Sindrome metabolica, obesità e terapia con anti TNF alfa

Luigi Landolfi AOU Medicina Interna Salerno

Criteri per la diagnosi di Sindrome Metabolica

TNF–α ?

Il Ruolo del TNF – α nel metabolismo degli adipociti Il Ruolo del TNF – α nel metabolismo degli adipociti

Modula il metabolismo lipidico : Riduce l’uptake dei FFA e

la sintesi dei trigliceridi (lipogenesi)

Incrementa la lipolisi

Il Ruolo del TNF – α nel metabolismo degli adipociti Il Ruolo del TNF – α nel metabolismo degli adipociti

Modula il metabolismo lipidico :

Induce Insulinoresistenza

Il Ruolo del TNF – α nel metabolismo degli adipociti Il Ruolo del TNF – α nel metabolismo degli adipociti

Modula il metabolismo lipidico :

Induce Insulinoresistenza

Regola la produzione di leptina

Il Ruolo del TNF – α nel metabolismo degli adipociti Il Ruolo del TNF – α nel metabolismo degli adipociti

Modula il metabolismo lipidico :

Induce Insulinoresistenza

> Livelli di PAI-1 adipocitari e circolanti

plasminogen activator inhibitor PAI-1.

Il Ruolo del TNF – α nel metabolismo degli adipociti Il Ruolo del TNF – α nel metabolismo degli adipociti

Modula il metabolismo lipidico :

Induce Insulinoresistenza

Potente inibitore della differenziazione degli adipociti

Il Ruolo del TNF – α nel metabolismo degli adipociti Il Ruolo del TNF – α nel metabolismo degli adipociti

Modula il metabolismo lipidico :

Induce Insulinoresistenza

> l’apoptosi nel tessuto adiposo

Obesità Infiammazione e Insulinoresistenza Obesità Infiammazione e Insulinoresistenza

Adipokine expression and secretion by adipose tissue in lean subjects

Obesità Infiammazione e Insulinoresistenza Obesità Infiammazione e Insulinoresistenza

Obese subjects

Infiammazione

Insulinoresistenza

Insulin ResistanceMortality / Morbidity

Celluleschiumose

StriaLipidica

LesioneIntermedia Ateroma

Lesionecomplicata

Obesity is characterized by inflammation

Obesity is characterized by inflammation

Expression of TNF-α mRNA in adipose tissue from lean and obese female human subjects .

INFIAMMAZIONE

Adipose tissue inflammation The increase in fat cell size is accompanied by the increased infiltration of immune cells including macrophages (arrows).

Lipidi e mediatori dell’infiammazione : integrazione delle risposte metaboliche e immunitarie in adipociti e macrofagi attraverso meccanismi condivisi

Time course of hypothalamic inflammation after the onset of HFD feeding.

Radiologic evidence of gliosis in the MBH of obese humans

Implications and future directions

This finding advances knowledge about the pathological changes affectingthe central nervous system during the development of metabolic syndrome,and provides support for the idea that hypothalamic neuropathy contributesto the condition.

TNF – α e insulinoresistenza in obesi con DM 2 TNF – α e insulinoresistenza in obesi con DM 2

TNF – α e insulinoresistenza in obesi con DM 2 TNF – α e insulinoresistenza in obesi con DM 2

anti TNF–α ?

Inhibition of Hypothalamic Inflammation Reverses Diet-Induced Insulin Resistance in the Liver

Marciane Milanski 1, 2, Ana P. Arruda 1, Andressa Coope 1, Let ícia M. Ignacio-Souza 1, Carla E. Nunez 1, Erika A. Roman 1, Tal i ta Romanatto 1, Livia B. Pascoal 1, Andrea M. Caricil l i 3, Marcio A. Torsoni 1,2, Patr icia O. Prada 2, Mario J. Saad 3 and Licio A. Velloso 1

The inhibition of TLR4 and TNFα in the hypothalamus reduces hypothalamic inflammation and corrects leptin resistance .

Toll-Like Receptors TLR 4

anti TNF–α ?

All patients received the same dose of methotrexate during the study as before the study plus four infusions of infliximab (Remicade, Janssen) at a dose of 3 mg per kilogram of body weight at the initiation of treatment (week 0) and at weeks 2, 6 and, 14.

In addition to the anti-inflammatory action, infliximab

• improves insulin sensitivity • alters lipid profile. • reduction in insulin resistance• contributes to the recently reported decreased incidence of cardiovascular events in RA .

Infliximab

Nature Reviews Rheumatology , | doi:10.1038/nrrheum.2012.158

Rheumatoid arthritis: Obesity impairs efficacy of anti-TNF therapy in patients with RA

Miguel A. González-Gay & Carlos González-Juanatey

Pazienti con A.R. : anti-TNF oltre all’effetto antiinfiammatorio migliorano anche la sensibilità all’insulina riducendo l’insulinoresistenza solo nei pazienti con normale BMI .

J Rheumatol. 2014 Jun;41(6):1112-7. doi: 10.3899/jrheum.131150. Epub 2014 Apr 15.

Early increase of abdominal adiposity in patients with spondyloarthritis receiving anti-tumor necrosis factor-α treatment.

Hmamouchi I1, Roux C2, Paternotte S2, Kolta S2, Dougados M2, Briot K2.

