Yannick Degboé

Modulation of pro-inflammatory activation of monocytes and dendritic cells by aza-bis-phosphonate dendrimer as an experimental therapeutic agent

IntroductionOur objective was to assess the capacity of dendrimer aza-bis-phosphonate (ABP) to modulate phenotype of monocytes (Mo) and monocytes derived dendritic cells (MoDC) activated in response to toll-like receptor 4 (TLR4) and interferon γ (IFN- γ) stimulation.MethodsMo (n = 12) and MoDC (n = 11) from peripheral blood of healthy donors were prepared. Cells were preincubated or not for 1 hour with dendrimer ABP, then incubated with lipopolysaccharide (LPS; as a TLR4 ligand) and (IFN-γ) for 38 hours. Secretion of tumor necrosis factor α (TNFα), interleukin (IL) -1, IL-6, IL-12, IL-10 and IL-23 in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Bead Array. Differentiation and subsequent maturation of MoDC from nine donors in the presence of LPS were analyzed by flow cytometry using CD80, CD86, CD83 and CD1a surface expression as markers.ResultsMo and MoDC were orientated to a pro-inflammatory state. In activated Mo, TNFα, IL-1β and IL-23 levels were significantly lower after prior incubation with dendrimer ABP. In activated MoDC, dendrimer ABP promoted IL-10 secretion while decreasing dramatically the level of IL-12. TNFα and IL-6 secretion were significantly lower in the presence of dendrimer ABP. LPS driven maturation of MoDC was impaired by dendrimer ABP treatment, as attested by the significantly lower expression of CD80 and CD86.ConclusionOur data indicate that dendrimer ABP possesses immunomodulatory properties on human Mo and MoDC, in TLR4 + IFN-γ stimulation model, by inducing M2 alternative activation of Mo and promoting tolerogenic MoDC.

New autoantibodies associated with rheumatoid arthritis recognize posttranslationally modified self-proteins.

Citrullination, carbamylation and oxidation are posttranslational modifications of proteins that produce neoepitopes. Rheumatoid arthritis (RA) is an autoimmune disease of which one distinctive feature is the development of B-cell-mediated immunity against these neoepitopes. Antibodies to citrullinated proteins (ACPAs) were identified nearly two decades ago and are now widely used in clinical practice. The identification of additional citrullinated proteins as potential autoantibody targets has suggested new pathophysiological hypotheses and prompted studies of potential associations with disease severity or specific disease patterns. Carbamylation is a nonenzymatic posttranslational modification that produces homocitrullines, against which newly identified autoantibodies different from ACPAs have been found in over 15% of patients with RA. Finally, the development of antibodies to oxidized type II collagen reflects immunization against collagen modified by oxidation in relation to intraarticular oxidative stress. These new autoantibodies are both sensitive and specific and may therefore serve as early disease markers and as useful tools for therapeutic monitoring.

Osteoporosis and ischemic cardiovascular disease.

Osteoporosis and cardiovascular disease were long viewed as independent of each other. However, numerous epidemiological studies, which are discussed in the first part of this review, have provided incontrovertible evidence of a link. Thus, the risk of coronary artery disease and stroke is higher in patients with a history of osteoporotic fracture or low bone mineral density than in non-osteoporotic patients. In the other direction, patients with cardiovascular disease are at higher risk for bone loss and osteoporotic fracture. The link between osteoporosis and cardiovascular disease is due in part to shared conventional risk factors such as estrogen deprivation in women, smoking, low physical activity, and diabetes. In addition, atheroma plaque calcification involves cytokines and growth factors that also play a role in bone turnover, including proinflammatory cytokines (IL-6 and TNFα), osteoprotegerin, sclerostin, matrix GLA protein, and FGF-23. Several recent studies have provided support for these pathophysiological hypotheses. Thus, elevation of osteoprotegerin, sclerostin, or FGF-23 levels may explain and predict the occurrence of both osteoporotic fractures and cardiovascular events. The association between osteoporosis and cardiovascular disease found in most epidemiological and pathophysiological studies suggests a need for evaluating potential benefits from routine bone absorptiometry and osteoporotic fracture detection in patients with cardiovascular disease and from exercise testing and arterial Doppler imaging in patients with osteoporosis.

Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis.

