Linfedema torino 4 e 5 marzo gaal palma [modalità compatibilità]
Di matteo luigi il6 dismetabolismi_infiammazione_torino gennaio 2011_14° convegno patologia immune e ma
1. Dismetabolismi,
infiammazione cronica
ed IL-6
Luigi Di Matteo
Capo Dipartimento delle Specialità Mediche
Direttore U.O.C. di Reumatologia – Pescara
S. di Specializzazione in Reumatologia -
Università “G. d’Annunzio” Chieti/Pescara
Luciano Di Battista – Ciro Lauriti
9. Intra-abdominal adiposity and glucose
metabolism
Glucose Insulin
1 1,2
15 1200 1,2 1,2
Area
Area
12 1 1,2
1 1 1,2 1,2
mmol/L
800
pmol/L
9 1,2
1 1
1 1,2
1 1 1,2
6
400 1,2
3 1,2
0 0
0 60 120 180 0 60 120 180
Time (min) Time (min)
Non-obese Obese low IAA Obese high IAA
IAA: intra-abdominal adiposity
Significantly different from 1non-obese, 2obese with low intra-abdominal adiposity levels
Pouliot et al 1992
10. Abdominal obesity increases the risk of
developing type 2 diabetes
24
20
16
Relative risk
12
8
4
0
<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3
Waist circumference (cm)
Carey et al 1997
11. La rimozione del grasso viscerale previene il
diabete (ratti ZDF vs. sham)
6
Casi
5
di sham
diabete 4 senza grasso viscerale
3
2
1
0
2 3 4 5 6
Mesi Gabriely I et al.: Diabetes 51:2951, 2002
14. prima
captazione di glucosio
Effetti metabolici di una
massiva asportazione
7.5
per liposuzione di
6.0
tessuto adiposo SC - 7 kg di peso
mmol.min-1
4.5
addominale -14 cm di CV
3.0
1.5
0
prima dopo
dopo
15. DISMETABOLISMI
Obesità Diabete
INSULINORESISTENZA
Infiammazione cronica di
basso grado
Pickup JC, Diabetes Care 2004
Dandona P et al, Trends Immunol 2004
16. Quali le evidenze?
Livello cellulare (macrofago e adipocita)
Livello molecolare (recettori, enzimi e citochine)
17. Sovrapposizione biologica e funzionale di
macrofagi e di adipociti nell’obesità
Wellen K, Hotamisligil GS, J Clin Invest 2005
18. I macrofagi esprimono molti dei prodotti genici degli
adipociti come il FABP (Fatty Acids Binding Protein) ed il
PPARs (Peroxisome Proliferator Activated Receptors);
Makowski L et al, Nat Med 2001; Tontonoz P et al Cell 1998
Gli adipociti possono esprimere proteine di pertinenza
macrofagica come il TNF-α e l’IL-6. I macrofagi nel tessuto
adiposo producono mediatori infiammatori di per sé ed in
sinergia con gli adipociti;
Hotamisligil GS et al Science 1993; Bouloumie A et al Diabetes 2001
In condizioni pro-aterosclerotiche (obesità, iperlipemia) i
macrofagi accumulano lipidi diventando cellule schiumose;
Nell’immunità innata gli adipociti rilasciano lipidi che
possono modulare lo stato infiammatorio e partecipano alla
neutralizzazione dei patogeni.
Wellen K, Hotamisligil GS J Clin Invest 2005
21. Sindrome di Sjögren
Immunopatogenesi
Le stesse cellule epiteliali diventano autolesive
partecipando alla secrezione paracrina ed
autocrina di citochine flogogene.
Espressione da parte delle cellule epiteliali di Fas
L (interazione apoptotica con i linfociti produttori
di Fas) e secrezione di citochine.
Componente epiteliale
22. “Il condrocita come
cellula Il profilo infiammatorio dei condrociti
infiammatoria”
23. “Il condrocita come
cellula Il profilo infiammatorio dei condrociti
infiammatoria”
Indagini condotte a livello dell’ RNA messaggero2
evidenziano una potenzialità infiammatoria dei condrociti, in
quanto questi producono un ampio pannello di mediatori
infiammatori, tra cui IL-8, GRO-α, MCP-1, MIP-1β3, IL-6 e
di osteoprotegerina.
GRO-α = chemochina CXC ligand-1 o Growth
regulated protein alpha precursor o Melanoma
Growth stimulating activity o Neutrophil activating
protein 3 (NAP-3);
MCP = Monocyte Chemotactic Protein;
MIP = Macrophage Inflammatory Protein.
De Ceuninck F., et al. Biochem Biophys Res Commm:
2004; 323. 960-969.
Attur M.G., et al. Osteoarthritis Cartilage 2002; 10. 3-4.
Borzi R.M., et al. FEBS Lett 1999; 455, 238-242.
