Clinical significance of serum IL-18 levels for the diagnosis and monitoring of disease activity

Clinical significance of serum IL-18 levels for the diagnosis and monitoring of disease activity

@SJIA_Foundation
@SJIA_Foundation
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2 months ago 411

Presentation from Dr. Masaki Shimizu for NextGen 2024. Dr. Shimizu was the Keynote Speaker and talked about his IL-18 lab work.

Clinical significance of serum IL-18 levels for the diagnosis and monitoring of disease activity

@SJIA_Foundation2 months ago

Clinical significance of serum IL-18 levels for the diagnosis and monitoring of disease activity in systemic juvenile idiopathic arthritis and macrophage activation syndrome

Masaki Shimizu, MD, PhD

Department of Pediatrics and Developmental Biology Institute of Science Tokyo

          Systemic juvenile idiopathic arthritis (s-JIA)

          skin rash

          hepatosplenomegaly

          Textbook of Pediatric Rheumatology 8 th edition, Elsevier

          a systemic inflammatory disorder of unknown etiology and is characterized by arthritis and systemic features, such as spiking fever, skin rash, generalized lymphadenopathy, hepatosplenomegaly, and serositis

                  Role of cytokines in the pathogenesis of s-JIA

                  IL-1β, IL-6 and IL-18 are key cytokines in the pathogenesis of systemic JIA.

                  These cytokines initiate the inflammatory cascade through their effects on the vascular endothelial cells, hypothalamus, liver, bone marrow, and synovial joints, and then drive systemic and joint inflammation.

                          Macrophage activation syndrome (MAS)

                          NK cells

                          a life-threatening complication of s-JIA that occurs in about 5-8% of patients.

                          clinically characterized by continuous fever, hepatosplenomegaly, altered liver function, lymphadenopathy, intravascular coagulation, profound depression of all three blood-cell lines, central nervous system dysfunction and phagocytosis of hematopoietic cells by macrophages in bone marrow examination.

                                  Macrophage activation syndrome (MAS)

                                  Shimizu M. Immunol Med 2021;13:1-9

                                  The hallmark of MAS is uncontrolled immune response involving continual activation and expansion of T lymphocytes and macrophages, resulting in marked hypercytokinemia, namely, cytokine storm.

                                          The diagnostic dilemma, s-JIA or KD ?

                                          Kawasaki Disease

                                          CLINICAL BRIEF

                                          Incomplete Kawasaki Disease Juvenile Idiopathic Arthri ís- The Diagnostic Dilemma

                                          Overlapping clinical manifestations

                                          Fever

                                          Rash

                                          Cervical lymphadenopathy

                                          Arthritis

                                          Coronary artery dilation

                                          CRP↑ GOT↑ Complication of MAS

                                          Scuccimarri R. Pediatr Clin North Am. 2012;59:425-45.

                                          The diagnosis of s-JIA is based on the combination of clinical symptoms and laboratory findings.

                                          Currently, there is no reliable biomarker for the diagnosis of s-JIA.

                                          Therefore, it is sometimes challenging to differentiate s-JIA from other inflammatory diseases.

                                          Kawasaki disease (KD) is much more common in Japan. We often have the diagnostic dilemma, s-JIA or KD, because clinical manifestations of s-JIA and KD are overlapping.

                                                  A case of s-JIA misdiagnosed with KD

                                                  The s-JIA patients misdiagnosed with KD often show severe clinical courses complicated with MAS.

                                                          CQ1.

                                                          What is a useful biomarker for the diagnosis of s-JIA ?

                                                                  Serum cytokine levels in patients with s-JIA

                                                                  • IL-1β was not detected in most patients with s-JIA.

                                                                  De Benedetti F, et al. Clin Exp Rheumatol. 1995;13:779-84.

                                                                  Serum IL-6 and sTNF-RII levels were significantly elevated in patients with s-JIA.

                                                                  However, these levels were not useful for the differentiation between s-JIA and KD.

                                                                          Serum cytokine levels in patients with s-JIA

                                                                          Serum IL-18 levels were massively elevated in patients with s-JIA and was useful for the differentiation between s-JIA and other diseases.

