical use of glucocorticoids Abi Karam Ghada. Pathophysiology and management of glucocorticoid induced osteoporosis. Bianchi, Genoa, Italy Biphasic."— Transcription de la présentation:

1 Clinical use of glucocorticoids Abi Karam Ghada

2 Pathophysiology and management of glucocorticoid induced osteoporosis. Bianchi, Genoa, Italy Biphasic Bone loss : rapid reduction of BMD during the first year (6% to 12%), followed by a slower annual loss of about 3% for as long as glucocorticoids are administered. The relative risk of fracture increases more rapidly (up to 75% within the first 3 months), and fragility fractures often occur before a significant decline in BMD become evident, (corticosteroid use does has an effect on fracture risk independently of the effects on bone density).

3 Pathophysiology: 1.Direct interaction with the bone cells: produce a decrease in osteoblastogenesis and an increase in osteoblasts apoptosis, leading to a continual decrease of synthetic ability and bone formation. Osteoclasts survival is improved by glucocorticoids. an effect on osteocytes has been also described: increased osteocyte apoptosis and decreased canalicular circulation, leading to an alteration of bone quality. 2. GH, muscle mass, sex hormones, intestinal Ca absorbtion: reduced. 3. Genetic variation in GC receptors, polymorphism in Vit D receptors.

4 Treatment of GC induced OP: 1.General measures: Ca, vit D, smoking cessation, physical activity… 2.Bisphosphonates and teriparatide: RCTs showed significant beneficial effects in preserving and/or improving the bone mineral density. Some of these agents also demonstrated to reduce the risk of vertebral fractures. The anti-fracture and long-term efficacy has not been fully clarified mainly due to the small samples studied and to the short-term follow-up of RCTs.

5 DENOSUMAB FOR PATIENTS RECEIVING LONG-TERM GLUCOCORTICOIDS WHO DO NOT HAVE ADEQUATE RESPONSE TO BISPHOSPHONATE TREATMENT: A RANDOMIZED CONTROLLED TRIAL. Hong-Kong Objectives: To evaluate the efficacy of denosumab on BMD in patients receiving long-term glucocorticoids who do not have satisfactory response to bisphosphonate treatment.

6 Methods: The inclusion criteria : (1) adult patients ≥18 years of age; (2) Daily dose of prednisolone ≥2.5mg within 3 months of study entry; (3) Inadequate BMD response or the development of new fracture despite bisphosphonate treatment for ≥2 years. 40 Participants were randomized to receive either: (1) Denosumab (60mg SQ /6 mo) + discontinuation of Bph or (2) Continuation of oral bisphosphonates (control group). Calcium (3g/day of caltrate), vitamin D (rocaltrol 0.25ug/day) and other medications as usual. Baseline and follow-up BMD (femoral neck, femoral trochanter, total hip, lumbar spine and whole body) at 6 and 12 months Markers of bone turnover (serum osteocalcin, serum P1NP, serum CTX, and urine DPD) were also assayed at the same time points. The primary outcome was the BMD change in the lumbar spine at month 12 compared to baseline.

7 Results: At month 12, a significant gain in BMD at the lumbar spine (+3.4±0.9%; p=0.002) and the hip (+1.4 ± 0.6%; p=0.03) observed in denosumab-treated patients. The increase in BMD of the spine and total hip was not statistically significant in the control group of patients. No new fractures occurred in the participants at month 12. Minor upper respiratory tract infection was numerically more commonly reported with denosumab (30% vs 10%) while other adverse events occurred at similar frequency between the two groups. One patient of each group was withdrawn from the study because of non-compliance to treatment. None of the patients withdrew from study because of adverse events.

8 Conclusion: In patients receiving long-term glucocorticoids but not having adequate response to bisphosphonates, denosumab was effective in raising the BMD at the spine and hip after 12 months’ therapy. Denosumab was well tolerated.

9 ONE-YEAR EFFECTS OF GLUCOCORTICOIDS ON BONE DENSITY. A META-ANALYSIS IN COHORTS OF PATIENTS ON HIGH AND LOW DOSE THERAPY. Amesterdam Objectives: To investigate GC-induced bone loss in patients with chronic inflammatory diseases (low dose) or transplants (high dose) through a metaanalysis of cohorts. Methods: A search of published studies in PubMed (1995 – 2012), Cochrane databases (1995 – 2012), EMBASE (1995 – 2012), and bibliographic references extending and expanding a previous systematic review on chronic disease up to articles(n=1565pts) CID, 16 articles (n=635) transplant pts. Study selection: Prospective studies were included of patients receiving GC who underwent at least 2 BMD measurements by DEXA over a period of at least 8 months. Only supplementation with calcium and/or Vitamin D3 was allowed. Cohorts studying patients using bisphosphonates or other anti- osteoporotic drugs or diseases associated with influence on bone loss were excluded. Primary outcome was the one-year change in lumbar spine BMD; secondary outcome the change in femoral neck BMD.

10 Results: In the chronic inflammatory diseases group (both starters and chronic users): mean daily dose of GC = 8,8 mg (1.2 – 16.4). Bone loss at the lumbar spine= -1.8% [95%CI: -2.2; -1.3]. Only 39 cohorts (N=1255) also measured femoral neck; in these bone loss was -1.5% [-2.1; -0.9] in the lumbar spine, and -1.3% [-1.8; -0.8] in the femoral neck. In the transplantation group (almost all starters) the mean daily dose of GC was 20.4 mg (7.7 – 52.7). Bone loss at the lumbar spine was -4.9%[-6.6; -3.1]. Only 18 cohorts (N=551) also measured femoral neck; in these bone loss was -4.1% [-6.0; -2.2] in the lumbar spine, and -3 [-4.8; -1.3] in the femoral neck.

11 BMD % change from baseline. The graph depicts individual studies, weighted mean and 95%CI.

12 Conclusions: This meta-analysis provides definitive data on one-year bone loss across a range of diseases and GC doses. It shows GC treatment at the high doses used in transplantation patients leads to considerable bone loss, especially in the lumbar spine. In contrast, bone loss is limited during GC treatment at the lower doses used in chronic inflammatory disease. Existing guidelines should be updated to reflect this data

13 NOVEL GLUCOCORTICOIDS AND GLUCOCORTICOID RECEPTOR LIGANDS: TEACHING OLD DRUGS NEW TRICKS. Charite, Berlin Selective GR agonists (SEGRAs). This approach is based on the suggestion that some GC actions (the so called transrepression effects) are to a greater extent responsible for desirable anti-inflammatory and immuno modulating effects than the other actions (the so called transactivation effects) that are associated with frequently occurring side effects (but also with some immunosuppressive activities). The idea of developing SEGRAs is to use transrepression mediated GC effects almost exclusively thereby inducing potent GC therapeutic activity with reduced side effects. (ongoing study, USA, www.

14 Other targeted molecules Targeted delivery of GC using liposomal formulations: ongoing study. Prednisone + dypiridamole combination: not > prednisone alone. Development stopped.

15 Chronotherapeutic prednisone formulation MR/DR prednisone: release 4h after ingestion 2 studies: CAPRA-1: MR prednisone : clinically superior to the conventional immediate release preparation with respect to reducing morning joint stiffness and clinical control of the disease. Same safety profile. CAPRA-2:

16 CAPRA-2: 12-week, double-blind, placebo-controlled trial. MR prednisone 5 mg once daily plus DMARD therapy resulted in higher response rates for ACR20 and ACR50, and a greater median relative reduction from baseline in morning stiffness (22%) at week 12 compared with placebo plus DMARD therapy. Significantly greater reductions in severity of RA and fatigue, as well as a greater improvement in physical function were seen at week 12 with MR prednisone compared with placebo. The incidence of adverse events was similar for MR prednisone and placebo.

