, Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING...

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TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*, Sunarso Suyoso*, Rahmadewi*, Cita Rosita SP*, Indropo Agusni* *Dermatoveneorology Departement, Dr. Soetomo Hospital / Airlangga University School of Medicine, Surabaya Indonesia

Transcript of , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING...

Page 1: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of

ERYTHEMA NODOSUM LEPROSUM TREATED

with CORTICOSTEROID

Irmadita

Citrashanty*, Sunarso

Suyoso*, Rahmadewi*,

Cita Rosita SP*,

Indropo Agusni*

*Dermatoveneorology

Departement, Dr.

Soetomo Hospital /

Airlangga University

School of Medicine,

Surabaya Indonesia

Page 2: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

INTRODUCTION

Page 3: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,
Page 4: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

2011 (Dr. Soetomo General Hospital Surabaya) 29,8% among new MB patients with ENL (141 patients) treated with corticosteroid

33 patients suffer from continuous ENL

Page 5: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

• ENL reaction hypersensitivity type 3 / immune complex / arthus phenomenon

• Characteristic of ENL increase of TNF-α, IL-1 also IL-6, IL-8 and IL-10

• The secretion of adrenocorticotropin hormone (ACTH) increases adrenal glucocorticoid increase

• TNF-α inhibit adrenal function directly

Prolong

cytokine

release

Exogenous corticosteroid

decrease

Page 6: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

HIGH RECURENCE

Page 7: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

INCREASE of TNF-A in ENL

Page 8: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

The decrease of Cortisol in ENL

Cortisol Serum in ENL Patient Treated with Corticosteroid Natalia Wahyudi, Sunarso Suyoso, M. Yulianto Listiawan. 2008

17 patients (47,2 %) < 5 μg/dl

15 patients (41,7 %)

5-10 μg/dl

4 patients (11,1 %)

≥ 10 μg/dl

Cortisol Serum in New Multibacilary Patients Ika Christiantika, Sunarso Suyoso, Diah Mira Indramaya

41 (100%) ≥ 10 μg/dl

Page 9: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

TNF-α in Leprosy decreases Cortisol

Page 10: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

• High TNF-α in ENL increases severity of ENL

Anti-TNF-α ?

Cortisol Serum Appropriate time to stop treatment

ENL treated with Corticosteroid

Page 11: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Questions? • How is the profile of serum TNF-A in ENL patients treated

with corticosteroid based on severity scale?

• How is the profile of cortisol serum in ENL patients treated with corticosteroid based on severity scale?

Page 12: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Brief Theory

Page 13: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Erythema Nodosum Leprosum

Page 14: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Reaction Severity Assessment (RSA)

Treatment?

Page 15: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

TNF-α as Primary Cytokine TNF-α?

Page 16: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

The Expression of TNF-α in ENL Circulation?

Page 17: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Treatment Choice in ENL

Page 18: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Thalidomide as an anti TNF-α

Page 19: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Cortisosteroid in ENL

ADRENAL SUPRESSIOn

Page 20: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

The Stimulation of Cortisol

Page 21: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

ENL Chronic release of Cytokine

Chronic release of IL-6

Inhibit production of ACTH

TNF-α depress cortisol synthesis

Cortisol decreases (Adrenal Insufficiency)

Page 22: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Secondary Adrenal Insufficiency

Page 23: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

< 10 μg/dl Adrenal insuficiency

Page 24: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

CONCEPTS of RESEARCH

Page 25: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

METHOD

• Design

Observational descriptive measuring TNF-α, cortisol serum and ENL severity scale in patient treated with corticosteroid

• Samples

21 MB patients with ENL suffer from deterioration during the tapering off of corticosteroid fulfilling inclusion and exclusion criterias

Page 26: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Method…

Inclusion

• Age > 15 years old

• ENL patients treated with corticosteroid

• Agree to participate in research

Exclusions

• Having severe infection: TB, diabetes

• Under hormonal treatment

• pregnancy

• ENL patients never got corticosteroid

Page 27: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Research Scheme

BL or LL type leprosy with ENL

Inclusion and exclusion criteria

Measure ENL severity score (RSA)

Measure TNF-α and Cortisol serum

Data and graphic

Page 28: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

RESULTS

Page 29: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Variabel Tipe Kusta (%)