Objectives To assess the risk of losing remission, low disease activity (LDA) or radiographic progression in the case of (1) discontinuing or (2) tapering doses of biological disease-modifying antirheumatic drugs (bDMARDs) compared with continuation of the initial treatment regimen in rheumatoid arthritis (RA) patients with remission or LDA. Materials and methods A systematic literature analysis was carried out through May 2017 on the PubMed, Embase, Cochrane and international congress databases, selecting controlled trials comparing bDMARDs discontinuation/tapering versus continuation in RA patients with remission or LDA. The meta-analysis assessed the risk ratio (RR) and 95% CI of losing remission or LDA and the risk of radiographic progression after (1) discontinuing and (2) tapering doses of bDMARDs versus continuing the initial treatment. Results The meta-analysis comparing bDMARDs discontinuation versus continuation performed on nine trials showed an increased risk of losing remission (RR (95%u2009CI)=1.97(1.43 to 2.73), P<0.0001) or LDA (RR (95%u2009CI)=2.24(1.52 to 3.30), P<0.0001) and an increased risk of radiographic progression (RR (95%u2009CI)=1.09(1.02 to 1.17), P=0.01) in case of bDMARD discontinuation. The meta-analysis comparing bDMARDs tapering versus continuation performed on 11 trials showed an increased risk of losing remission (RR (95%u2009CI)=1.23(1.06 to 1.42), P=0.006) but no increased risk of losing LDA (RR (95%u2009CI)=1.02 (0.85 to 1.23), P=0.81) nor any increased risk of radiographic progression (RR (95%u2009CI)=1.09(0.94 to 1.26), P=0.26) in case of bDMARD tapering. Conclusion Discontinuation of bDMARDs leads to an increased risk of losing remission or LDA and radiographic progression, while tapering doses of bDMARDs does not increase the risk of relapse (LDA) or radiographic progression, even though there is an increased risk of losing remission.

Valeur diagnostique de l’IRM, de l’échographie et de la scintigraphie osseuse pour le diagnostic de spondylarthrite : Analyse systématique de la littérature

Resume Objectif – Definir la valeur diagnostique de l’imagerie par resonnance magnetique (IRM), de l’echographie articulaire et de la scintigraphie osseuse pour les differentes formes de spondylarthropathies (SpA). Methodes – Nous avons realise une analyse systematique de la litterature sur la base de donnees Pubmed pour rechercher tous les articles originaux rapportant la valeur diagnostique de ces examens. Resultats – Dix-sept articles concernent l’IRM. La performance de l’IRM des sacro-iliaques est etablie, avec une definition consensuelle de la sacro-iliite active en IRM. Sa specificite est comprise entre 86 et 97% dans les etudes recentes, pour une sensibilite d’environ 90% pour les SpA axiales etablies, et de 50% dans les SpA pre-radiographiques. L’evaluation de l’IRM du rachis manque de standardisation, mais il semble que le nombre de lesions evocatrices de SpA rapporte a l’âge des patients lui confere une valeur diagnostique interessante. L’IRM est egalement un examen performant pour le diagnostic des atteintes peripheriques de SpA, hormis l’aponevrosite plantaire. Douze articles concernent l’echographie articulaire. Leurs resultats sont tres heterogenes, principalement du fait de l’absence de score d’enthesite radiographique standardise. Des etudes prospectives sont attendues. La scintigraphie osseuse n’est pas un examen performant pour le diagnostic des formes axiales de SpA (sensibilite d’environ 50% pour une specificite de moins de 80%), et il n’existe pas d’etude sur sa performance pour le diagnostic des atteintes peripheriques. Conclusion – L’IRM des sacro-iliaques est un examen performant, qui a ete inclus dans les derniers criteres de classification des SpA. Les autres examens d’imagerie manquent pour le moment de standardisation, mais une cooperation internationale a ete lancee pour y remedier.