MIP-1β IL-8
28. Mediatori attivanti l’insulino-resistenza
PKC-theta (protein kinasi C theta)
JNK (Jun N terminal Kinasi) gruppo serin-
treonin kinasi Aguirre V et al J Biol Chem 2000
Hotamisligil GS et al Science 1996
IkB (inibitori della via NFkB) Yin MJ et al Nature 1998
Zick Y Int J Obes Relat Metab Disord 2003
Hirosumi J et al Nature 2002
IKKB (inibitori della chinasi IkB) Perseghin G et al Int J Obes Relat Metab Disord 2003
TNF-α
IL-6
Mediatori inibenti l’insulino-resistenza
Adiponectina Berg AH et al Trends Endocrinol Metab 2002
Mediatori bimodali dell’insulino-resistenza
Leptina Lord GM et al Nature 1998
31. Mediatori attivanti l’insulino-resistenza
PKC-theta (protein kinasi C theta)
JNK (Jun N terminal Kinasi) gruppo serin-
treonin kinasi Aguirre V et al J Biol Chem 2000
Hotamisligil GS et al Science 1996
IkB (inibitori della via NFkB) Yin MJ et al Nature 1998
Zick Y Int J Obes Relat Metab Disord 2003
Hirosumi J et al Nature 2002
IKKB (inibitori della chinasi IkB) Perseghin G et al Int J Obes Relat Metab Disord 2003
TNF-α
IL-6
Mediatori inibenti l’insulino-resistenza
Adiponectina Berg AH et al Trends Endocrinol Metab 2002
Mediatori bimodali dell’insulino-resistenza
Leptina Lord GM et al Nature 1998
32. Zick Y Int J Obes Relat Metab Disord 2003
Shoelson SE et al Int J Obes Relat Metab Disord 2003
33. Zick Y Int J Obes Relat Metab Disord 2003
Shoelson SE et al Int J Obes Relat Metab Disord 2003
S
P-Y S
Y-P
IRS-
IRS-1 IKKβ
IKKβ IKK IKKβ
IKKβ Iκ B NFκB
NFκ
S
P-Y S
Y-P
NFκB
NFκ
INFIAMMAZIONE M-CSF
MCP-1 V-CAM
MCP- ICAM
34. Mediatori attivanti l’insulino-resistenza
PKC-theta (protein kinasi C theta)
JNK (Jun N terminal Kinasi) gruppo serin-
treonin kinasi Aguirre V et al J Biol Chem 2000
Hotamisligil GS et al Science 1996
IkB (inibitori della via NFkB) Yin MJ et al Nature 1998
Zick Y Int J Obes Relat Metab Disord 2003
Hirosumi J et al Nature 2002
IKKB (inibitori della chinasi IkB) Perseghin G et al Int J Obes Relat Metab Disord 2003
TNF-α
IL-6
Mediatori inibenti l’insulino-resistenza
Adiponectina Berg AH et al Trends Endocrinol Metab 2002
Mediatori bimodali dell’insulino-resistenza
Leptina Lord GM et al Nature 1998
36. Berg AH et al Trends Endocrinol Metab 2002
Effetto antinfiammatorio Ouchi N et al Curr Opin Lipidol 2003
AMPK ACC
Malonyl-
Malonyl- CoA
Peroxisome receptor
PPARα
PPARα
Inibizione nei macrofagi e negli adipociti dell’espressione di geni
infiammatori
37. Seo JB et al Mol Cell Biol 2004
Effetto antinfiammatorio Moller DE Int J ObesRelat Metab Disord 2003
Joseph SB Nat Med 2003
AMPK ACC
Malonyl-
Malonyl- CoA
Ligando del recettore x del fegato
LXR
Apoptosi del macrofago
38. Ruolo antinfiammatorio dell’Adiponectina
I livelli circolanti di adiponectina:
- correlano inversamente con il BMI (F>M)
ed aumentano in seguito a perdita di peso;
- correlano con la sensibilità insulinica.