17 Treatment of Undifferentiated early arthritis Dr. Alla Saad



20 2010 UA patients have milder baseline characteristics and milder outcome than 1987 UA patients Remaining presentation: UA = 1987-UA

21 Undifferentiated arthritis at baseline is not similar to arthritis that remains undifferentiated over time



24 When to Treat?

25 Why treating UA? Why treating early? Systematic Literature Review Strong evidence that the timing of intervention is associated with the severity of radiological progression

26 Relationship of prolonged symptom duration and DMARD free sustained remission General “the earlier the better” principle Window of Opportunity Early treatment is beneficial at any point in time Specific time frame in which disease is more susceptible no treatment


28 What are relevant disease outcomes for UA-patients? Perhaps not: fulfilling classification criteria for RA Not any more: Structural damage Persistence of the disease = Chronic use of medication / DMARDs Functioning

29 Prediction of persistence within early UA (or RA) A model predicting persistence within UA or within RA lacking Validated risk factors for persistence:  ACPA/RF  Symptom duration

30 UA patients with a high chance to progress to RA can be estimated adequately Risk prediction for other outcomes of UA not existing

31 Trials in UA


33 ADJUST: Abatacept in UA Anti CCP+ UA, 26 abatacept, 24 placebo RA 1yr in: 46% abatacept arm 67% placebo arm NOT SIGNIFICANT DIFFERENCE

34 SAVE trial: single injection corticosteroids 120mg IM 389 UA patients All symptoms < 16 weeks One single 120mg prednison or placebo Primary outcome (clinical remission) : not significant difference


36 STIVEA trial: three injections corticosteroids IM Sec outcome: Persistent remission (arthritis resolved yr 1) - Steroids 20% - Placebo 10% Three doses of steroids in early UA: less persistence of arthritis

37 EMPIRE trial Patients with >1 SJC and symptom duration < 3 months, positive for ACPA, RF or HLA-SE MTX + placebo versus MTX + etanercept No DMARD-free placebo arm No swollen or tender joints at yr1: 32% versus 28% DMARD free remission: 7% versus 9% Etanercept not additive to MTX in ACPA/RF pos UA

38 Treatment in UA No trials performed extensive risk stratification in UA Early intervention more effective than late intervention IM steroids Single injection not disease modifying Repeated injections less DMARDs needed, less persistence MTX, abatacept Not disease modifying in persistent UA No placebo controlled trials in early UA Etanercept no additive value to MTX in early UA










48 EULAR 2014 Polyarthrite rhumatoide Baddoura

49 LUNG DISEASE AMONG RHEUMATOID ARTHRITIS PATIENTS – RESULTS FROM ONTARIO BIOLOGICS RESEARCH INITIATIVE (OBRI) S. Mittoo et al. EULAR 2014, Paris, juin 2014 Etude prospective 2328 PR 204 (8.8%) avec atteinte pulmonaire. – Asthme54 % – BPCO24% – PI 19% – Autres3% Initialement, il y a une différence dans – l’âge – la durée de la maladie, – dans le statut inflammatoire mais pas dans le nombre d’AD ou AT. – Les sujets avec pneumopathie reçoivent moins de MTX et plus de biothérapie. A un an, l’activité de la maladie, le nombre d’AD et AT et l’HAQ sont plus élevés de façon significative. Malgré une activité initiale similaire, les PR avec atteinte pulmonaire sont plus sévères à 1 an, peut être en lien avec l’absence de MTX

50 PREVALENCE OF VITAMIN D DEFICIENCY IN RA: DATA FROM THE COMEDRA COHORT S. Cecchetti et al. EULAR 2014, Paris, juin PR avec une durée moyenne de 11,2 ans. – Erosions73,3 % – FR / anti-CCP.83,9 % – DAS283 ± 1,3 – Biothérapie 70,4 % – Corticoïdes. 38,1 % Vitamine D – ng/ml56 % – < 10 ng/ml3,5 % Taux inversement corrélé au BMI. Pas de différence géographique en fonction de la carence en vitamine D. Pas de corrélation avec les anticorps ni les traitements Par rapport à des contrôles appariés, les PR ont moins de carence et de déficience Pas de corrélation avec les facteurs de risque cardio-vasculaire. Lors de l’analyse multivariée, les facteurs associés à une carence en vitamine D sont: – l’activité de la maladie, – le dosage de CRP, – le nombre d’articulations tuméfiées, – le CDAI et le SDAI.

51 RADIOGRAPHIC PROGRESSION OF ≥5 OF 448 UNITS OVER 1 YEAR IN THE ESPOIR FRENCH EARLY ARTHRITIS COHORT IS SEEN IN FEWER THAN 15% OF PATIENTS, BUT MORE LIKELY IN PATIENTS NOT IN REMISSION, WITH NO DIFFERENCES ACCORDING TO 6 REMISSION CRITERIA I. Castrejón et al. EULAR ,1% des patients en rémission ont une progression ≥ 5 U après un an versus 13 % en cas de non rémission, cette différence n’est pas significative. Elle devient significative pour une progression > 10 U avec DAS28 et RAPID≤3+SJ≤1 602 PR. 110 (18%) à 247 (41%) sont en rémission selon les critères utilisés Critères rémission DAS28

52 EVIDENCE THAT BOTH THE DISEASE COURSE & STRUCTURAL OUTCOMES IN RA HAVE BECOME LESS SEVERE OVER TIME. A 25-YEAR LONGITUDINAL DATA ANALYSIS BASED ON TWO CONSECUTIVE UK INCEPTION COHORTS Elena Nikipourou et al. EULAR 2014 Deux cohortes de 2701 PR récentes, naïves de traitement de fond conventionnel : – ERAS – ERAN Fréquence élevée dans les premières années de la monothérapie séquentielle Abandon des AINS seuls après 1999 Montée des anti-TNF jusqu’en 2006 et des traitements combinés par la suite. Pas de différence dans le sex- ratio, la présence du FR ou les érosions initiales. L’âge de début de la maladie augmente de 0,22 années par an. L’activité de la maladie (DAS28) diminue de 0,03 / an Les chirurgies mineures (main, pied) ont diminué mais pas les interventions majeures (prothèses)

53 HIGH RISK OF DEVELOPING FATAL INFECTIONS IN RA PATIENTS WITH CONGESTIVE HEART FAILURE Anja Strangfeld et al. EULAR 2014 A partir du registre RABBIT, patients. – 242 (2.3%) ont un antécédent d’insuffisance cardiaque (IC) Comparés au reste de la cohorte, les patients ayant eu une IC – Sont plus âgés de 12 ans – Sont plus souvent des hommes – Ont un DAS28 plus élevé La mortalité de ces infections y est plus importante (15%) Avec antécédent d’insuffisance cardiaque Sans antécédent d’insuffisance cardiaque 16/100 patients/années 3,4/100 patients/années Incidence des infections

54 A TRANSATLANTIC CARDIOVASCULAR RISK CALCULATOR FOR RHEUMATOID ARTHRITIS (ATACC-RA) E Arts et al. EULAR 2014 Cohorte internationale [8 centres, 7 pays] 3176 PR sans antécédent CV, suivis en moyenne de 7,8 ans 314 ont eu une maladie CV pendant l’étude Facteurs de risque: 2 modèles incluant le FR ou anti-CCP et le DAS28

55 INFLUENCE OF BODY MASS INDEX ON OUTCOMES IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOCILIZUMAB MA Vollmer et al. EULAR 2014, 60 patients traités par TCZ pendant au moins 6 mois et divisés en 2 groupes en fonction de la valeur médiane du BMI. Critère principal: DAS28. En début de traitement, plus de 9 patients sur 10 ont une activité modérée. La majorité des patients a reçu la dose conventionnelle de 8 mg/kg /4 sem. Dans les 2 groupes, amélioration clinique statistiquement comparable. – Diminution médiane du DAS28 de 2,3 (1,6 – 3,8) chez les sujets à BMI élevé versus 1,5 (0,9 – 3,0) chez les sujets à BMI plus bas (p = 0,09). Les taux de rémission et de LDA à 6 mois sont comparables.

56 TOCILIZUMAB IN THE TREATMENT OF PATIENTS WITH RA IN REAL CLINICAL PRACTICE: RESULTS OF TRUST STUDY R. Gerli et al. EULAR 2014 Etude observationnelle des 322 patients (59 centres). – Age moyen 55,8 ans – Durée moyenne 10 ans – DAS28 moyen initial 5,3 – Après 6 mois de traitement (226 patients évalués, monothérapie 32,6 %): – réponse LDA 57,2 % – rémission DAS28 38,05 % Réponse comparable entre monothérapie et stratégies de combinaison, mais aussi selon la ligne stratégique (patients DMARDs-IR ou anti-TNF-IR). Arrêts prématurés19,2 %

57 EFFECTIVENESS AND DRUG ADHERENCE OF BIOLOGIC MONOTHERAPY IN DANISH RHEUMATOID ARTHRITIS PATIENTS: A COHORT STUDY OF CLINICAL PRACTICE IN THE DANBIO REGISTRY Jorgensen T. et al. EULAR 2014, Paris, juin patients (de Mai 2011 à Avril 2013). DAS28 moyen initial de 4,4 ± 1,6. Biologique en monothérapie Moins de 10 % des patients obtiennent une rémission CDAI à 6 mois lorsqu’ils sont traités par abatacept, certolizumab ou infliximab Les résultats apparaissent meilleurs avec plus de 20% de rémission avec adalimumab, etanercept, golimumab et tocilizumab (résultats intermédiaires avec le RTX). Près de 30% ont une réponse ACR50 à 6 mois (résultats moindres avec IFX 14 % et RTX 16 %

58 SUSTAINED CLINICAL BENEFIT WITH MULTIPLE COURSES OF RITUXIMAB IN SECOND LINE FOR ALL RHEUMATOID ARTHTRITIS PATIENTS IRRESPECTIVE TO THE INHIBITOR OF TUMOUR NECROSIS FACTOR PREVIOUSLY USED: 3-YEAR DATA FROM REPEAT STUDY I. Ancuta et al. EULAR 2014, Paris, juin 2014 L’objectif principal est d’évaluer le rapport bénéfices / risques du RTX dans la PR après échec de >= 1 anti-TNFα patients traités par RTX depuis – 929 ont eu un échec préalable d’un anti-TNF 401 infliximab, 318 etanercept, 210 adalimumab – 158 ont été traités par >2 anti-TNF. Le DAS28 moyen à l’initiation est de 5,76 pour atteindre 3,98 à 6 mois et 3,43 à 1 an.