Prevalence and risk factors for fragility fracture in systemic mastocytosis

OBJECTIVESnSystemic mastocytosis (SM) is characterized by the accumulation of mast cells in tissues other than the skin. Bone involvement although frequent has not been thoroughly evaluated. Primary objective was to determine risk factors associated with fragility fractures (FF) in SM. Secondary objectives were to evaluate the ability of bone marrow tryptase (BMT) level to identify patients with FF, and to describe bone involvement in SM.nnnMETHODSnWe analyzed retrospectively all consecutive patients seen in our expert center, with a diagnosis of SM according to the 2001 WHO criteria, and with complete bone assessment. We collected data about lifetime fractures, types of cutaneous manifestations, degranulation symptoms, blood and BMT levels, bone mineral density assessed by densitometry and KIT mutation. We performed a univariate analysis investigating the factors associated with FF and then a logistic multivariable regression analysis. We assessed the ability of bone marrow tryptase to identify patients with FF.nnnRESULTSnEighty-nine patients with SM were included. Thirty-six patients (40.4%) suffered from osteoporosis and twenty-five (28.1%) experienced lifetime FF. Univariate analysis identified age at diagnosis and disease onset, presence of telangiectasia macularis eruptiva perstans, digestive symptoms, mast cells activation symptoms, elevated BMT, low femoral and lumbar BMD, as associated with FF. Multivariate analysis identified elevated BMT, low femoral T score and older age at diagnosis as independently associated with FF.nnnCONCLUSIONSnLow femoral T-score, BMT level, and older age at diagnosis are markers associated with FF in SM. BMT may represent an important biomarker to predict FF in SM patients.

Effet des médicaments de l’ostéoporose sur les maladies cardiovasculaires et effet des médicaments à visée cardiovasculaire sur l’ostéoporose

Osteoporosis and cardiovascular diseases are epidemiologically associated. Calcification phenomena of atherosclerotic plaque involve cytokines and growth factors also involved in bone remodeling. Drugs given for either of these two conditions could act on these mechanisms. Can osteoporosis drugs have an influence on the occurrence of cardiovascular events? Conversely, can the treatment of hypertension alter the course of osteoporosis? It is possible that administration of high doses of calcium (1g/day) in patients who already have important dietary intake can increase the risk of myocardial infarction. Epidemiological studies show links between low serum vitamin D levels and cardiovascular disease but interventional studies show that vitamin D administration in moderately deficient subjects vitamin D does not prevent the occurrence of cardiovascular events. Cohort studies show a beneficial effect of beta-blockers and thiazides administered to hypertensive patients: they reduce by 20% risk of fracture of the proximal femur. Should we focus on these anti-hypertensive treatments for our patients with osteoporosis?

Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha

INTRODUCTIONnAlthough biotherapy has greatly improved the prognosis of RA many patients have still recourse to an orthopaedic surgery. The current recommendation for scheduled surgery is to discontinue administration of the biological agent two to six weeks before surgery. Reinitiating anti-TNF therapy is proposed when the patient has healed. We wanted to know whether patients treated with anti-TNFα were exposed to an infectious risk undergoing a surgical procedure and if discontinuation of anti-TNFα therapy altered the risk of surgical infection.nnnMETHODSnWe conducted a systematic review of the literature in PubMed, Embase and Cochrane until March 2014. We selected studies that reported post-operative infections by comparing patients treated with anti-TNFα to patients treated with csDMARD without biological treatment, or patients who continued anti-TNFα therapy to the patients who discontinued treatment prior to surgery.nnnRESULTSnA first meta-analysis of 12 studies evaluating postoperative infection risk in patients treated with anti-TNFα showed that the postoperative infection risk doubled (RR=1.81 [1.31-2.50]). Seven studies were grouped into a second meta-analysis to evaluate the benefit of the preventive discontinuation of anti-TNFα. Discontinuation of treatment did not alter the post-operative infection risk significantly: RR=0.69 [0.39-1.21].nnnCONCLUSIONnThis study showed that patients treated with anti-TNFα were more at risk of post-operative infection undergoing orthopaedic surgery. Preventive discontinuation of anti-TNFα does not seem to change this risk.

