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Clinical use of glucocorticoids

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

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Clinical use of glucocorticoids

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  1. Clinical use of glucocorticoids AbiKaramGhada

  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: • 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. • Osteoclastssurvival is improved by glucocorticoids. • an effect on osteocyteshas 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 VitD receptors.

  4. Treatment of GC induced OP: • General measures: Ca, vit D, smoking cessation, physical activity… • 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-TERMGLUCOCORTICOIDS WHO DO NOT HAVE ADEQUATERESPONSE TO BISPHOSPHONATE TREATMENT:A RANDOMIZED CONTROLLED TRIAL. Hong-Kong • Objectives: To evaluate the efficacy of denosumabon BMD in patients receiving long-term glucocorticoids who do not have satisfactory response to bisphosphonatetreatment.

  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. • Denosumabwas well tolerated.

  9. ONE-YEAR EFFECTS OF GLUCOCORTICOIDS ON BONEDENSITY. A META-ANALYSIS IN COHORTS OF PATIENTS ONHIGH 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 2012. 44 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 GLUCOCORTICOIDRECEPTOR 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 transactivationeffects) 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. clinicaltrials.gov)

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

  15. Chronotherapeuticprednisone 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

  18. 2010 UA patients havemilder baseline characteristics and milder outcome than 1987 UA patients Remaining presentation: UA = 1987-UA

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

  20. When to Treat?

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

  22. 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

  23. Prediction of persistence within early UA (or RA) A model predicting persistence within UA or within RA lackingValidated risk factors for persistence: • ACPA/RF • Symptom duration

  24. UA patients with a high chance to progress to RA can be estimated adequatelyRisk prediction for other outcomes of UA not existing

  25. Trials in UA

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

  27. 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

  28. 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

  29. 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

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

  31. EULAR 2014Polyarthrite rhumatoide Baddoura

  32. LUNG DISEASE AMONG RHEUMATOID ARTHRITIS PATIENTS – RESULTS FROM ONTARIO BIOLOGICS RESEARCH INITIATIVE (OBRI)S. Mittoo et al.EULAR 2014, Paris, 11-14 juin 2014 • Etude prospective 2328 PR • 204 (8.8%) avec atteinte pulmonaire. • Asthme 54 % • BPCO 24% • PI 19% • Autres 3% • 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

  33. PREVALENCE OF VITAMIN D DEFICIENCY IN RA: DATA FROM THE COMEDRA COHORTS. Cecchetti et al.EULAR 2014, Paris, 11-14 juin 2014 • 894 PR avec une durée moyenne de 11,2 ans. • Erosions73,3 % • FR / anti-CCP. 83,9 % • DAS28 3 ± 1,3 • Biothérapie 70,4 % • Corticoïdes. 38,1 % • Vitamine D • 10-30 ng/ml 56 % • < 10 ng/ml 3,5 % • 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.

  34. 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 CRITERIAI. Castrejón et al. EULAR 2014 602 PR. 110 (18%) à 247 (41%) sont en rémission selon les critères utilisés 10,1% 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 Critères rémission DAS28

  35. 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 1986 - 1998 • ERAN 2002 - 2012 • 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 diminuémais pas les interventions majeures (prothèses)

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