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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
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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
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• 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
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INCREASE of TNF-A in ENL
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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
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TNF-α in Leprosy decreases Cortisol
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• High TNF-α in ENL increases severity of ENL
Anti-TNF-α ?
Cortisol Serum Appropriate time to stop treatment
ENL treated with Corticosteroid
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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?
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Erythema Nodosum Leprosum
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Reaction Severity Assessment (RSA)
Treatment?
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TNF-α as Primary Cytokine TNF-α?
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The Expression of TNF-α in ENL Circulation?
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Treatment Choice in ENL
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Thalidomide as an anti TNF-α
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Cortisosteroid in ENL
ADRENAL SUPRESSIOn
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The Stimulation of Cortisol
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ENL Chronic release of Cytokine
Chronic release of IL-6
Inhibit production of ACTH
TNF-α depress cortisol synthesis
Cortisol decreases (Adrenal Insufficiency)
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Secondary Adrenal Insufficiency
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< 10 μg/dl Adrenal insuficiency
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CONCEPTS of RESEARCH
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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
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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
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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
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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
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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
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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
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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
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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
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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 ?
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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
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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
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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
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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
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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
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THANK YOU MERCI BEAUCOUP