DKK1 and sclerostin are early markers of relapse in multiple myeloma

Recent studies have shown that Dickkopf-related protein (DKK1) and sclerostin decrease when a complete response (CR) is obtained after chemotherapy in myeloma multiple (MM). To study variations in DKK1, sclerostin and P1NP in patients treated for MM, between complete response (CR) and relapse, we carried out a prospective study ancillary to the IFM 2009 protocol (IFM). The aim of IFM was to compare progression-free survival between patients treated with chemotherapy with or without transplantation. We selected 69 patients who reached CR and relapsed. We assayed by ELISA: DKK1, sclerostin and P1NP at 3 end points T1: CR, T2: 4u202fmonths before relapse and T3: relapse. There was a significant increase in DKK1 and sclerostin between T1, T2 and T3. (DKK1 medians (IQR): T1u202f=u202f30u202fpmol/l (20.4-41.1), T2u202f=u202f37.4u202fpmol/l (29.8-49.4), pu202f<u202f0.0001, T3u202f=u202f42u202fpmol/l (33.8-55.5), pu202f<u202f0.0001 sclerostin medians (IQR): T1u202f=u202f0.57 (0.47-0.69), T2u202f=u202f0.62u202fng/ml (0.53-0.79), pu202f<u202f0.0001, T3u202f=u202fn0.64u202fng/ml (0.56-0.79), pu202f=u202f0.005). No significant variation was detected in the levels of P1NP. No association was observed between the characteristics of the MM, or the treatment received and the variation between T1-T3 for DKK1, sclerostin or P1NP. A significant increase in DKK1 and sclerostin was observed four months before relapse.

AB0703 Impact of ANTI-TNF agents on patient-reported outcomes in spondyloarthritis: a systematic review of the literature and meta-analysis

Background Disability, alteration in quality of life and fatigue are frequently reported in spondyloarthritis (SpA). Anti-TNF demonstrated clinical efficacy in SpA. However efficacy on patient-reported outcomes (PROs) may differ from medical assessment. Objectives To assess the impact of anti-TNF on quality of life, disability and fatigue reported by SpA patients. Methods Design: systematic review and meta-analysis of the literature. Data sources: two authors (SL and YD) independently screened PubMed-Medline, Cochrane library and EMBASE databases until November 2016. Key words: (“Patient reported” OR “quality of life” OR fatigue OR FACIT) AND (spondyloarthritis OR “psoriatic arthritis” OR “ankylosing spondylitis”) AND (anti-TNF OR certolizumab OR etanercept OR adalimumab OR infliximab OR golimumab). Articles selection: randomized controlled trials (RCTs), published in English, assessing efficacy of anti-TNF on PROs, in ankylosing spondylitis (AS), psoriatic arthritis (PsA) or SpA according to the ASAS criteria. Data collected: fatigue assessed by FACIT score, quality of life assessed by Short Form 36 (SF36) mental and physical component or by Health AssessementQuestionnary Disability Index (HAQ). Data analysis: Article quality was evaluated by the JADAD scale. For SF36 and HAQ outcomes, pooled variations at 12 and 24 weeks were computed by meta-analysis. Heterogeneity was measured by I2 index. Results Of the 604 articles identified, 37 references were eligible for systematic review and 13 for meta-analysis. Our systematic review identified 10 RCTs concerning AS, 20 concerning PsA and 7 concerning axial SpA. However due to the heterogeneity in available statistical data, references eligible for meta-analysis were mainly related to PsA. HAQ assessment was available for a meta-analysis in 8 studies. HAQ was significantly improved at 12 and 24 weeks with anti-TNF. The impact on HAQ variation at week 24 was -0.29 points [95% CI: -0.37, -0.22]. Heterogeneity was important (I2 =57%; see figure). Ten studieswere eligible for a meta-analysis of anti-TNF effect on SF36 mental form. An improvement was observed at 12 and 24 weeks, although superior at 24 weeks. The effect at week 24 was 2.78 [95% CI: 1.87 - 3.68], without heterogeneity (I2 =0%; see figure). Twelve studies were eligible for a meta-analysis of anti-TNF effect on SF36 physical form. We observed a similar and significant improvement at 12 and 24 weeks. The effect at week 24 was 6.74 [95% CI: 5.34 – 8.13], with an important heterogeneity (I2 =84%; see figure) Fatigue was evaluated in 3 studies. Adalimumab induced a significant improvement in FACIT score at 12 and 24 weeks in one study. Two studies using different scores (Fatigue Assessment Scale, BASDAI fatigue item) to assess certolizumab effect highlighted similar findings: an early improvement in fatigue at week 12, remaining significant and stable at week 24. Conclusions Anti-TNFs agents significantly improve disability, quality of life and fatigue in patients with PsA. Acknowledgements Abbvie France pharmaceutical company provided logistic support by organizing a meta-analysis methods workshop, but played no further role in the project. Disclosure of Interest None declared