Arita et al, BBRC 1999
40. Mediatori attivanti l’insulino-resistenza
PKC-theta (protein kinasi C theta)
JNK (Jun N terminal Kinasi) gruppo serin-
treonin kinasi Aguirre V et al J Biol Chem 2000
Hotamisligil GS et al Science 1996
IkB (inibitori della via NFkB) Yin MJ et al Nature 1998
Zick Y Int J Obes Relat Metab Disord 2003
Hirosumi J et al Nature 2002
IKKB (inibitori della chinasi IkB) Perseghin G et al Int J Obes Relat Metab Disord 2003
TNF-α
IL-6
Mediatori inibenti l’insulino-resistenza
Adiponectina Berg AH et al Trends Endocrinol Metab 2002
Mediatori bimodali dell’insulino-resistenza
Leptina Lord GM et al Nature 1998
42. Zick Y Int J Obes Relat Metab Disord 2003
Hotamisligil GS et al Science 1996
S
P-Y S
Y-P
IRS-
IRS-1 IKKβ
IKKβ IKK IKKβ
IKKβ Iκ B NFκB
NFκ
S
P-Y S
Y-P
NFκB
NFκ
INFIAMMAZIONE M-CSF
MCP-1 V-CAM
MCP- ICAM
44. Hundal RS J Clin Invest 2002
Aspirina alte
dosi
S
P-Y S
Y-P
IRS-
IRS-1 IKKβ
IKKβ IKK IKKβ
IKKβ Iκ B NFκB
NFκ
S
P-Y S
Y-P
45. Mediatori attivanti l’insulino-resistenza
PKC-theta (protein kinasi C theta)
JNK (Jun N terminal Kinasi) gruppo serin-
treonin kinasi Aguirre V et al J Biol Chem 2000
Hotamisligil GS et al Science 1996
IkB (inibitori della via NFkB) Yin MJ et al Nature 1998
Zick Y Int J Obes Relat Metab Disord 2003
Hirosumi J et al Nature 2002
IKKB (inibitori della chinasi IkB) Perseghin G et al Int J Obes Relat Metab Disord 2003
TNF-α
IL-6
Mediatori inibenti l’insulino-resistenza
Adiponectina Berg AH et al Trends Endocrinol Metab 2002
Mediatori bimodali dell’insulino-resistenza
Leptina Lord GM et al Nature 1998
47. Infiammazione ed insulinoresistenza
Cytokines
Insulin
Insulin IL-6
Tyr-P
Ser-P Tyr-P
Ser-P
Tyr-P
Ser-P Tyr-P
Ser-P
307
JNK
307 Tyr-P
Tyr-P
Ser-P Ser-P
IRS-1 MAPK
307
Tyr-P
Ser-P Tyr-P
Ser-P
Gao Z et al Mol Endocrinol 2004; Hirosumi J et al Nature 2002
48. Correlation between IL-6 expression in adipose tissue
of obese and insulin resistance (HOMA)
3.5
3.0 r = 0.32
P = 0.007
2.5
2.0
Log HOMA
1.5
1.0
0.5
0
-4 -2 0 2 4 6
Log IL-6 mRNA Expression
Cardellini et al. Diabetes Care submitted
49. Rui L et al J Biol Chem 2002; Mooney RA et al J Biol Chem 2001
Emanuelli B et al J Biol Chem 2001; Ueki K et al Mol Cell Biol 2004
P-S
Y S-P
Y
IRS-
IRS-1 UBIQUITIN SOCS Suppressor
P-S
Y S-P
Y
of cytokine
signaling
50. Mediatori attivanti l’insulino-resistenza
PKC-theta (protein kinasi C theta)
JNK (Jun N terminal Kinasi) gruppo serin-
treonin kinasi Aguirre V et al J Biol Chem 2000
Hotamisligil GS et al Science 1996
IkB (inibitori della via NFkB) Yin MJ et al Nature 1998
Zick Y Int J Obes Relat Metab Disord 2003
Hirosumi J et al Nature 2002
IKKB (inibitori della chinasi IkB) Perseghin G et al Int J Obes Relat Metab Disord 2003
TNF-α
IL-6
Mediatori inibenti l’insulino-resistenza
Adiponectina Berg AH et al Trends Endocrinol Metab 2002
Mediatori bimodali dell’insulino-resistenza
Leptina Lord GM et al Nature 1998
51. LEPTIN
• Nel 1994 viene scoperto il gene ob (espresso
principalmente dal tessuto adiposo bianco) e,
successivamente, il suo prodotto genico, la leptina (dal
greco leptos: magro)
• “An adipocytokine with pleiotropic actions”
Seven A et al Rheumatol Int 2009 29:743-747
53. LEPTIN
• La leptina è un ormone di natura peptidica del peso di 16 kDa
prodotto quasi esclusivamente dalle WAT cells
• Il suo ruolo principale consiste nella regolazione del peso corporeo
a livello dei nuclei ipotalamici, attraverso l’ inibizione dell’ introito
calorico e la promozione della spesa energetica.