59 RITUXIMAB IN RHEUMATOID ARTHRITIS – 4 YEARS INTERIM ANALYSIS OF THE NON-INTERVENTIONAL BRIDGING STUDY Krause et al. EULAR patients avec un suivi de 4 ans – Recul >= 24 semaines pour 996 patients Age moyen de 60,4 ans, DAS28 initial à 5,3. 67,6 % des patients ont eu >= un anti-TNFα Infections sévères, 4 /100 patient- années. A 6 mois: – Amélioration moyenne du DAS28: 1,6 – LDA30,4 % – Rémission DAS2816,7 % Absence de différence significative en fonction du poids ou l’intoxication tabagique.

60 THE INFLUENCE OF ANTI-TNF OR RITUXIMAB ON CANCER INCIDENCE IN PATIENTS WITH RHEUMATOID ARTHRITIS WHO HAVE HAD A PRIOR MALIGNANCY (BSBR) Sulva-Fernandez L et al. EULAR 2014, Paris, juin 2014 RTXAnti-TNFCs DMARDs Total 23 (8.9%)242 (1.7%)159 (4.2%)Antecedent néoplasique 5.4 ( ) )7.9 ( )Le délai médian entre l’initiation du traitement et l’antécédent néoplasique 17.4%56.8%37.1%Antécédent néoplasique > 10 ans 3.9 ( )6.9 ( )6.6 ( )Suivi median 0.47( )0.55( )Hazard ratio for malignancy vs CsDMARDS ajusted for age and sex Le rôle des biomédicaments dans la survenue d’une affection néoplasique reste débattu. Pas de contre-indication officielle à l’utilisation des biomédicaments chez des sujets ayant un antécédent néoplasique Le CRI recommandant de ne pas utiliser les biomédicaments chez les sujets ayant un antécédent néoplasique récent (moins de 5 ans / à l’exception des cancers cutanés non mélanomes)

61 IMPACT OF CORTICOSTEROID USE ON REMISSION SUSTAINABILITY AND INFECTION RATES AMONG RHEUMATOID ARTHRITIS PATIENTS IN REMISSION WHILE ON INFLIXIMAB: TREATMENT IMPLICATIONS BASED ON A REAL-WORLD POPULATION B. Haraoui et al. EULAR 2014, Paris Registre BioTRAC: 628 PR et traitées par IFX sur la période de 2002 à – Age moyen55,8 ± 13,6 ans – Durée moyenne10,2 ± 10 ans. – Rémission DAS28 46,5 % – Rémission CDAI30,4 % – Corticothérapie chez un peu plus de 16 % des patients Rémission prolongée sans lien avec la corticothérapie – HR-DAS28 = 1,4 [0,95 – 2,06] – HR-CDAI = 1,19 [0,75 – 1,88] Survenue précoce de pathologies infectieuses sous corticothérapie : – Patients en rémission DAS28: HR = 1,78 (1,00 – 2,19) – Patients en rémission CDAI: HR = 2,38 (1,14 – 4,99)

62 INDUCTION OF CLINICAL REMISSION FOLLOWED BY DRUG-FREE WITHDRAWAL WITH ABATACEPT COMBINATION AND MONOTHERAPY IN EARLY RA: RESULTS FROM THE AVERT STUDY OVER 18 MONTHS P. Emery et al. EULAR 2014, Paris, juin 2014 Objectif principal: rémission à 1 an et maintien de cette rémission après arrêt à 1 an de tous les traitements (période de suivi de 6 mois). (91, 81 et 84 patients par bras) PR débutantes: > 2 synovites, des anti-CCP et un DAS28 ≥ 3,2, depuis < 2 ans, naïves de MTX et biothérapie.

63 MRI RESULTS FROM THE AVERT STUDY: A RANDOMIZED, ACTIVE- CONTROLLED TRIAL TO EVALUATE INDUCTION OF REMISSION AND MAINTENANCE OF DRUG-FREE REMISSION USING ABATACEPT IN COMBINATION WITH METHOTREXATE OR AS MONOTHERAPY IN PATIENTS WITH EARLY RA C. Peterfy et al. EULAR 2014, Paris, juin 2014 Evaluation ancillaire par IRM (1,5 Tesla / examen réalisé tous les 6 mois / examen sur la main et le poignet cliniquement le plus atteints / score RAMRIS (91, 81 et 84 patients par bras).

64 INFLUENCE OF BIOLOGIC AGENTS ON POSTOPERATIVE INFECTION IN RHEUMATOID ARTHRITIS PATIENTS M Tada et al. EULAR 2014, Paris, juin patients avec 408 interventions chirurgicales. – Durée moyenne16,8 ans, – Age moyen64,9 ans, – Diabétiques11,5 % – Biothérapies 31,6 % [59 patients IFX, 33 ETN, 8 TCZ, 6 ADA et 3 ABA] 27 cas d’infections (6.6%) des interventions: 18 superficielles, 9 profondes. – 22,2% des patients avec infections étaient sous biothérapie – 32,1% des patients sans infections étaient sous biothérapie Les facteurs de risque – Pour les infections superficielles (sur la cicatrice): l’âge, le temps opératoire. – Pour les infections profondes: le temps opératoire et l’activité de la maladie.

65 WHEN DOES THE THERAPEUTIC WINDOW OF OPPORTUNITY IN RHEUMATOID ARTHRITIS CLOSE? A STUDY IN TWO EARLY RA COHORTS. J. A. Van Nies et al. EULAR 2014, Paris, juin cohortes: Leiden (15 ans) et ESPOIR (4 ans). Critère de jugement: rémission prolongée sans traitement de fond (absence d’arthrite clinique + absence de traitement de fond sur une durée ≥ 1 an). – Leiden18 % (157/864) – ESPOIR 5 % ( 26/558) La probabilité d’obtenir une rémission prolongée sans traitement de fond diminue de façon significative lorsque les symptômes évoluent depuis plus de – 14 semaines dans la cohorte de Leiden (11,6 – 15,4) 14,6 semaines [PR ACPA positives] vs 18,9 semaines [ACPA négatives] – 15 semaines dans la cohorte ESPOIR (10,7 - 28,0). Résultats comparables entre PR ACR 1987 et PR ACR/EULAR 2010 Pas de relation linéaire entre la durée d’évolution des symptômes et l’obtention d’une rémission prolongée sans traitement de fond.

66 CONCOMITANT FIBROMYALGIA IN RHEUMATOID ARTHRITIS IS ASSOCIATED WITH INCREASED USE OF BIOLOGICAL THERAPY P. R. Lage-Hansen et al. EULAR 2014, Paris, juin 2014 Registre DANBIO: – 19 PR associées à une fibromyalgie comparées à 122 PR sans fibromyalgie. Pas de différence significative pour – l’âge – la durée d’évolution de la maladie – le sex-ratio – le recours au tabagisme DAS28 moyen: 4,51 avec fibromyalgie versus 3,02 sans fibromyalgie (p < 0,001) – Cette augmentation du DAS28 correspond bien à une valeur significativement plus élevée du score d’articulations douloureuses (p = 0,011) et de l’EVA globale (p < 0,001). Le recours aux biomédicaments: 68 % avec fibromyalgie versus 32 % sans fibromyalgie (p = 0,002)