J Rheumatol. 2014 Jun;41(6):1112-7. doi: 10.3899/jrheum.131150. Epub 2014 Apr 15.

Early increase of abdominal adiposity in patients with spondyloarthritis receiving anti-tumor necrosis factor-α treatment.

Hmamouchi I1, Roux C2, Paternotte S2, Kolta S2, Dougados M2, Briot K2.

In patients with SpA receiving anti-TNF-α therapy, there is an early significant increase in abdominal obesity with significant increase in both VAT and SAT after 1 and 2 years of treatment.

Prospective studies are required to investigate the relationship between these changes and cardiovascular risk.

Postepy Dermatol Alergol. 2014 Feb;31(1):29-31. doi: 10.5114/pdia.2014.40656. Epub 2014 Feb 25.

Influence of ustekinumab on body weight of patients with psoriasis: an initial report.Owczarczyk-Saczonek A, Placek W, Rybak-d'Obyrn J, Wygonowska E.

Postepy Dermatol Alergol. 2014 Feb;31(1):29-31. doi: 10.5114/pdia.2014.40656. Epub 2014 Feb 25.

Influence of ustekinumab on body weight of patients with psoriasis: an initial report.Owczarczyk-Saczonek A, Placek W, Rybak-d'Obyrn J, Wygonowska E.

Postepy Dermatol Alergol. 2014 Feb;31(1):29-31. doi: 10.5114/pdia.2014.40656. Epub 2014 Feb 25.

Influence of ustekinumab on body weight of patients with psoriasis: an initial report.Owczarczyk-Saczonek A, Placek W, Rybak-d'Obyrn J, Wygonowska E.

Postepy Dermatol Alergol. 2014 Feb;31(1):29-31. doi: 10.5114/pdia.2014.40656. Epub 2014 Feb 25.

Influence of ustekinumab on body weight of patients with psoriasis: an initial report.Owczarczyk-Saczonek A, Placek W, Rybak-d'Obyrn J, Wygonowska E.

Body mass increase was determined in 7 patients (64%), on average by 2.27 kg (p < 0.05), and the BMI increased by 3.35% (p < 0.1).

Rheumatology (Oxford). 2014 May;53(5):875-81. doi: 10.1093/rheumatology/ket433. Epub 2014 Jan 9.

Body weight, gender and response to TNF-α blockers in axial spondyloarthritis.

Gremese E1, Bernardi S, Bonazza S, Nowik M, Peluso G, Massara A, Tolusso B, Messuti L, Miceli MC, Zoli A, Trotta F, Govoni M, Ferraccioli G.

- 170 Pazienti con “active axial SpA” (BASDAI > 4) , - trattati per 12 mesi con anti TNF-α :

adalimumab (ADA), etanercept (ETA), infliximab (IFX)

Patients were divided according to the baseline BMI as normal weight (BMI < 25), overweight (BMI 25-30) and obese (BMI ≥ 30).

After 12 months of treatment : - a 50% improvement of the initial BASDAI (BASDAI50) was the primary end point - and BASDAI ≤ 1 was the secondary end point.

BASDAIBath Ankylosing SpondylitisDisease Activity Index

1. How would you describe the overall level of fatigue/tiredness you have experienced?

NONE _____________________________________________ VERY SEVERE 2. How would you describe the overall level of AS neck, back or hip pain you have had?

NONE _____________________________________________ VERY SEVERE 3. How would you describe the overall level of pain/swelling in joints other than neck, back, hips you have had?

NONE _____________________________________________ VERY SEVERE 4. How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure?

NONE _____________________________________________ VERY SEVERE 5. How would you describe the overall level of morning stiffness you have had from the time you wake up?

NONE _____________________________________________ VERY SEVERE 6. How long does your morning stiffness last from the time you wake up?

_____________________________________________ 0 hrs ½ 1 1½ 2 or more hours

Rheumatology (Oxford). 2014 May;53(5):875-81. doi: 10.1093/rheumatology/ket433. Epub 2014 Jan 9.

Body weight, gender and response to TNF-α blockers in axial spondyloarthritis.

Gremese E1, Bernardi S, Bonazza S, Nowik M, Peluso G, Massara A, Tolusso B, Messuti L, Miceli MC, Zoli A, Trotta F, Govoni M, Ferraccioli G.

- 170 Pazienti con “active axial SpA” (BASDAI > 4) , - trattati per 12 mesi con anti TNF-α :

adalimumab (ADA), etanercept (ETA), infliximab (IFX)

Minor tasso di successo della terapia

- Nelle donne , in sovrapeso - e soprattutto nelle obese

Diabetes and Vascular Disease Research 2006

CONCLUSIONI

Sindrome metabolica : Malattia Infiammatoria Cronica

TNF–α ?Ruolo importante - nella sindrome metabolica - nell’insulinoresistenza- flogosi cronica Rischio metabolico CardiovascolareNeoplastico …

anti TNF–α Sembrano migliorare - la sindrome metabolica - l’insulinoresistenza- la flogosi cronica < Rischio metabolico ? < Cardiovascolare ? < Neoplastico ?

?

Riduzione del peso corporeo

Miglioramento della s. metabolica

Migliora / Ripristina la risposta agli

anti TNF–α ?