• Le concentrazioni plasmatiche di leptina correlano direttamente con
il tessuto adiposo (WAT) e con il BMI; sono più alte nelle donne che
negli uomini;
• Vi è una stretta correlazione strutturale e funzionale della leptina con
IL-6, e del recettore della leptina (Ob-R) con la famiglia dei recettori
citochinici di classe 1 (il cui prototipo è il recettore di IL-6)
Seven A et al Rheumatol Int 2009 29:743-747
Targonska-Stepniak B et al Rheumatol Int 2010 30:731-737
55. Infiammazione ed insulinoresistenza
Insulin
Insulin Stress ossidativo su
cellula muscolare
Tyr-P
Ser-P Tyr-P
Ser-P
Insulino- NOs
Tyr-P
Ser-P Tyr-P
Ser-P
resistenza
307 307
Tyr-P Tyr-P
Ser-P
Ser-P
NO
IRS-1
307
Tyr-P
Ser-P Perreault M et al Nat Med 2001
Tyr-P
Ser-P
Shimabukuro M et al J Clin Invest 1997
60. Proinflammatory cytokines
α
IL-1, TNF-α
ICAM
Insulin Deficiency
IL-6 VCAM
Selectin
Insulin Resistance
CRP, SAA
DIABETE Il processo infiammatorio ATEROSCLEROSI
60
può causare
61. Relevant biomarkers of inflammation and their
role in atherosclerosis
Biomarkers of Sources Role in atherosclerosis
inflammation
Acute Phase Protein Liver, CRP induces production of inflammatory
CRP, SAA, Fibrinogen adipose tissue cytokines, chemokines, TF, chemiotaxis of
Endothelial cells monocytes, downregulation of eNOS
Cytokines
α
IL-1, IL-6, TNFα, IL-18 Endothelial cells, Pro-atherogenic and augment monocyte-
macrophages, endothelial adhesion (IL-6 CRP)
adipose tissue
Chemokines MCP-1, IL-8 Endothelial cells, Stimulate chemotaxis
macrophages
Adhesion Molecules Promote monocyte- endothelial adhesion
ICAM, VCAM, E- Endothelial cells
Selectin, P-Selectin
Inibitor of Fibrinolysis Endothelial cells, Promotes atherothrombosis
PAI-1 macrophages, Reduced Fibrinolysis 61
adipose tissue
62. Relative Risk of Cardiovascular Events According to
Several Biochemical Markers
Relative Risk of Future CV Events
Lipoprotein(a)
Homocysteine
TC
LDLC
Apolipoprotein B
TC:HDLC
hs-CRP
hs-CRP + TC:HDL-C
0 1.0 2.0 4.0 6.0
L’hs_CRP è in grado di segnalare una minima reazione infiammatoria anche
laddove la tradizionale CRP fosse normale. Insieme al valore del ratio colesterolo
totale/HDL (TC:HDL-C) mostra il più alto valore predittivo.
CV, cardiovascular; TC, total cholesterol; LDLC, low-density lipoprotein cholesterol; HDL-C, 62
high-density lipo-protein cholesterol; CRP, C-reative protein; hs-CRP, high-sensitivity C-reactive protein; TC, total cholesterol.
Adapted from Rifai N, et al. Clin Chem. 2001;47:28-30.
64. Effetto delle statine sull’ hs-CRP
Median hs-CRP Concentration (mg/dL) 0.25 Placebo
0.24
0.23
-21.6%
0.22 (P=.007)
0.21
CRP
0.20
0.19 Pravastatin
0.18
Baseline 5 Years
64
Ridker PM, et al. Circulation. 1999;100:230
65. Inflammation, Statin Therapy, and Relative
Risk of Recurrent Coronary Events
P Trend=.005
3
2
Relative Risk
1
0
Pravastatin Placebo Pravastatin Placebo
Inflammation Absent Inflammation Present
65
Ridker PM, et al. Circulation. 1998;98:839-844. (with permission from Lippincott Williams & Wilkins, www.lww.com)
66. Effetto antinfiammatorio delle statine
La proteina C reattiva è un marker infiammatorio la cui
aumentata presenza nel siero avrebbe valore prognostico
sfavorevole per la coronaropatia.
Le statine sono in grado di abbassare i livelli di PCR,
facendo ipotizzare che il loro effetto protettivo
cardiovascolare si esplichi mediante una soppressione
dell'infiammazione.
il dosaggio della PCR può essere un criterio aggiuntivo
per indirizzare la prescrizione delle statine.
Ridker PM et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005 Jan 6;352(1):20-8.
Nissen SE et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med.
2005 Jan 6;352(1):29-38. 66
69. J Rheumatol. 2009 Jun;36(6):1346-7; author reply 1347.
Increased adiponectin levels in women with rheumatoid arthritis after etanercept treatment.
Lewicki M, Kotyla P, Kucharz E.
Comment on:
•J Rheumatol. 2008 May;35(5):936-8.
69
70. Ann Rheum Dis. 2009 Jul 28. [Epub ahead of print]
Lack of effect of TNF{alpha} blockade therapy on circulating adiponectin levels in patients with autoimmune
disease: results from two independent prospective studies.
Peters MJ, Watt PH, Cherry L, Welsh P, Henninger E, Dijkmans BA, McInnes IB, Nurmohamed MT, Sattar N.
VU University Medical Center, Netherlands.
Abstract
BACKGROUND: Adiponectin is an anti-inflammatory and potentially anti-atherogenic molecule. Some recent reports
suggest that TNFalpha blockade therapy increases circulating adiponectin levels but data are sparse and inconsistent.
