This document discusses the role of TNF-α in metabolic syndrome and insulin resistance, and the potential effects of anti-TNFα therapy. It notes that TNF-α plays an important role in metabolic syndrome, insulin resistance, and chronic inflammation, increasing metabolic and cardiovascular risk. Anti-TNFα therapies seem to improve metabolic syndrome, insulin resistance, and chronic inflammation, potentially reducing these risks. However, obesity may impair the efficacy of anti-TNFα therapies, so weight loss could improve or restore response to anti-TNFα treatments.

1. Sindrome metabolica, obesità e
terapia con anti TNF alfa
Luigi Landolfi
AOU Medicina Interna Salerno

2. Criteri per la diagnosi di Sindrome Metabolica

3. TNF–α ?

5. Il Ruolo del TNF – α nel metabolismo degli adipocitiIl 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

6. Il Ruolo del TNF – α nel metabolismo degli adipocitiIl Ruolo del TNF – α nel metabolismo degli adipociti
Modula il metabolismo lipidico :
Induce Insulinoresistenza

7. Il Ruolo del TNF – α nel metabolismo degli adipocitiIl Ruolo del TNF – α nel metabolismo degli adipociti
Modula il metabolismo lipidico :
Induce Insulinoresistenza
Regola la produzione di
leptina

8. Il Ruolo del TNF – α nel metabolismo degli adipocitiIl 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.

9. Il Ruolo del TNF – α nel metabolismo degli adipocitiIl Ruolo del TNF – α nel metabolismo degli adipociti
Modula il metabolismo lipidico :
Induce Insulinoresistenza
Potente inibitore della
differenziazione degli
adipociti

10. Il Ruolo del TNF – α nel metabolismo degli adipocitiIl Ruolo del TNF – α nel metabolismo degli adipociti
Modula il metabolismo lipidico :
Induce Insulinoresistenza
> l’apoptosi nel tessuto
adiposo

11. Obesità Infiammazione e InsulinoresistenzaObesità Infiammazione e Insulinoresistenza
Adipokine expression and secretion by adipose tissue in lean subjects

12. Obesità Infiammazione e InsulinoresistenzaObesità Infiammazione e Insulinoresistenza
Obese subjects

15. Infiammazione

16. Insulinoresistenza

17. Insulin Resistance
Mortality / Morbidity

18. Cellule
schiumose
Stria
Lipidica
Lesione
Intermedia Ateroma
Lesione
complicata

20. Obesity is characterized by inflammation

21. Obesity is characterized by inflammation

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

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

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

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

30. Radiologic evidence of gliosis in the MBH of obese humans

32. Implications and future directions
This finding advances knowledge about the pathological changes affecting
the central nervous system during the development of metabolic syndrome,
and provides support for the idea that hypothalamic neuropathy contributes
to the condition.

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

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

35. anti TNF–α ?

37. Inhibition of Hypothalamic Inflammation Reverses
Diet-Induced Insulin Resistance in the Liver
Marciane Milanski1
,2
, Ana P. Arruda1
, Andressa Coope1
, Letícia M. Ignacio-Souza1
,
Carla E. Nunez1
, Erika A. Roman1
, Talita Romanatto1
, Livia B. Pascoal1
, Andrea M. Caricilli3
, Marcio A. Torsoni1
,2
,
Patricia O. Prada2
, Mario J. Saad3
and Licio A. Velloso1
The inhibition of TLR4 and
TNFα in the hypothalamus
reduces hypothalamic inflammation
and corrects leptin resistance .
Toll-Like Receptors TLR 4

38. anti TNF–α ?

39. 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.

41. 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 .

43. Infliximab

44. 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 .

45. 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.

46. 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.

47. 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).

48. 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.

49. BASDAI
Bath Ankylosing Spondylitis
Disease 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

50. 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

52. Diabetes and Vascular Disease Research 2006

53. CONCLUSIONI

54. Sindrome
metabolica :
Malattia
Infiammatoria
Cronica

55. TNF–α ?
Ruolo importante
- nella sindrome metabolica
- nell’insulinoresistenza
- flogosi cronica
Rischio metabolico
Cardiovascolare
Neoplastico …

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

57. Riduzione del peso corporeo
Miglioramento della s. metabolica
Migliora / Ripristina la risposta agli
anti TNF–α ?