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
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;721-728 Traditional cardiovascular risk factors do not adequately account for the extent of cardiovascular disease in RA del Rincon ID Arthritis Rheum 2001, 44:2737-2745 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: 2317-22 , 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;108:2957-2963 In RA, primary site of inflammation is synovial tissue, from which cytokines can be released into systemic circulation
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; 423:356361. 2. Smolen JS, et al. Nat Rev Drug Disc 2003; 2:473488.
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.
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;25:241-253; Scheller J, Rose-John S. Med Microbiol Immunol. 2006;195(4):173-183. DRAFT version – For information only 5
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 8mg/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
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 6.59 + 0.24 Sex, % female 100 Swollen joint count (range 0-28) 18.36 + 1.1 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) 57.4 + 8..9 Receiving NSAIDs, % Early morning stiffness (minutes) 66.36 ± 20. Receiving Corticosteroid (Prednisolone<10 mg od) % 18.1 CRP (mg/dl) 34.87 + 8.0 DMARD regimen: Serum Nitrite 7.41 + 0.18 MTX (7.5-15 mg/wk) + SSZ (500 mg bd) 45.4 Brachial artery diameter (mm) 2.78 ± 0.12 MTX (7.5-15 mg/wk) + SSZ (500 mg bd) + HCQ (200 mg bd) FMD % 8.21 + 0.88
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
TOCILIZUMAB IMPROVES INFLAMMATORY DISEASE ACTIVITY: CRP, TBARS & ESR * p < 0.001, statistically significant
TOCILIZUMAB IMPROVES INFLAMMATORY DISEASE ACTIVITY: DAS 28, HAQ-DI * p < 0.001, statistically significant
Association of Endothelial Dysfunction with Inflammatory Disease Activity Multivariate Linear Regression Analysis: Independent predictors of FMD in RA patients Predictor β p CRP 0.054 0.042* Serum nitrite -2.840 0.022* Univariate Correlation Analysis: FMD with selected variables in RA patients Variables r p Serum nitrite -0.683 0.0206* DAS score -0.660 0.0234* Brachial artery diameter -0.191 0.574 ESR 0.0784 0.819 CRP 0.620 0.0419* TBARS -0.465 0.150 HAQ-DI 0.241 0.450 Physical health 0.086 0.776 Mental health 0.251 0.433
Association of Endothelial Dysfunction with Inflammatory Disease Activity Relation between Serum nitrite level and FMD
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.
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.
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