METHODS: Data from a double-blind placebo-controlled study of onercept in 126 psoriatic arthritis patients (PsA) and
data from pre- and post adalimumab treatment in 171 rheumatoid arthritis (RA) patients were used to examine the effect of
TNFalpha blockade therapy on adiponectin. RESULTS: Despite expected associations of adiponectin to gender and
baseline HDL-cholesterol and triglyceride, adiponectin levels did not change over time with TNFalpha blockade therapy
in either group. Absolute change in adiponectin levels were -0.23 +/-4.6microg/ml in onercept 50mg and onercept 100mg
combined group (versus placebo, p=0.60) in PsA patients and 0.28 +/-3.23microg/ml (p=0.66 versus baseline) in RA
patients treated with adalimumab. Discussion: These results go against a significant effect of TNFalpha blockade therapy
on circulating adiponectin levels in patients with autoimmune disease.
PMID: 19640853 [PubMed - as supplied by publisher]
70
71. Fundam Clin Pharmacol. 2009 Oct;23(5):595-600. Epub 2009 Jun 25.
Effects of a 6-month infliximab treatment on plasma levels of leptin and adiponectin in patients with rheumatoid
arthritis.
Derdemezis CS, Filippatos TD, Voulgari PV, Tselepis AD, Drosos AA, Kiortsis DN.
Laboratory of Physiology, Medical School, University of Ioannina, 45110 Ioannina, Greece.
Abstract
Patients with rheumatoid arthritis (RA) appear to have increased plasma levels of leptin and adiponectin. These adipokines
may be implicated in the pathophysiology of RA. Tumour necrosis factor alpha (TNF-alpha) is a potential modulator of
adipokines. The effects of long-term anti-TNF treatment on plasma levels of leptin and adiponectin are not clear. The aim
of this study was to assess the effects of 6-month anti-TNF treatment (infliximab) on leptin and adiponectin plasma levels
in RA patients. Thirty women with RA were included in the study. Patients with diabetes mellitus, any endocrine disorder
or receiving any hypolipidemic or antidiabetic medication were not included. Thirty healthy age- and body mass index-
matched women served as controls. Plasma levels of leptin and adiponectin were measured with enzyme immunoassay
methods prior to and after the 6-month treatment with infliximab. Mean age and disease duration of patients were 51.8 +/-
14.4 and 12.2 +/- 6.7 years, respectively. Body weight did not change significantly over the 6-month period. Plasma levels
of leptin and adiponectin were higher in patients than controls and did not change significantly after 6-month treatment.
Interestingly, in the tertile of patients with the highest baseline adiponectin concentrations, adiponectin levels were
significantly reduced (P < 0.05). Infliximab treatment did not change plasma levels of leptin and adiponectin after 6-month
treatment in the whole study population. However, a reduction of adiponectin levels was observed in patients with higher
baseline adiponectin levels.
71
73. Clin Exp Rheumatol. 2009 Mar-Apr;27(2):222-8.
Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis.
Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, Gonzalez-Juanatey C, Miranda-Filloy JA, Vazquez-Rodriguez TR, de Matias
JM, Martin J, Dessein PH, Llorca J.
Division of Rheumatology, Hospital Xeral Calde, Lugo, Spain. miguelaggay@hotmail.com
Abstract
OBJECTIVE: The adipocytokine leptin regulates weight centrally and participates in the regulation of the immune and
inflammatory responses. Chronic systemic inflammation is of major importance in the development of atherosclerosis in
rheumatoid arthritis (RA). In the present study we investigated whether inflammation, obesity or both of these characteristics are
potential determinants of circulating leptin concentrations in a group of RA patients on periodical treatment with the TNF-alpha-
blocker-infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating leptin
concentrations in patients with severe RA. METHODS: We investigated 33 patients with RA on periodical treatment with
infliximab. Serum leptin levels were determined immediately prior to and after infliximab infusion. RESULTS: There was a
positive correlation between body mass index of RA patients and baseline serum level of leptin (rho=0.665, p<0.001). Apart from
a significant correlation with VCAM-1 (rho=0.349, p=0.04), no significant correlations between baseline leptin levels and the age
at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity,
adhesion molecules, resistin, adiponectin, ghrelin or the cumulative prednisone dose at the time of the study were found. Leptin
levels did not change upon infliximab infusion (p=0.48). CONCLUSION: In RA patients on TNF-alpha blocker treatment,
circulating leptin levels are unrelated to disease activity but constitute a manifestation of adiposity. The beneficial effect of anti-
TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by reduction in serum levels of leptin.
PMID: 19473561 [PubMed - indexed for MEDLINE]
73
76. Incremento del rischio di IMA con l’incremento
della concentrazione di IL-6
Apparently healthy men (n=14,916)
3.0 p=0.01
p=0.003
Relative risk of MI
2.0
p=0.3
1.0
0
1 2 3 4
≤1.04 1.04–1.46 1.47–2.28 ≥2.28
Quartile of IL-6 (pg/mL)
Ridker PM, et al. Circulation 2000; 101:1767–1772.