Jumlah (%) BL LL

Kelompok umur

(tahun)

15 – 24 1 ( 4,7) 4 (19,1) 5 (23,8)

25 – 34

35 – 44

3 (14,3)

3 (14,3)

5 (23,8)

4 (19,1)

8 (38,1)

7 (33,4)

45 – 64 1 ( 4,7) 0 (0) 1 (4,7)

Jumlah 8 (38,0) 13 (62,0) 21( 100)

Jenis kelamin

Laki-laki 5 (23,8) 7 (33,3) 12 (57,1)

Perempuan 3 (14,3) 6 (28,6) 9 (42,9)

Jumlah 8 (38,1) 13 (61,9) 21( 100)

Pengobatan MDT Jumlah (%)

Jumlah BL LL

< 6 bulan 1(4,7) 3 (14,3) 4 (19,0)

≥ 6 bulan 7 (33,3) 4 (19,1) 11 (52,4)

RFT 4 (19,1) 2 (9,5) 6 (28,6)

Jumlah 12 (57,1) 9 (42,9) 21(100,0)

S A M P L E C H A R A C T E R

Distribution of First occurence of ENL with period treatment of MDT (in months)

• Male > female • Mean age 33 ± 9 years old • Type LL > BL

Mean: 8 ± 3 months

Page 30: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

3 (14,3%)

4 (19%)

3(14,3%)

2 (9,5%)

2 (9,5%)

7 (33,3%)

Ringan Sedang Berat

BL LL

Distribution of ENL severity score based on type of leprosy

• RSA (Reaction severity assesment)

• Adjust treatment

Page 31: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Distribution Serum TNF-

based on type of leprosy

1 (4,8%)

0

7 (33,3%)

9 (42,9%)

0

4 (19%)

0.550-2.816 pg/mL

> 2.816-5.90 pg/mL

> 6.0 pg/mL

BL LL

Mean TNF- α total : 4,511 (SD 1,7) pg/mL

Mean TNF- α type BL : 3,919 (SD 1,2)

pg/mL

Mean TNF- α type LL : 4,875 (SD 1,9)

pg/mL

Mean TNF-α type LL > BL Bacteriology index LL >

138N =

Tipe Kusta

LLBL

TNF_

A

10

9

8

7

6

5

4

3

2

Page 32: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Distribution of serum TNF-α based on ENL Severity scale

957N =

Derajat Keparahan ENL

beratsedangringan

TN

F_A

10

9

8

7

6

5

4

3

2

Mean TNF- α in mild ENL : 3,033 (SD 0,3) pg/mL

Mean TNF- α in moderate ENL : 3,685 (SD 0,5) pg/mL

Mean TNF- α in severe ENL : 6,133 (SD 1,3) pg/mL

• TNF-α has protective manner • level >> patologic (ENL) • Indication of admitting anti-TNF-α

Page 33: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Distribution of Serum Cortisol

based on leprosy type

Mean cortisol total : 7,82 (SD

6,1) μg/dL

Mean cortisol BL type : 9,32 (SD

5,2) μg/dL

Mean cortisol LL type : 6,89 (SD

6,6) μg/dL

• ~ Natalia Wahyudi (2008) cortisol <10 μg/dL

Angela (2003) kortisol LL/BL > TT/BT

TNF-α with protective manner > in paucibacilary, cortisol secretion

138N =

Tipe Kusta

LLBL

KO

RTI

SO

L

20

10

0

-10

Page 34: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Distribution cortisol serum based on ENL severity scale

957N =

Derajat Keparahan ENL

beratsedangringan

KO

RT

ISO

L

20

10

0

-10

15

Mean cortisol in mild ENL : 3,35 (SD 4,3) μg/dL

Mean cortisol in moderate ENL: 11,75 (SD 7,0) μg/dL

Mean cortisol in severe ENL : 9,11 (SD 5,1) μg/dL

• ENL severity scale ~ TNF-α

• ENL severity scale ~ cortisol ?