67 LOW-DOSE PREDNISOLONE TREATMENT OF EARLY RHEUMATOID ARTHRITIS WAS ASSOCIATED WITH INCREASED RISK OF CEREBROVASCULAR BUT NOT CORONARY ARTERY EVENTS: TEN YEAR FOLLOW-UP OF A TWO-YEAR RANDOMIZED TRIAL S. Ajeganova et al. EULAR 2014 BARFOT, étude randomisée, ouverte, 2 ans, comparant dans la PR récente, prednisolone 7,5 mg/j + csDMARD versus csDMARD seul. 223 patients sans antécédents cardiovasculaires suivis pendant 10 ans. La moitié des patients du groupe prednisolone ont arrêté le traitement après les 2 ans de l’étude et un quart supplémentaire a arrêté à 4 et 5 ans. Dans le groupe sans corticoïdes, 6% ont pris par la suite une corticothérapie Apres ajustement sur l’âge – pas de différence de fréquence pour IDM et décès – différence significative [OR à 3,7] pour AVC dans le groupe prednisolone

68 18FFDG PET IN GIANT-CELL ARTERITIS: A PROGNOSTIC TOOL FOR AORTIC COMPLICATIONS. De Boysson H et al. Eular 2014 Etude rétrospective de 133 cas de maladie de Horton (66% de femmes, d’âge allant de 50 à 86 ans); diagnostic prouvé histologiquement dans 59% des cas. TEP scan réalisé au départ chez 67 patients et durant le suivi chez 66 d’entre eux. Au 1er examen – Hypermétabolisme vasculaire chez 51% des patients avec atteinte médiane de 4 territoires vasculaires sur l’aorte thoracique ou abdominale et ses principales branches – Dans 79% des cas l’aorte thoracique était concernée. – Manifestations extracéphaliques cliniques (59% versus 37%, p = 0,001) Au cours du suivi, – Anévrisme aortique survenu chez 14 patients (11%), 11 d’entre eux avaient un TEP positif initial. – Dissection aortique survenue chez 3 patients qui fixaient tous en TEP.

69 SIGNATURE OF CIRCULATING MICRORNAS IN OSTEOARTHRITIS C. Beyer et al. Eular 2014, Paris, juin 2014 Etude de phase IV randomisée contre placebo: 22 patients ayant une gonarthrose traités pendant 4 mois par chondroïtine sulfate (CS 800 mg/j) et 27 patients traités par placebo. Seul le paracétamol était autorisé lors de l’étude comme traitement dit de « sauvetage ». La réponse à une stimulation douloureuse par pression rotulienne ou de l’interligne fémoro-tibiale interne était évaluée par IRM cérébrale fonctionnelle Après 4 mois de traitement, cliniquement, la pression rotulienne tendait à être moins douloureuse dans le groupe CS. La variation en IRM cérébrale des zones activées par le stimulus douloureux de pression rotulienne était significativement plus importante dans le groupe CS vs groupe placebo. Pas d’effet de la CS avec le test de pression de l’interligne articulaire interne, possiblement plus complexe en terme de stimulation douloureuse que la pression rotulienne

70 UPDATED EULAR EVIDENCE-BASED RECOMMENDATIONS FOR THE MANAGEMENT OF GOUT P. Richette et al. Eular 2014, Paris, juin Recevoir des informations sur la physiopathologie de la maladie, l’existence de traitements efficaces, des comorbidités associées, et les principes des traitements des crises et des traitements hypouricémiants (THU) au long cours (FR=9) 2.Recevoir des conseils sur l’hygiène de vie : perte de poids si nécessaire, arrêt de la consommation des alcools (en particulier bières et spiritueux) et des sodas sucrés, éviter des consommations excessives de viandes et de poissons. Des produits peu gras sont conseillés ainsi que des exercices physiques réguliers (FR=9) 3.Avoir un dépistage des comorbidités et des facteurs de risque cardiovasculaire : maladie rénale chronique, insuffisance coronarienne et cardiaque, artériopathie des membres inférieurs, diabète, HTA, dyslipidémie, obésité, tabac. Il s’agit d’une prise en charge globale de la maladie goutteuse (FR=9) 4.Substituer, si possible, un traitement par diurétique de l’anse ou un thiazidique. En cas d’hypertension, préférer un traitement par losartan ou inhibiteur calcique et en cas de dyslipidémie, une statine ou le fénofibrate (FR=9) 5.Le traitement des crises doit être débuté le plus tôt possible dès les premiers signes et les prémices reconnus par le patient. L’éducation pour l’automédication des crises est recommandée. Le choix du traitement dépend des contre-indications, de l’expérience antérieure des patients, du délai de prescription par rapport au début de la crise, et du nombre et du site de l’articulation touchée (FR=9)

71 UPDATED EULAR EVIDENCE-BASED RECOMMENDATIONS FOR THE MANAGEMENT OF GOUT P. Richette et al. Eular 2014, Paris, juin Les traitements recommandés en première intention sont : colchicine (si crise durant moins de 12 heures) avec une dose de charge de 1 mg suivie une heure plus tard de 0.5 mg pour le premier jour ; AINS (associée à un IPP si besoin), corticothérapie orale (30-35 mg/j d’équivalent de prednisone pendant 3 à 5 jours), ou en injection intra-articulaire. Colchicine et AINS ne sont pas indiqués en cas d’insuffisance rénale. La colchicine est contre-indiquée chez des patients recevant des traitements dépendant du transporteur P- glycoprotéine ou des inhibiteurs du cytochrome CYP3A4 comme la cyclosporine ou la clarithromycine (FR=9) 7.En cas de crises fréquentes et de contre-indication à la colchicine, aux AINS et à la corticothérapie, un traitement par inhibiteur de l’interleuikine-1β (IL-1β) peut être utilisé. Une infection active contre-indique l’utilisation temporaire de ce traitement. L’adaptation du traitement par THU pour obtenir une uricémie cible peut être effectuée au décours d’une crise traitée par inhibiteur de l’IL-1β (FR=8) 8.Le traitement prophylactique des crises doit être expliqué au patient. Il est recommandé dans les 6 premiers mois du THU. Il utilise la colchicine à la dose de mg/jour, dose à diminuer en cas d’insuffisance rénale. En cas d’insuffisance rénale ou d’utilisation concomitante de statine, il y a un risque accru de toxicité neuromusculaire. Si la colchicine est contre-indiquée, on peut utiliser des AINS à faible dose. 9.L’initiation du THU est à discuter avec le patient dès le diagnostic certain de goutte. Il est indiqué en cas de crises récidivantes, de tophus, d’arthropathies uratiques, et de lithiase rénale d’origine urique. Il est recommandé dès la première crise chez les patients jeunes (moins de 40 ans), ou ayant une uricémie très élevée (supérieure à 480 µmol/l ou 8 mg/dl) ou des comorbidités (insuffisance rénale, HTA, insuffisance coronarienne, insuffisance cardiaque). Des informations sur le THU doit être délivrées et l’implication des patients sollicitée (FR=8.5)

72 UPDATED EULAR EVIDENCE-BASED RECOMMENDATIONS FOR THE MANAGEMENT OF GOUT P. Richette et al. Eular 2014, Paris, juin Sous THU, l’uricémie doit être vérifiée régulièrement pour obtenir un taux sérique inférieur à 360 µmol/l (6 mg/dl). Une uricémie plus basse, inférieure à 300 µmol/l (5 mg/dl) est recommandée dans les gouttes sévères (tophus, arthropathies uratique) pour accélérer la dissolution des cristaux. Un taux sérique inférieur à 180 µmol/l (3 mg/dl) au long cours n’est pas recommandé (FR=9) 11.Le THU est initié à faible dose puis adapté pour obtenir la valeur cible de l’uricémie. Un taux sérique de l’urate inférieur à 360 µmol/l (6 mg/dl) doit être maintenu tout le temps 12.Chez des patients à fonction rénale normale, l’allopurinol est le traitement de première intention. Il est initié à faible dose (100 mg/jour) et augmenté de 100 mg tous les 2-4 semaines en fonction de l’uricémie jusqu’à l’obtention de l’uricémie cible. Si celle ne peut pas être atteinte avec une dose optimale d’allopurinol, les traitements suivants peuvent être proposés : fébuxostat, uricosurique ou association allopurinol/uricosurique. Le fébuxostat et l’uricosurique sont aussi utilisés en cas d’intolérance à l’allopurinol (FR=9) 13.La dose de l’allopurinol est adaptée à la clairance de la créatinine en cas d’insuffisance rénale. Si l’uricémie cible n’est pas atteinte avec la dose maximale autorisée, le fébuxostat ou la benzbromarone peut être utilisé sauf chez les patients avec DFG < 30 ml/min 14.Dans les gouttes sévères tophacées avec diminution de la qualité de vie, et si l’uricémie cible ne peut pas être atteinte avec les doses maximales des médicaments habituels (y compris en association), la pégloticase peut être utilisée (SR=8).