77. Eventi CV: IL-6 è implicata nell’evoluzione
di malattia coronarica (CAD)
Outcomes according to IL-6 levels
• IL-6 is the chief inducer of
48 hours following hospitalisation
CRP1 which stimulates 80 for unstable angina
macrophages to produce
tissue factor – a
60
pro-coagulant found in
IL-6 (pg/mL)
atherosclerotic plaques2
• IL-6 induces 40
6
thrombocytosis3
• IL-6 levels predict outcome 20
following hospitalisation for
unstable angina3 0
Good Refractory AMI and
outcome angina death
1. Biasucci LM, et al. Circulation 1999; 99:2079–2084;
2. Georgiadis AN, et al. Arthritis Res Ther 2006; 8:R82;
AMI = acute myocardial infarction 3. Choy E, et al. Rheum Dis Clin N Am 2004; 30:405–415.
78. Cardiovascular event rates over
6-monthly intervals
TCZ (n=4,009)
Event rate per 100 PY (95% CI)
2.5
Myocardial infarction Stroke
2.0
1.5
1.0
0.5 No
events
0.0
0–6 7–12 13–18 19–24 25–30 31–36 37–42 >42
1,805 PY 1,664 PY 1,542 PY 1,440 PY 1,290 PY 964 PY 528 PY
Time (months)
* Clinical cut-off date of 6 February 2009 van Vollenhoven R, et al. ACR 2009. Presentation 1955.
79. The 11th EULAR Annual European Congress of Rheumatology
6–19 June 2010 Rome, Italy
POSTER
SAT0158 HUMANIZED ANTI-HUMAN INTERLUKIN-6 RECEPTOR MONOCLONAL ANTIBODY TOCILIZUMAB (TCZ)
INCREASES HIGH MOLECULAR WEIGHT ADIPONECTIN (HMW-AN) IN THE PATIENTS WITH RHEUMATOID ARTHRITIS
(RA): RESULT FROM THE ESCORT STUDY
K. Saito 1,*, K. Hanami 1, M. Nawata 1, N. Yunoue 1, Y. Tanaka 1
1The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, kitakyushu, Japan
Background: TCZ has been shown to provide clinical benefits in the patients who did not adequately respond to methotrexate (MTX) and TNF
inhibitors in RA. In several studies, moderate increase in total cholesterol (TC) and triglyceride (TG) was observed, but no increase in
cardiovascular events or atherosclerosis associated with TCZ has been reported1). Although we previously reported that infliximab increased
AN2), an anti-atherogenic adipocytokine, role of TCZ in lipid metabolism remain unclear.
Objectives: The aim of this study is to evaluate the effect of TCZ on lipid metabolism, especially on AN, in RA patients.
Methods: 50 patients who did not adequately respond to DMARDs and TNF inhibitors were enrolled in this study and were analyzed at 0, 24 wks
with disease activity using DAS28, biological markers including CRP, TC, LDL-C, HDL-C, TG and AN as well as intima-media thickness (IMT)
of carotid artery examined by ultrasonography. Patients were treated with 8mg/kg of TCZ every 4 wks.
Results: The baseline characteristics of the 50 patients were average of age was 63.3 and disease duration was 158.4 months. The percentage of
patients who concomitantly used MTX was 28 (56%), and those who used TNF inhibitors before TCZ was 31 (62%). The clinical parameters of
the 50 pts responded dramatically to TCZ (DAS28 at 0 wk: 6.18 ± 1.06, at 24 wk: 3.14 ± 1.06). After 24 wks of therapy, atherosclerosis index
remained in the normal range, though TC (193.4 to 221.9 mg/dl), HDL-C (62.5 to 73.6 mg/dl) and LDL-C (117.2 to 133.7 mg/dl) increased. In
addition, AN significantly increased from 10.7±6.1 to 13.9±9.0µg/ml. Changes of AN were not related to sex, disease duration, the cortocosteroid
dose, with or without concomitant MTX and prior use of TNF inhibitors. It is noteworthy that AN levels and their changes were also not
correlated with DAS28 at baseline and changes of DAS28 at 24 wks, indicating that production of AN was independent on synovitis. IMT also did
not change at all and cardiovascular events due to TCZ were not observed. Univariate analysis and logistic regression analysis demonstrated that
0w-BMI and changes of HDL-C at 24 wks were independently associated with changes of AN.
Conclusion: Although disorders of lipid metabolism were shown in the clinical trial of TCZ, our data suggest TCZ might have preventive effect
on the progression of arteriosclerosis by increase of AN. It is notable that TCZ increased AN independent on baseline levels and change of disease
activity as well as the prior use of anti-TNF biologics, suggesting action of TCZ for lipid metabolism could be independent on inflammation in
synovitis. However, this pilot study would warrant further investigation with more subjects and longer duration.