Page 35: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Serum TNF-α based on cortisol serum

TNF_A

98765432

KO

RT

ISO

L

20

10

0

-10 1641N =

Rentang TNF Alfa

tinggisangat tnormal

KO

RT

ISO

L

20

15

10

5

0

-5

-10 0.550 - 2.816 >2.816 - 5.90>2.816 - 5.90>6.0

Increase serum kortisol ~ serum TNF-α

Mean cortisol range normal TNF-α : 1,25 μg/dL

Mean cortisol range high TNF-α : 7,14 (SD 6,0) μg/dL

Mean cortisol range very high TNF-α : 12,15

(SD 4,9) μg/dL

Page 36: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Distribution Period of ENL (in months) treated with corticosteroid

and Serum TNF-α

Mean TNF-α period ENL 1-12 months

: 6,062 (SD 2,2) pg/mL

Mean TNF-α period ENL >12-24 months

: 4,728 (SD 1,4) pg/mL

Mean TNF-α period ENL >24-36 months

: 3,078 (SD 0,3) pg/mL

• Better with treatment (cortikosteroid?)

• Fatigue mechanism

Mean period of ENL 19 ± 7,51 months

Riwayat Lamanya ENL (bulan)

403020100

TNF_

A

9

8

7

6

5

4

3

2

Page 37: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Distribution Period of ENL treated with corticosteroid and Serum

Kortisol

Mean cortisol in range ENL 1-12 months

: 15,23 (SD 2,3) μg/dL

Mean cortisol in range ENL >12-24 months

: 8,75 (SD 4,8) μg/dL

Mean cortisol in range ENL >24-36 months

: 1,17 (SD 0,7) μg/dL

Secondary Adrenal Insufficiency:

• Exposed to chronic cytokine (TNF-α)

• Long term corticosteroid treatement

Riwayat Lamanya ENL (bulan)

403020100

KO

RTI

SO

L

20

10

0

-10

Page 38: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Mean TNF- α total : 4,511 (SD 1,7) pg/mL

Mean TNF- α mild ENL: 3,033 (SD 0,3) pg/mL

Mean TNF- α mpderate ENL: 3,685 (SD 0,5) pg/mL

Mean TNF- α severe ENL : 6,133 (SD

1,3) pg/mL Mean cortisol total : 7,82 (SD 6,1) μg/dL

Mean cortisol in mild ENL: 3,35 (SD 4,3) μg/dL

Mean cortisol in moderate ENL: 11,75 (SD 7,0) μg/dL

Mean cortisol in severe ENL: 9,11 (SD 5,1) μg/dL

Conclusions Severe ENL severity scale 42,9% Mild ENL sverity scale 33,3% Moderate ENL severity scale 23,8%

ENL Severity Scale ~ TNF-α

Increase of cortisol serum ~ TNF-α serum

Secondary Adrenal Insuficiency Chronic exposed of cytokine /

exogenous long-term corticosteroid

1

2

3

4 Mean cortisol in range normal TNF-α : 1,25

μg/dL

Mean cortisol in range high TNF-α : 7,14 (SD 6,0) μg/dL

Mean cortisol in range very high TNF-α : 12,15

(SD 4,9) μg/dL

Adrenal Insufficiency

Mean TNF-α in range ENL 1-12 months

: 6,062 (SD 2,2) pg/mL

Mean TNF-α in range ENL >12-24 months : 4,728 (SD 1,4) pg/mL

Mean TNF-α in range ENL >24-36 months : 3,078 (SD 0,3) pg/mL Mean kortisol in range ENL 1-12 months: 15,23 (SD 2,3) μg/dL

Mean cortisol in range ENL >12-24 months: 8,75 (SD 4,8) μg/dL

Mean cortisol in range ENL >24-36 months: 1,17 (SD 0,7) μg/dL

Page 39: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

Suggestion

• Perform a measurement of cortisol serum in ENL patients with long term corticosteroid. If ≥ 10 μg/dL corticosteroid can be stopped

• TNF-a measurement for severe ENL which doesn’t improve with corticosteroid admit anti TNF-a

• Further research with larger sample size and good study design

Dr. Hansen

Page 40: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,

THANK YOU MERCI BEAUCOUP

Page 41: , Sunarso Suyoso*, Rahmadewi*, TNF- SERUM in VARYING ... · TNF-α and CORTISOL SERUM in VARYING SEVERITY SCALE of ERYTHEMA NODOSUM LEPROSUM TREATED with CORTICOSTEROID Irmadita Citrashanty*,