                                                                                  Serum cytokine levels in patients with s-JIA

                                                                                  Shimizu M et al. Rheumatology 2010;49:1645-1653

                                                                                  The patterns of serum cytokine profile are characteristic in each disease and are useful for the differentiation between s-JIA and other inflammatory diseases associated with MAS.

                                                                                          Cut off value of serum IL-18 levels for the differentiation between s-JIA and other diseases

                                                                                          Mizuta M, et al. Rheumatology. 2021;60:2421-2426

                                                                                        The cutoff value of serum IL-18 levels >4,800 pg/mL might be useful for the differentiation of s-JIA from other diseases.

                                                                                                Serum IL-18 levels

                                                                                                as a biomarker for the diagnosis of s-JIA

                                                                                                Kaneko S, et al. Cytokine 2024. in press

                                                                                              • · We evaluated the performance of the PRINTO criteria compared with the ILAR criteria and determined whether serum IL-18 levels improve their diagnostic performances.
                                                                                              • · The PRINTO criteria had higher sensitivity but lower specificity than the ILAR criteria.
                                                                                              • · With the addition of serum IL-18 levels ≥ 4,800 pg/mL, the sensitivity of the ILAR criteria and specificity of the PRINTO criteria were improved to 1.000 and 1.000, respectively.
                                                                                              • · Serum IL-18 levels could improve the diagnostic performance of the PRINTO and ILAR criteria for s-JIA. The PRINTO criteria plus serum IL-18 levels ≥ 4,800 pg/mL could be the best diagnostic performance for s-JIA.

                                                                                                      CQ2.

                                                                                                      Is serum IL-18 level useful for the monitoring of disease activity in s-JIA?

                                                                                                              Disease courses of s-JIA

                                                                                                              Monophasic

                                                                                                              a single episode of active disease not lasting more than 24 months, followed by inactive disease and without recurrence of active disease during the follow-up period

                                                                                                              Polycyclic

                                                                                                              active disease for any period of time, followed by inactive disease for any period of time and then recurrence of active disease.

                                                                                                              Persistent

                                                                                                              active disease for more than 24 months' duration

                                                                                                                      Serum IL-18 levels as an indicator of disease activity of s-JIA

                                                                                                                      Shimizu M et al. Rheumatology 2010;49:1645-1653

                                                                                                                      Serum IL-18 levels markedly rose with the development of the complication of MAS, but gradually reduced after this manifestations resolved. However, even a few weeks after normalization of other inflammatory markers, IL-18 levels were still well above the normal value. In this patient, MAS was frequently complicated in this phase with high levels of serum IL-18.

                                                                                                                              Serum IL-18 levels as an indicator of disease activity of s-JIA

                                                                                                                              Serum IL-18 levels change in agreement with the disease course and reflect disease activity of s-JIA.

                                                                                                                                      Prognosis of s-JIA

                                                                                                                                      Takei S. Japanese J of Clin Med 2014;72:1854-60

                                                                                                                                      It seems that there are different subtypes in s-JIA, chronic arthritis type and systemic type.

                                                                                                                                              CQ3.

                                                                                                                                              Are there different subtypes of s-JIA based on cytokine expression pattern?

                                                                                                                                                      Distinct clinical features of the 2 s-JIA subsets based on their serum IL-6 and IL-18 levels

                                                                                                                                                      Shimizu M et al. Clin Immunol 2015;160:277-81

                                                                                                                                                      There were 2 subsets of patients with s-JIA based on their serum IL-6 and IL-18 levels: IL-6-dominant and IL-18-dominant subset.

                                                                                                                                                      • IL-6-dominant subset had more severe joint disease, whereas IL-18-dominant subset had a more severe systemic disease and developed MAS.

                                                                                                                                                              CQ4.

                                                                                                                                                              Are Serum IL-18 levels useful for the prediction and diagnosis of MAS?

                                                                                                                                                                      Interleukin-18

                                                                                                                                                                      for predicting the development of MAS

                                                                                                                                                                      Shimizu M et al. Clin Immunol. 2015 ; 160 : 277-81

                                                                                                                                                                    To determine clinical significance of serum IL-18 levels as a parameter to predict MAS development, we compared serum IL-18 levels in s-JIA patients with active disease who later developed MAS (MAS+) and those who did not (MAS-).

                                                                                                                                                                    Serum IL-18 levels in MAS+ patients were significantly higher than in MAS- patients.