References: 1) E Choy, N Sattar. Ann Rheum Dis. 2009
2) Nishida K, Okada Y, Nawata M, Saito K, Tanaka Y. Endocr J. 2008
Disclosure of Interest: None declared
79
80. FRI0003 INHIBITION OF INTERLEUKIN-6 SIGNALLING IMPROVES INSULIN SENSITIVITY AND
REDUCES LIPOPROTEIN (A) LEVELS IN HUMANS
M. Laudes 1,*, O. Schultz 1, F. Oberhauser 1, J. Saech 2, A. Rubbert-Roth 2, W. Krone 1
1Department of Internal Medicine II, 2Department of Internal Medicine I, UNIVERSITY OF COLOGNE, GERMANY, Köln,
Germany
Objectives: Interleukin-6 (IL-6) is a pro-inflammatory cytokine which has been found increased in type 2 diabetic subjects.
However, it remains still unclear if these elevated IL-6 levels are co-incidental or if this cytokine is of causal relevance in the
development of insulin resistance and type 2 diabetes in humans. Therefore, in the present study we examined insulin
sensitivity, adipokine serum levels and lipid parameters in human subjects before and after treatment with the interleukin-6
receptor antibody Tocilizumab.
Methods: 11 non-diabetic patients with rheumatoid disease were included into the study. HOMA-index and serum levels for
leptin, adiponectin, triglycerides, LDL-cholesterol, HDL-cholesterol and lipoprotein (a) were measured before as well as one
and three months after Tocilizumab treatment
Results: The HOMA-index for insulin resistance decreased significantly from 4.9±1.1 to 2.4±0.6. While leptin
concentrations were not altered by inhibition of IL-6 signalling, adiponectin concentrations significantly increased from
11.1±1.2 to 16.1±2.1 µg/ml. Thereby the leptin to adiponectin ratio, a novel marker for insulin resistance, exhibited a
significant decrease. In respect to lipid parameters, triglycerides, LDL-cholesterol and HDL-cholesterol were not
significantly altered whereas lipoprotein (a) levels significantly decreased by approximately 40% by Tocilizumab.
Conclusion: Inhibition of IL-6 signalling improves insulin sensitivity in humans suggesting that elevated IL-6 levels in type
2 diabetic human subjects are of causal relevance in the pathogenesis of insulin resistance. Furthermore, our data indicate that
lipid metabolism in human subjects is influenced by IL-6 as shown by the profound decrease of lipoprotein (a) levels due to
Tocilizumab treatment.
Disclosure of Interest: None declared
80
85. L’AR rappresenta un fattore di
rischio CV indipendente
(analogo al diabete mellito)
Van Halm et al. Ann Rheum Disease 2009
Peters MJ et al. Arthritis Rheum 2009
85
86. Esordio precoce
E’ dimostrato che nell’AR il rischio CV assoluto è
simile a quello degli individui, nella popolazione
generale, di 5-10 anni più anziani.
Kremers HM et al. Arthritis Rheum 2008
86
87. La mortalità in corso di A.R.
Numerose evidenze dimostrano che l’aumento di mortalità è per lo
più legato alle malattie cardiovascolari (CV).
• Malattie cardiovascolari
• Infezioni………………..
• Neoplasie……………....
• Altre cause (amiloidosi,
rene, polmone, ecc.)……
• Artrite Reumatoide
– Vasculiti………………
– Dislocazione
atlantoassiale…………
– Farmaci……………….
Dougados M et al. Ann Rheum Dis 2004;63:1172–76.
Avina-Zubieta JA et al. Arthritis Rheum 2008;59:1690–7. 87
92. Profilo Lipidico Aterogeno
LDL
Piccole, dense ↑ TG
da 3 a 6 ↑ # Pazienti
Rischio Coronarico 40 36 Si CV
No CV
30
20
14
↓ HDL-C 10 9 9
0
Nuovi markers di LDL Dense LDL Leggere
rischio χ2 = 9.53; p = 0.002
92
cardiovascolare Faggin, Zambon et al. JACC 40:1059, 2002
93. Struttura delle LDL
Mantello superficiale
di fosfolipidi e
colesterolo libero
apoB
Core idrofobico
di trigliceridi e esteri
del colesterolo
93
Murphy HC et al. Biochemistry 2000;39:9763-970.