73 Best of EULAR 2014 Abdel Fattah Masri, MD

74 Update on Giant Cell Arteritis EULAR 2014 Paris Agenda 1. Case presentation 2. Modern approaches to diagnose GCA: Temporal artery biopsy: Gold standard Imaging modalities: a) Diagnosis b) Outcome of therapeutic responses 3. Biologic therapy 4. Etiologic considerations

75 Case presentation AFH a 56 year old man admitted to AUBMC on 2 August with FUO. Presenting manifestations were fatigue, weight loss, prostration, myalgias, and fever. Previous episode(s) of bitemporal headache? Leukocytosis, mild anemia, elevated ESR and CRP. W/U for infectious disease and neoplasia were negative. Previous history of herpes zoster infection in abdomen.

76 DDX : Adult onset Still’s disease Giant cell arteritis Temporal artery biopsy (TAB) declined. Carotid Duplex Scan on temporal arteries: TA measuring the right 2.1 mm and the left 1.6 mm in diameter with thickened wall bilaterally.

77 GCA and EULAR 2014

78 Giant Cell Arteritis (GCA) 1. Pathogenic Mechanisms in GCA 2. Imaging Modalities: A) Ultrasonography in diagnosis B) Monitoring response of therapy by imaging C) Imaging and temporal artery biopsy D) Managing resistant to treat PMR/GCA


80 SP0002 Giant cell arteritis: new perspectives PATHOGENIC MECHANISMS IN GIANT-CELL ARTERITIS M.C. Cid, on behalf of Vasculitis Research Unit. Systemic Autoimmune Diseases, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain

81 Giant-cell arteritis (GCA) is a chronic inflammatory disease of large vessels. The epidemiology of GCA suggests that a genetic background plays a role in its pathogenesis. Several polymorphisms have been associated with increased susceptibility to GCA, but the strongest association has been found with MHC class II variants, supporting the concept that GCA is an antigen-driven disease

82 Activated dendritic cells are present in lesions and considered to play an important role in T-cell activation. GCA is characterized by a marked Th1- mediated immuneresponse with strong expression of IFNγ. Th17 immune response also contributes to GCA and patients with prominent IL-17 expression respond better to glucocorticoid treatment.

83 Amplification cascades following initial events are crucial in the development and maintenance of GCA lesions. IFNγ is a potent activator of macrophages which produce pro-inflammatory cytokines IL-1, TNFα and IL-6, among others. Tissue expression and serum concentrations of TNFα and IL-6 are associated with persistent/relapsing disease. Chemokines and adhesion molecules are also expressed in lesions and amplify inflammatory loops. Angiogenic factors promote neovascularization, providing new entries for infiltrating leukocytes.

84 Currently, GCA treatment relies on glucocorticoids which induce a dramatic improvement of symptoms but are unable to achieve sustained remission in % of patients. The association between increased expression of TNFα and persistent disease activity led to the performance of clinical trials blocking TNF with various agents which, unfortunately, have not been able to maintain remission, probably due to redundancy in cytokine pathways.

85 Currently, blocking IL-6 receptor with tocilizumab or interfering with CD28-mediated T-cell co-stimulation with abatacept, are being tested in multi-centre clinical trials. IL-6 is a multifunctional cytokine involved not only in inducing the acute phase response and related symptoms but also in maintaining the activation of the Th17 pathway.

86 Growth factors produced by activated macrophages or by injured vascular smooth muscle cells induce myofibroblast differentiation, migration and production of matrix proteins, leading to intimal hyperplasia and vessel occlusion, source of the ischemic complications in GCA. PDGFs, TGFβ and endothelin-1, may contribute to myofibroblast activation. Their expression in lesions is not down-regulated by glucocorticoids suggesting that mechanisms of vessel occlusion may require a specific approach.

87 Ultrasonography 2. Imaging Modalities

88 Extracranial duplex of left superficial temporal artery (STA) showing reduced color-filling and vessel-wall thickening in form of a dark halo in axial (A) and longitudinal (C) plane. Note the normal color-filling in right STA in axial (B) and longitudinal (D) plane. Blood flow velocity spectra have been included as inserts in C and D. Left STA biopsy (×100) showing inflammatory infiltrates involving the entire vessel wall, marked intimal thickening, and fragmentation of the internal elastic lamina (E). Presence of giant cells is shown at a higher magnification (×400) (F).


90 Ultrasonography in diagnosis

91 AB0476 THE DIAGNOSTIC VALUE OF ULTRASONOGRAPHY-DERIVED EDEMA OF THE TEMPORAL ARTERY WALL (DARK HALO SIGN) IN GIANT CELL ARTERITIS: A SECOND META-ANALYSIS A. Arida, M. Kyprianou, M. Kanakis, P. Sfikakis First Department of Propaedeutic and Internal Medicine, Laikon Hospital, Athens University Medical School, Athens, Greece

92 Objectives: Ultrasonography of temporal arteries is used by many in the diagnostic approach of patients with suspected giant cell arteritis (GCA) in clinical practice. A meta-analysis of primary studies available through April 2004 concluded that ultrasonography could indeed be helpful in diagnosing GCA (Ann Intern Med 2005;142: ). We specifically re-examined the diagnostic value of the ultrasonography-derived halo sign.

93 Conclusion: Temporal artery edema demonstrated as dark halo sign should be always looked for in ultrasonography when GCA is suspected. Providing that currently accepted technical quality criteria are fulfilled, halo sign’s sensitivity and specificity seem comparable to those of established autoantibody measurements used in the classification criteria of rheumatoid arthritis and systemic lupus erythematosus. Validation of revised GCA classification criteria which will include the halo sign may be warranted.

94 3. Monitoring response of therapy by imaging

95 AB0454 GIANT CELL ARTERITIS MONITORING WITH COLOUR DOPPLER ULTRASONOGRAPHY C. Castillo, E. De Miguel, E. Martin-Mola Rheumatology, Hospital Universitario La Paz, Madrid, Spain

96 Background: Erythrocyte sedimentation rate (ESR) is, in addition to medical progress, the most common tool used to monitor patients with giant cell arthritis (GCA). However, there are patients diagnosed with GCA with normal or low ESR. Other conditions, such as infections or anemia, may increased the ESR. Objectives: To assess disease activity in patients with GCA with colour Doppler ultrasonography (CDUS) when compared to ESR.

97 We studied 42 patients with GCA, 16 female and 26 male. The mean age was years (SD ±7.5 years, range: years). Complete resolution of ultrasound signs of GCA took weeks on average. Baseline ESR was 66.96mm/h on average (SD 27.18mm/h). The mean drop in ESR after complete GCA ultrasound signs disappearance, was 22.10mm/h (SD 17.71mm/h) with a significant decrease compare to the baseline ESR (p<0,0001).

98 The mean ESR of the group without halo was 22.10mm/h (n=28), in the group with 1 branch involved (n=20) the mean ESR was 26.85mm/h, in the group with 2 branches involved (n=27) it was 50.96mm/h, in the group with 3 branches involved (n=14) it was 34mm/h, and finally, in the group with 4 branches with halo sign (n=27) the mean ESR was 52.59mm/h. Differences between groups were statistically significant when compared to the ESR (p<0.001).

99 Conclusion: CDUS can objectively assess the edema in the vessels of patients with GCA, and have concurrent validity when compared to the ESR. In addition, it is an useful tool to monitor patients with normal ESR and to avoid bias of concomitant diseases.

100 SP0003 THE ROLE OF IMAGING MODALITIES IN THE DIAGNOSIS AND FOLLOWUP OF GIANT CELL ARTERITIS N. Pipitone. Rheumatology, Reggio Emilia, Italy Imaging studies have proved useful to detect inflammatory changes in the temporal arteries, and are invaluable in demonstrating inflammation in large arteries, which are not easily accessible to biopsy. Color-Doppler sonography (CDS), magnetic resonance (MR) angiography (MRA) and contrast-enhanced computerized tomography (CT) angiography (CTA) can visualize both the arterial wall and the lumen. All these techniques can aid in diagnosing early arteritis by demonstrating inflammation of the arterial wall even before vascular complications such as stenoses and aneurysms develop.

101 Precocious inflammatory signs of arteritis include vessel wall thickening and transmural edema, which shows as a hypoechoic “halo” surrounding the lumen of an inflamed artery on CDS and as contrast enhancement on MRA and CTA. CDS is particularly suited to investigate the superficial arteries (including the temporal arteries), while CT and MR are able to depict well deep, large vessels such as the thoracic and abdominal aorta, which can hardly or not be visualized by CDS. Alternatively, large-vessel inflammation can be assessed by 18F-Fluorodeoxyglucose positron emission tomography (PET)

102 However, PET cannot demonstrate changes in the temporal or renal arteries. Moreover, PET is unable to delineate the anatomical details of the arterial wall, and is thus not helpful in detecting stenoses or aneurysms. For monitoring purposes, CDS, MRI/MRA, and CT/CTA are helpful in that they can demonstrate both arterial wall and lumen changes. PET can also be used to monitor the extent and intensity of vascular inflammation in large vessels.

