1. IL 6 blockade Improves Endothelial Dysfunction in Rheumatoid Arthritis
Ashit Syngle, MD
Senior Consultant Physician & Rheumatologist Fortis Multispeciality Hospital & Director Healing Touch City Clinic
Chandigarh, India

2. Study background RA patients, 2-5 times more prone to CV morbidity &
mortality; CVD contributes
to 1/3 to 1/2 of premature RA deaths
Heeneman D et al Circulation 2002,106, 2184–7
RA patients die prematurely & CV disease is the major cause of excessive mortality
Taylor PC Rheumatology 2005;44;
Traditional cardiovascular risk factors do not adequately account for the extent of cardiovascular disease in RA
del Rincon ID Arthritis Rheum 2001, 44:
IL-6 is the most abundant cytokine in RA;
people with high levels of IL-6 are 2-5 times more likely have MI, stroke & other CV events
Cesari M et al Circulation 2003; 108:
, primary site of inflammation is synovial tissue, from which cytokines can be released into systemic circulation. These circulating cytokines alter function of distant tissues, including adipose, skeletal muscle, liver, and vascular endothelium, to generate a spectrum of proatherogenic changes that include insulin resistance, characteristic dyslipidemia, pro-oxidative effects, and endothelial dysfunction and damage. +ve indicates positive; P>C, peripheral greater than central; TG, triglyceride; vWF, von Willebrand factor; and tPA, tissue plasminogen activator.
Sattar N et al. Circulation 2003;108:
In RA, primary site of inflammation is synovial tissue, from which cytokines can be released into systemic circulation

3. Pivotal role of IL-6: Biological activities
Endothelial cells
Mesenchymal cells,
fibroblasts/
synoviocytes
Monocytes/
macrophages
T-cell activation
IL-6
Hepatocytes
Acute-phase response
Hepcidin, CRP ↓ CYP450
Maturation of
megakaryocytes
Osteoclast activation
B-cells
Bone resorption
Thrombocytosis
Auto-antibodies
(e.g. rheumatoid factor)
Hyper--globulinemia
Adapted from: 1. Firestein GS, Nature 2003; 423:356361.
2. Smolen JS, et al. Nat Rev Drug Disc 2003; 2:473488.

4. IL-6 has numerous articular effects in RA
Synoviocytes
Osteoclast activation
bone resorption
Endothelial cells
VEGF
Pannus formation
Joint destruction
Mediation of chronic
inflammation
IL-6
Macrophage
T-cell
B-cell
Neutrophil
Antibody
production
Adapted from: 1. Choy E, Rheum Dis Clin North Am 2004;30:405–415.
2. Gabay C, Arthritis Res Ther 2006;8(suppl 2):S3.

5. Tocilizumab inhibits IL-6R membrane-bound signaling and trans-signaling
IL-6 cannot bind
gp130
sIL-6R
mIL-6R
Tocilizumab binds mIL-6R and sIL-6R
gp130
Membrane-bound signaling
Trans-signaling
Jones SA, et al. J Interferon Cytokine Res. 2005;25: ; Scheller J, Rose-John S.
Med Microbiol Immunol. 2006;195(4):
DRAFT version – For information only 5

6. Study Design Active RA Screening n=15 Inclusion: 1.Age > 18 yrs.
2.DAS28 score > 3.2
3.Six or more SJC and TJC.
4.Morning stiffness > 45 min.
5.ESR at least 28 mm in 1st hr or CRP>2mg/dl
6.Stable dose of DMARDs from past 6 months
Exclusion:
1. Inflammatory joint disease other than RA
2. Diabetes, hypertension, IHD, dyslipidemia, renal &
hepatic.impairment, pregnant & lactating women
4. Use of drugs that affect endothelial function .
5. Drug sensitivity
Initiate Tocilizumab mg/kg i.v. infusion every 4 weeks, n=11
Assessment of Inflammatory Disease Activity:
ESR, CRP
DAS28,
HAQ-DI
Assessment at 0 & 12 weeks
Assessment of Vascular Endothelial Function:
Serum nitrite
FMD
NTG induced vasodilatation
10 age & sex matched healthy
subjects acted as controls

7. Baseline characteristics in study participants n=11
Patient Profile
Baseline characteristics in study participants n=11
Mean Age, years
51.64 ± 1.44
DAS 28 score
Sex, % female
100
Swollen joint count (range 0-28)
Rheumatoid Factor positive, %
90.9
Tender joint count (range 0-28)
13.7 ± 1.45
Disease duration, years
11.36 ± 2.58
Pain score (range 0-10 cm VAS)
6.95 ± 0.62
Systolic blood pressure (mm Hg)
128 ± 3.52
Patient’s global assessment (range 0-10 cm VAS)
7.9 ± 0.44
Diastolic blood pressure (mm Hg)
82 ± 11.21
Physician’s global assessment (range 1-10)
8.0 ± 0.23
Body mass index (kg/m2)
27.18 ± 1.16
ESR (mm in 1st hr)
Receiving NSAIDs, %
Early morning stiffness (minutes)
66.36 ± 20.
Receiving Corticosteroid (Prednisolone<10 mg od) %
18.1
CRP (mg/dl)
DMARD regimen:
Serum Nitrite
MTX ( mg/wk) + SSZ (500 mg bd)
45.4
Brachial artery diameter (mm)
2.78 ± 0.12
MTX ( mg/wk) + SSZ (500 mg bd) + HCQ (200 mg bd)
FMD %

8. TOCILIZUMAB IMPROVES VASCULAR ENDOTHELIAL FUNCTION:
Results……
TOCILIZUMAB IMPROVES VASCULAR ENDOTHELIAL FUNCTION:
FMD & NTG induced Vasodilation Serum Nitrite Concentration
p=0.50
p < 0.001*
p < 0.001*
* p < 0.001, statistically significant

9. TOCILIZUMAB IMPROVES INFLAMMATORY DISEASE ACTIVITY: CRP, TBARS & ESR
* p < 0.001, statistically significant

10. TOCILIZUMAB IMPROVES INFLAMMATORY DISEASE ACTIVITY: DAS 28, HAQ-DI
* p < 0.001, statistically significant

11. Association of Endothelial Dysfunction with Inflammatory Disease Activity
Multivariate Linear Regression Analysis: Independent predictors of FMD in RA patients Predictor β p CRP * Serum nitrite * Univariate Correlation Analysis: FMD with selected variables in RA patients Variables r p Serum nitrite * DAS score * Brachial artery diameter ESR CRP * TBARS HAQ-DI Physical health Mental health

12. Association of Endothelial Dysfunction with Inflammatory Disease Activity
Relation between Serum nitrite level and FMD

13. Adverse Effects Tocilizumab was well tolerated
All subjects completed the study
No significant change of haematological or biochemical profile
No infusion reaction during administration
Minor adverse effects: two episodes of infection (upper respiratory tract infection & gastroenteritis) in 2 patients during study period.

14. CONCLUSIONS
IL-6 inhibitor tocilizumab improves both endothelial dysfunction and inflammatory disease activity in RA
Endothelial dysfunction is part of the disease process in RA and is also mediated by IL-6.

15. Thank You