94. Eventi cardiovascolari: contributo di IL-6 al
rischio CV
• IL-6 decreases total cholesterol by reducing the levels of both HDL
and LDL.1 Studies suggest that
– The decrease in cardio-protective HDL is more pronounced than the reduction in LDL and
total cholesterol2
– High HDL concentrations are associated with a significant reduction in IL-6 levels3
• IL-6 therefore may raise CV risk by altering the ratio of
– ApoB:ApoA
– Total cholesterol:HDL
– HDL:LDL
• IL-6 has also been shown to reduce lipoprotein lipase activity in adipose
tissue resulting in elevated circulating triglycerides2
1. Khovidhunkit W, et al. J Lipid Res 2004; 45:1169–1196;
HDL = High density lipoprotein 2. Woods A, et al. European Heart Journal 2000; 21:1574–1583;
LDL = Low density lipoprotein 3. Popa C, et al. Ann Rheum Dis 2005; 64:303–305.
95. Nei pazienti con AR soprattutto se in fase attiva si rinvengono alti
rapporti colesterolo totale/colesterolo HDL per un decremento delle
HDL. Si osservano, inoltre, alti livelli di trigliceridi.
Choi HK et al. J Rheumatol 2005;32:2311–6.
Park YB et al. J Rheumatol 1999;26:1701–4.
Yoo WH.. J Rheumatol 2004;31:1746–53.
Sembra che questo profilo lipidico sfavorevole sia presente già 10
anni prima che la malattia esordisca.
van Halm VP et al. Ann Rheum Dis 2007;66:184–8.
95
96. I DMARDs inclusi i corticosteroidi sembrano avere un effetto
vantaggioso sul profilo lipidico nei pazienti con ERA. Si ha un
aumento del colesterolo totale ma anche un aumento più
pronunciato delle HDL, il che si traduce in un rapporto
col.Tot/col.HDL più favorevole.
Munro R et al. Ann Rheum Dis 1997;56:374–7.
Park YB et al. Am J Med 2002;113:188–93.
Boers M et al. Ann Rheum Dis 2003;62:842–5.
Nei primi mesi di trattamento la terapia con anti TNF alfa ha un
effetto favorevole sul rapporto col.Tot/col.HDL sebbene entrambi
aumentino (col. HDL > col. Totale).
Vis M et al. J Rheumatol 2005;32:252–5.
Spanakis E et al. J Rheumatol 2006;33:2440–6.
Popa C et al. Ann Rheum Dis 2005;64:303–5.
96
97. Ad oggi il rapporto
Colesterolo totale
Colesterolo HDL
rappresenta il marker più attendibile del rischio dislipidemico
nell’AR.
Peters MJL et al. Ann Rheum 2010 69: 325-331
97
99. IL-6 incrementa la trombopoiesi per via
TPO (trombopoietina)
The regulation of
thrombopoiesis during the
inflammatory cascade of
rheumatoid arthritis.
A. Induction of
megakaryocytopoiesis
during the inflammatory
cascade.
B. Megakaryocytopoiesis
in the bone marrow under
the influence of cytokines.
C. Constitutive production
of TPO from the liver and
the kidney.
D. Regulation of TPO levels
in the peripheral blood. E
Platelets
in the disease process of
rheumatoid arthritis
Ihsan Ertenli, et al.Rheumatol Int (2003) 23: 49–60
100. IL-6 in RA: Systemic effects
Liver
Acute-phase The acute-phase
proteins response
IL-6
Hepcidin
production
Anaemia
Inflammation
HPA axis Fatigue and mood
Systemic osteoporosis
Increased
cardiovascular risk
101. IL-6 induce la produzione di epcidina degli
epatociti
• Hepcidin inhibits:
– Release of iron from macrophages (reticuloendothelial block)
– Absorption of dietary iron (iron deficiency)
Inflammation
Macrophage
Hepcidin iron release
IL-6
Macrophage Hepatocytes Intestinal iron
absorption
Andrews NC, J Clin Invest 2004; 113:1251–1253; Nemeth E, J Clin Invest 2004; 113:1271–1276.
102. L’aumentata produzione di IL-6 causa anemia
• Increased serum IL-6 concentrations correlate with anaemia in
RA patients1
• IL-6 infusions induced anaemia in a rat model2
8 10.5 Control
7 6.8 IL-6
Serum IL-6 (pg/mL)
p=0.0001 10.0
6 9.5
Hb (mmol/L)
5 9.0
3.9
4 8.5
3 * *
8.0 *p<0.01
2 *
7.5 * Treatment
1
7.0
0 0 5 10 15 20 25
Anaemic Non-anaemic Day
1. Voulgari P, et al. Clin Immunol 1999; 92:153–160.
2. Jongen-Lavrencic M, et al. Clin Exp Immunol 1996; 103:328–334.
103. TOCILIZUMAB: normalizza I livelli di
emoglobina nei pazienti con AR anemizzati
ITT population
14 Placebo + DMARD TCZ 8 mg/kg + DMARD
women n=101 women n=154
Mean absolute Hb (g/dl)
13
12 LLN
11
10
0 2 4 8 12 16 20 24
Week
Smolen J, et al. EULAR 2008; Poster THU0168.