103 AB0565 CAN COLOR DOPPLER ULTRASOUND BE USED TO MONITOR TREATMENT RESPONSE IN LARGE VESSEL GIANT CELL ARTERITIS? A. Diamantopoulos, G. Haugeberg, G. Myklebust, on behalf of SONOVAS Study Group. Rheumatology, Hospital of Southern Norway Trust, Kristiansand S, Norway

104 Background: On ultrasound examinations large vessel vasculitis (LVV) has been reported to be present in up to 37% of giant cell arteritis (GCA) patients. In these patients, the axillary arteries are reported to be affected as high as 98% Color Doppler ultrasound (CDUS) yields a high sensitivity and specificity to diagnose GCA. Objectives: The aim of this study was to examine if CDUS of the axillary arteries could be used to monitor treatment response in LVV-GCA.

105 Conclusions: CDUS of the axillary arteries seems to be a useful tool to monitor treatment response in LVV-GCA. Thus, CDUS of the large vessels has the potential to be used for the assessment of disease activity in LVV-GCA patients. These promising results have to be confirmed in larger cohorts of patients.

106 3. Ultrasonography and temporal artery biopsy


108 Background: Temporal artery biopsy (TAB) has historically been considered the “gold standard” diagnostic test for Giant Cell Arteritis Objectives: The aim of this study was to evaluate the diagnostic utility of cranial duplex ultrasound (CDUS) in patients with a suspected diagnosis of GCA in routine clinical practice.

109 Results: A total of 87 patients underwent CDUS for suspected GCA. 36 patients (41%) had a confirmed clinical diagnosis at 3-month follow-up. When compared to clinical diagnosis at 3 months, the sensitivity of CDUS was 81%, specificity 98%, positive likelihood ratio 41, negative likelihood ratio 0.2, positive predictive value of 97% and negative predictive value of 88%. In contrast, when compared to clinical diagnosis at 3 months, TAB had a sensitivity of 53%, specificity 100%, positive likelihood ratio 2.3, negative likelihood ratio 0.2, positive predictive value of 100% and negative predictive value of 47%.

110 Conclusions: CDUS had a greater sensitivity than TAB and a comparable specificity to diagnose GCA. The CDUS result was the strongest predictor for a diagnosis of GCA at 3 months, whereas ACR criteria when used alone were insufficiently specific to accurately predict or exclude the diagnosis of GCA at 3 months. In contrast, the high positive and negative predictive value of CDUS over TAB indicates that TAB may be unnecessary particularly where clinical suspicion of GCA is high or quite low.

111 SAT0287 ASSOCIATION BETWEEN TEMPORAL ARTERY ULTRASOUND “HALO SCORE” AND BIOPSY IN NEWLY DIAGNOSED GIANT CELL ARTERITIS R. Brier, F.A. Borg, P. Patil, C. Dejaco, B. Dasgupta Rheumatology,Southend University Hospital, Westcliff-on-Sea, United Kingdom; Rheumatology, Medical University Graz, Graz, Austria

112 Background: Temporal artery ultrasound (TAUS) is increasingly used in the diagnosis of giant cell arteritis (GCA). Vessel wall edema (Halo) is suggestive of GCA. Objectives: To investigate whether the extent & severity of temporal and axillary artery edema (Halo Score, HS) or the number of affected arterial branches is associated with clinical and laboratory characteristics and TAB findings in newly diagnosed GCA.

113 Conclusions: The diagnostic sensitivity and specificity of CDS-TA for diagnosing GCA is comparable, if not superior to TAB. In case of characteristic sonographic changes, CDS-TA may obviate the need for TAB.

114 FRI0445 CAN COLOUR-DOPPLER SONOGRAPHY OF TEMPORAL ARTERIES REPLACE TEMPORAL ARTERY BIOPSY IN PATIENTS SUSPECT OF HAVING GIANT CELL ARTERITIS IN DAILY CLINICAL PRACTICE? Praprotnik, A. Hoˇcevar, Ž. Rotar, M. Tomšiˇc. Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia Objectives: To evaluate the diagnostic value of CDS-TA in suspected GCA cases in daily clinical practice.

115 Background: Temporal artery ultrasound (TAUS) is increasingly used in the diagnosis of giant cell arteritis (GCA). Vessel wall edema (Halo) is suggestive of GCA. Objectives: To investigate whether the extent & severity of temporal and axillary artery edema (Halo Score, HS) or the number of affected arterial branches is associated with clinical and laboratory characteristics and TAB findings in newly diagnosed GCA.

116 Conclusions: Our findings support vascular ultrasound as a useful non-invasive investigation in GCA. Halo findings were associated with demographic, clinical and laboratory features in GCA. Halo score was able to predict positive TAB findings. A high HS may replace the need for diagnostic TAB in some cases.

117 AB0597 FDG PET-CT VERSUS TEMPORAL ARTERY BIOPSY IN PATIENTS PRESENTING WITH GCA/PMR: A RETROSPECTIVE CROSS-SECTIONAL STUDY S.A. Just, R.A. Gildberg-Mortensen, R.A. Andreasen, N. Lomborg, M.B. Morillon, I.M.J. Hansen. Department of Medicine, Svendborg Hospital, Odense University Hospital (OUH), Svendborg, Denmark

118 Background: Giant Cell Arteritis (GCA) is a large vessel vasculitis, which can occur concomitant with Polymyalgia Rheumatica (PMR). Both diseases may also be seen as isolated disease entities. The two conditions are treated differently, and therefore correct diagnosis is essential. Positron-emission tomography (PET) is receiving increasing attention in the diagnostics of both GCA and PMR.

119 In GCA FDG uptake is often seen in the large vessels of the thorax and neck – hereafter called vasculitis pattern. In isolated Polymyalgia Rheumatica (PMR) uptake can be seen in the ischial tuberosities, the greater trochanters, and the lumbar spinous processes – hereafter called PMR pattern. Temporal artery biopsy is part of the diagnostic workup when GCA is suspected, confirming the diagnosis if characteristic vasculitis histology is found.

120 Objectives: To describe the sensitivity and specificity of vascular FDG uptake on PET-CT compared to temporal artery biopsy result, in suspected GCA and/or PMR.

121 Results: Information about 118 patients was retrieved. 83 of these had been diagnosed with isolated PMR, and 36 with GCA with or without PMR. 32 patients had undergone both FDG PET-CT scan and temporal artery biopsy at presentation (19 PMR and 13 GCA). PET-CT FDG uptake pattern: PET-CT FDG vasculitis uptake had a sensitivity of 78% (7/9) and a specificity of 78% (18/23). The positive and negative predictive value was 58% (7/12) and 90% (18/20), respectively.

122 Conclusions: This study shows that FDG PET- CT, as a measure of vascular involvement in suspected GCA and/or PMR, should be used with caution.

123 4. Management of resistant to treat PMR/GCA

124 SP0060 HOW TO MANAGE RESISTANT POLYMYALGIA RHEUMATICA/GIANT-CELL ARTERITIS C. Cid Systemic Autoimmune Diseases, HOSPITAL CLINIC. UNIVERSITY OF BARCELONA. IDIBAPS, Barcelona, Spain Abstract: Resistant giant-cell arteritis (GCA) may include a variety of clinical situations that may need to be differently and specifically addressed.

125 GCA symptoms or some complications may not completely respond to standard therapy during the induction of remission period or may recur during follow-up. In some instances, incomplete initial response may be due to misdiagnosis, particularly when diagnosis exclusively relies on clinical grounds. GCA may be mimicked by a variety of diseases including amyloidosis and other systemic vasculitides. Even biopsy-proven GCA may be sometimes equivocal and vascular or inflammatory diseases such as thromboangiitis obliterans or other systemic vasculitis may involve the temporal arteries.

126 Approximately 50% of patients with GCA follow a relapsing course when corticosteroids are tapered and may cumulate disease or treatment -related morbidity. For patients with relapsing disease, there are not definitely demonstrated options with clear efficacy. Among common immunosuppressive agents, only methotrexate has shown a modest corticosteroid –sparing effect in a meta-analysis of 3 randomized controlled trials. Insufficient understanding of the pathogenesis of the disease and the mechanisms involved in the persistence of inflammatory activity prevents the identification of suitable therapeutic targets.

127 Immunopathologic studies have shown that increased expression of TNFalpha in lesions and elevated circulating concentrations of TNFalpha are associated with disease persistence. However, blocking TNF alpha with infliximab has not demonstrated benefit over placebo in maintaining corticosteroid-induced remission in a randomized controlled trial. A few studies suggest that IFN gamma and IL2p40 expression may be associated with disease persistence, and these potential targets deserve further investigation. Other immunosuppressive or biologic agents have been tested in insufficiently powered studies (etanercept, azathioprine), in retrospective series, or in isolated case reports or small series.

128 Giant Cell Arteritis Etiologic considerations

129 FRI0193 HERPES ZOSTER INFECTION ACROSS AUTO-IMMUNE AND INFLAMMATORY DISEASES: IMPLICATIONS FOR VACCINATION J.R. Curtis, Yang, L. Chen, K. Winthrop, F. Xie, J.W. Baddley, K. Saag, J. Singh, H. Yun University of Alabama at Birmingham, Birmingham, United States;

130 Background: More than one million herpes zoster (HZ) cases occur in the United States every year. Currently, the live zoster vaccine is recommended for healthy older patients age ≥60 years. Whether the absolute risk for younger patients who have autoimmune or inflammatory conditions might be high enough to warrant vaccination of younger patients with these diseases is unclear. Objectives: To evaluate the overall and age-stratified absolute incidence of HZ infections associated with different autoimmune and inflammatory diseases compared to the general population currently recommended for vaccination by the CDC.

131 Table 1. Age, gender standardized incidence rate for herpes zoster per 1000 pys Cohorts All Male Female SLE IBD RA Psa AS Gout Diabetes Healthy The age-specific rate of HZ for RA, IBD and SLE patients age ≥40 was greater than the corresponding rate in healthy individuals age ≥60.

132 Conclusions: SLE, IBD and RA are associated with an increased incidence rate of HZ infection compared to healthy older people. Based upon comparable absolute risk to healthy individuals age ≥60, SLE, IBD and RA patients age ≥40 might reasonably be considered as appropriate candidates for vaccination for HZ.








140 FMF in heterozygous patients by Seza Ozen (Turkey) EULAR 2014 HIGHLIGHTS AUGUST 30, 2014
















156 Effect of polymorphisms( or else) in genes of the inflammatory pathway Complex genetic trait diseases( jia) are associated with MHC and non- MHC polymorphisms MEFV mutations are associated with s JIA and severity of RA In FMF- a monogenic disease, why shouldn’t polymorphisms in relevant genes affect phenotype/severity?
















172 Sjogren’s Syndrome Definition – An autoimmune disease (either primary or secondary) targeting the salivary and lacrimal glands. Common symptoms – dry eye and dry mouth.

173 Defining Sjögren’s Syndrome 1993 European criteria Diagnosis based on any 4/6 components Dry eye symptoms Dry mouth symptoms Objective findings of dry eyes Objective findings of salivary hypofunction Positive lip biopsy Positive serologies (SSA/B antibodies, ANA, RF) Arthritis Rheum 1993; 36:340; 2002 American‐European criteria Diagnosed based on 4/6 components, BUT Requirement for positive SSA/B antibodies or labial gland biopsy Ann Rheum Dis 2002; 61: ACR preliminary criteria 2/3 components, all objective Ocular surface staining Positive lip biopsy SSA/B antibodies or [ANA ≥ 1:320 and positive RF] Arth Care Res 2012; 64:475

174 Diagnosis Serologic testing (ANA, RF, anti SSA, anti SSB, ESR, CRP) Buccal mucosal biopsy Ophthalmologic testing to assess for tear quantity Ophthalmologic staining to assess for tear quality

175 Ocular Surface Staining Lissamine green staining of conjunctiva – Devitalized cells Fluorescein staining of cornea – Epithelial stroma

176 Ocular Staining Scoring SICCAOXFORD

177 Structure vs function Imaging Techniques for Sialadenitis Assessment of Salivary Gland Function

178 SALIVARY METABOLOMICS OF PRIMARY SJOGREN’S SYNDROME G. Kageyama, J. et al Japan Objectives: To compare the salivary metabolite profile (patients with pSS vs HC subjects.) 88 metabolites were detected. 32 metabolites were decreased. The decrease of Glysine, Tyrosine, Uric Acid and Fucose.

179 PATHOLOGICAL FINDINGS USING HIGH END ULTRASONOGRAPHY IN PRIMARY SJOGREN’S SYNDROME B-mode ultrasonography (BMUS). – 41/50 parotid glands in patients with pSS and 20/50 in the control group had abnormal findings (p<0.001). – 42/50 patients with pSS showed abnormal findings in submandibular gland BMUS compared to 31/50 in patients without confirmed pSS (p<0.001).

180 A NEGATIVE HIGH-RESOLUTION SALIVARY GLAND ULTRASOUND IS HIGHLY PREDICTIVE OF NEGATIVE LABIAL GLAND BIOPSY IN PATIENTS WITH SICCA SYMPTOMS Objectives: Here we investigated the capacity of high-resolution salivary gland US to predict the result of a LSGB biopsy. Concordance between US and LSGB was 91.76% (Kappa=0.826) – The positive predictive value of having a positive LSGB with abnormal US findings was 85.29% – whilst a negative US gave a negative LSGB predictive value of 96.08%.

181 PATTERNS OF INFLAMMATION AND DYSFUNCTION OF THE SALIVARY GLANDS IN PATIENTS NEWLY DIAGNOSED WITH SJOGREN’S SYNDROME Objectives: – To estimate the frequency of various patterns of inflammation and dysfunction of the salivary. – To compare clinical and serological features of pSS patients stratified into four different subgroups on the basis of the degree of lymphocytic infiltration detected in MSGB and on the variation of the salivary flow rate.

182 PATTERNS OF INFLAMMATION AND DYSFUNCTION OF THE SALIVARY GLANDS IN PATIENTS NEWLY DIAGNOSED WITH SJOGREN’S SYNDROME The correlation between salivary flow rate and MSGB focus score was poor (r=0.124, p=ns). Germinal centre-like structures were significantly more frequent in patients belonging to group 1 (9/12), group 3 (3/12). ESSDAI scores (p=0.02) and SGUS scores (p<0.0001) were significantly different between groups : – “group 1-patients” presenting the highest ESSDAI scores and the highest SGUS scores – “group 4-patients” showing the lowest ESSDAI and SGUS scores.

183 The Sicca Complex Patients who have dry eyes and/or mouth but do not meet established serologic or histopathologic criteria for primary SS Described in the literature as: – Sjogren’s syndrome (1993 European criteria) – Idiopathic keratoconjunctivitis sicca – Dry eyes and mouth syndrome (DEMS) – Sicca asthenia polyalgia syndrome (SAPS) Correlates – Thyroid antibodies – Cigarette smoking – Anti‐cholinergic drug use – Fibromyalgia Seronegative Sjögren’s Defined by a positive lip biopsy and the absence of SSA and SSB antibodies – Includes patients with [ANA≥1:320 AND RF] by ACR criteria – Older age at diagnosis – Less systemic/hematologic involvement – Greater fatigue – Higher frequency of sensory neuropathy Arthritis Care and Research 2008;59:1780 lin Exp Rheumatol 2001;19:313 Medicine 2011;90:133Medicine 2008; 87:210

184 Isolated keratoconjunctivitis sicca (KCS) vs Sjögren’s‐KCS

185 HOW DO WE TREAT PATIENTS WITH FOCUS SCORE ≥1, BUT NOT CONSISTENT WITH THE NEW AMERICAN COLLEGE OF RHEUMATOLOGY CLASSIFICATION CRITERIA FOR SJOGREN’S SYNDROME? EVALUATION FROM STUDY IN JAPANESE PATIENTS Conclusions: Pathologically, FS≥1 are useful for diagnosing SS. A significant number of patients with FS≥1 was found in both the SS and DM groups. However, patients with non characteristic SS may also have RA.

186 ETIOLOGY OF SICCA SYNDROME: THE FORGOTTEN CAUSES Differential diagnosis of sicca syndrome in a man is quiet extensive including – autoimmune (SS, IgG4- RD, sarcoidosis), infectious (HIV and HCV, HTLV-1) and metabolic (diabetes mellitus, lipoproteinemias) conditions, neoplastic/infiltrative disorders (lymphoma, tumors, amyloidosis), drug side effects (anticholinergic and antidepressant), and head and neck irradiation Chronic enlargement of salivary and lacrimal glands with histologic evidence of chronic inflammation Multiple etiologies for this presentation – Benign lymphoepithelial sialadenitis – Sjögren’s syndrome – Other systemic rheumatic diseases – IgG4‐related

187 Sjögren’s Syndrome vs IgG4‐Related Sialadenitis Khosroshahi et al, in Sjögren’s Syndrome, M. Ramos‐Casals et al, ed. London: Springer‐Verlag, 2012

188 THE RISK OF MYOCARDIAL INFARCTION AND CEREBROVASCULAR ACCIDENT IN PATIENTS WITH SJOGREN’S SYNDROME: A GENERAL POPULATION-BASED COHORT STUDY a significantly increased risk of MI in patients with SjS – particularly in the first year following diagnosis, indicating that the acute inflammatory state in SjS, particularly at disease onset,

189 EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI): Development of a consensus systemic disease activity index for primary Sjögren’s syndrome.

190 DEFINING DISEASE ACTIVITY SATES AND MINIMAL CLINICALLY IMPORTANT IMPROVEMENT (MCII) WITH THE EULAR PRIMARY SJOGREN’S SYNDROME DISEASE ACTIVITY INDEX (ESSDAI) Patients from 2 large prospective cohorts (EULAR [multicenter international] n=395, ASSESS [multicenter French] n=395). Follow up 6 and 12 month. low (ESSDAI <5), moderate (5 ≤ESSDAI ≤13) and high (ESSDAI≥14) activity. – Our proposal is to use the threshold of moderate activity as entry criteria (patients with ESSDAI≥5), – To define response to treatment as a significant improvement of ESSDAI (at least 3 points).

191 ASSOCIATION BETWEEN SYSTEMIC ACTIVITY AND LYMPHOMA IN PRIMARY SJOGREN SYNDROME: BASELINE ESSDAI PREDICTORS IN 921 SPANISH PATIENTS (GEAS-SS REGISTRY) Can the use of ESSDAI predicts the development of lymphoproliferative disease. – Fever >38.5°C, night sweats and/or significant weight loss. – Hematological and immunological profile (cytopenias, hypocomplementemia, monoclonal band and cryoglobulinemia) as laboratory predictors of hematological neoplasia in SS. Patients presenting with this clinical and laboratory profile at diagnosis of pSS need a closer follow-up.

192 THE DEGREE OF ACTIVITY MEASURED WITH THE EULAR-SS DISEASE ACTIVITY INDEX (ESSDAI) STRONGLY CORRELATED WITH DEATH IN PATIENTS WITH PRIMARY SJOGREN SYNDROME (GEAS-SS REGISTRY) To analyse the association between the new (ESSDAI) and death in a large cohort with primary Sjogren syndrome (pSS) The degree of activity measured in the majority of domains of the ESSDAI strongly correlated with mortality. – Activity of constitutional and lymphadenopathy domains (closely related to lymphoma) correlated with death – Extraglandular sites of involvement (in which high doses of corticosteroids and immunosuppressive agents are used) correlated principally with death caused by infection.

193 EFFICACY OF RITUXIMAB IN SYSTEMIC MANIFESTATIONS OF PRIMARY SJOGREN’S SYNDROME O. Logvinenko et al Russian Federation 24 patients with systemic lesions. (+/- BAFF) MONO 9 RTX COMBINATION 14 CYCLO+RTX. At month 3 after RTX therapy, a clinical complete and partial response was observed in 71.4% (15/21) and 19% (4/21) cases, respectively. A complete/ partial immunologic response was presented in 52.6% (10/19)/26.3% (5/19)patients. At month 6 clinical and immunologic relapse was noted in 25% (5/20) and 35.3% (6/17) cases, respectively. There was decrease median ESSDAI score from 8 (7-10) at baseline to 3 (2-4) at month 3 and to 3 (2-5) at month 6 (p<0.001). NO changes in sicci syndrome.

194 PATTERNS OF INFLAMMATION AND DYSFUNCTION OF THE SALIVARY GLANDS IN PATIENTS NEWLY DIAGNOSED WITH SJOGREN’S SYNDROME Objectives: – To estimate the frequency of various patterns of inflammation and dysfunction of the salivary. – To compare clinical and serological features of pSS patients stratified into four different subgroups on the basis of the degree of lymphocytic infiltration detected in MSGB and on the variation of the salivary flow rate.

195 LSR Staff Meeting 30 th AUG 2014 Best of EULAR 2014 AXIAL SPONDYLOARTHRITIS Nelly Ziade Zoghbi, MD, PhD Al Bustan hotel 195ZIADE 2014


197 Physiopathology Role of IL-23 Role of IL-17  new treatments in case of failure / intolerance of TNF i 197ZIADE 2014

198 Role of Intestinal Inflammation Migration of intestinal cells [OP 0017] Ileal, medullar biopsies, Blood and joint samples Expansion of IL23 cells in bowel, synovial liquid, bone marrow, production of IL17 and IL 22 – Disease Activity correlated to IBD [FRI0117] – Microscopic inflammation (systematic biopsies) predicts initiation of TNFi at 18 months [OPP0159, Cypers et al, 63 pts]: 56% (27/63) versus 29% 198ZIADE 2014 NEW !

199 Concept Non Radiographic Axial SpA More Women Younger Less HLA B27 Same Disease Activity Same response to: – NSAIDs [SAT0374] – TNFi [SAT0353] : Calhoff et al (CHARITE): meta-analysis 21 studies/ 3662 pts NR AxSpA  Radiographic Sacroiliitis: 2/3 at 10 years SP ZIADE 2014

200 Clinical Risk Factors Smokers : radiographic progression x 10 [THU0103] Obese: higher disease activity [THU0077] Vitamin D deficiency : higher disease activity [THU0083] DESIR cohort C-sections and premature delivery more frequent [THU081] Cardiovascular morbidity: higher risk in women [THU090] 200ZIADE 2014

201 Risk Factors for Radiographic Progression CRP Syndesmophytes Smoking No deleterious (nor protective) effect of TNFi 201ZIADE 2014

202 Link Disease Activity - Radiology Disease Activity correlated to MRI score [FRI0158] Huang et al, meta-analysis of 6 studies Disease Activity correlated to accelarated Radiographic Progression [FRI113] 202ZIADE 2014

203 TNFi and Radiographic Progression GLAS prospective cohort Maas et al, Netherlands [STA 0343] 105 patients Median symptom duration: 16 years 6 years TNFi Neither inhibition nor acceleration of radiographic progression over time at group level ZIADE

204 MI risk with NSAIDs Ducreuil et al [FRI0119] UK database ZIADE

205 TNFi therapy Still treatment of choice if refractory to 2 NSAIDs for >= 4 weeks, with BASDAI >=4 [SAT 0372, Maksymowych et al] Similar efficacy and similar retention rate at 8 years : ADA (62%), ETA (55%), IFX (54%) [SAT0335] Choquette et al. 170 pts 205ZIADE 2014

206 Anti-Medication Antibodies SAT 0346 [Kim et al, 106 pts] patients with antibodies have lower drug concentration and more discontinuation for inefficacy or side effects OP 0158 [Chen et al, retrospective, 1401 pts] : – more antibodies with ADA > ETA – similar risk of stopping treatment between ADA and ETA – Association with MTX 10 mg reduces risk of stopping – Association with NSAIDs reduces risk of stopping 206ZIADE 2014

207 Ustekinumab (anti-IL23) ASAS 20: 75% - ASAS 40: 65% - PR 30% Efficacy on MRI inflammation [OP0155] – sacroiliitis: 41% – spine 31% At 24 weeks Mainly in responders [Poddubnyy et al, TOPAS study, 17 pts] 207ZIADE 2014 New Treatments

208 Nilotinib Tyrosine kinase inhibitor Proof of concept trial [OP0156, Paramarta et al] Controlled study 29 pts Efficacy: synovial inflammation, cinical markers in peripheral forms No efficacy in axial form 208ZIADE 2014 New Treatments

209 FIRST EULAR Imaging Recommendations for SpA The first choice for diagnosing sacroiliitis should be conventional radiography of the sacroiliac joint. MRI (magnetic resonance imaging) is an alternative in selected cases. To detect peripheral enthesitis as well as peripheral arthritis, tenosynovitis, or bursitis in these cases, either ultrasound or MRI is appropriate. To assess and monitor disease activity, MRI of the sacroiliac joint is recommended. To monitor long-term for structural damage and especially new bone formation, conventional radiology of the sacroiliac joint and/or spine is acceptable and appropriate. 209ZIADE 2014 SP0143

210 FIRST EULAR Imaging Recommendations for SpA To assess suspected spinal fracture, conventional radiology is recommended as the initial method. To assess for osteoporosis in cases of axial SpA without radiographic evidence of syndesmophytes in the lumbar spine, dual emission x-ray absorptiometry of the hip and spine is in order. To detect syndesmophytes (and predict development of new syndesmophytes), initial conventional radiographs of the lumbar and cervical spine are "recommended" but MRI of vertebral corner inflammatory lesions "may also be used.” 210ZIADE 2014 SP0143

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