                                                                                                                                                                    The receiver operating characteristic curve analysis indicated that the cutoff for serum IL-18 levels to predict MAS development was 47,750 pg/mL with a sensitivity of 86.7% and a specificity of 70.5% .

                                                                                                                                                                            Interleukin-18

                                                                                                                                                                            for predicting the development of MAS

                                                                                                                                                                            In contrast, there was no significant difference in serum IL-18 levels in MAS+ patients whether measured before or during MAS. Serum IL-18 levels might not be useful for the diagnosis of MAS.

                                                                                                                                                                                    CQ5.

                                                                                                                                                                                    What is a useful biomarker for the diagnosis of MAS ?

                                                                                                                                                                                            Extensive cytokine expression analysis in MAS patients revealed CXCL9 might be a useful for the diagnosis of MAS

                                                                                                                                                                                            Mizuta M et al. Cytokine 2019;119 : 182-187

                                                                                                                                                                                            To identify the serum biomarkers for the diagnosis of MAS, we employed an antibody array that simultaneously detects 174 cytokines.

                                                                                                                                                                                            CXCL9 showed the most significant increase following the development of MAS.

                                                                                                                                                                                                    Comparison of serum biomarkers for the diagnosis of MAS

                                                                                                                                                                                                    Takakuwa M, et al. Clin Immunol 2019:208:108252.

                                                                                                                                                                                                    We compared the accuracy of serum biomarkers for the diagnosis of MAS.

                                                                                                                                                                                                    Receiver operating characteristic curve analysis revealed serum neopterin as well as CXCL9 levels is a useful marker to diagnose the transition to MAS from active-phase of s-JIA.

                                                                                                                                                                                                            Biologics modify clinical and laboratory findings of MAS

                                                                                                                                                                                                            Schulert GS et al. Arthritis Care Res 2018; 70: 409-419 より引用-部改変

                                                                                                                                                                                                            Treatment with biologics targeting IL-1 and IL-6 show a dramatic clinical effects for s-JIA. However, these drugs can modify and mask the clinical symptoms of MAS.

                                                                                                                                                                                                                    The diagnostic significance of IL-18

                                                                                                                                                                                                                    as a biomarker of s-JIA and MAS during TCZ therapy.

                                                                                                                                                                                                                    Increase of serum IL-18 levels in s-JIA and MAS were not suppressed by TCZ.

                                                                                                                                                                                                                    Increase of serum IL-18 levels in s-JIA and MAS were not suppressed by CAN too.

                                                                                                                                                                                                                    Serum IL-18 may be a useful biomarker of s-JIA and MAS even during the treatment with IL-1/IL-6 inhibitors.

                                                                                                                                                                                                                    Shimizu M et al. Cytokine 2012; 58: 287-294

                                                                                                                                                                                                                            Is this episode MAS?

                                                                                                                                                                                                                            Patient 1: 8 years old boy with s-JIA receiving canakinumab and in remission

                                                                                                                                                                                                                            He received canakinumab on Jan 18.

                                                                                                                                                                                                                            He visited us with fever persisting 2 days and arthralgia on Feb 22.

                                                                                                                                                                                                                                    Is this episode MAS?

                                                                                                                                                                                                                                    Patient 2: 5 years old girl with s-JIA receiving tocilizumab and in remission

                                                                                                                                                                                                                                    She received tocilizumab on Oct 3.

                                                                                                                                                                                                                                    She visited us with fever persisting 4 days on Oct 23.

                                                                                                                                                                                                                                            Is this episode MAS?

                                                                                                                                                                                                                                                    CQ5.

                                                                                                                                                                                                                                                    What is the role of IL-18 in the pathogenesis of MAS?

                                                                                                                                                                                                                                                            New murine model of MAS

                                                                                                                                                                                                                                                            Day1 Day8 Day10

                                                                                                                                                                                                                                                            Pump insert

                                                                                                                                                                                                                                                            CpG injection

                                                                                                                                                                                                                                                            C57BL/6

                                                                                                                                                                                                                                                            Normal Sarine IL-1β IL-18 IL-1β+IL-18

                                                                                                                                                                                                                                                            MAS

                                                                                                                                                                                                                                                          Mizuta M, et al. J Allergy Clin Immunol. 2023;152:940-948

                                                                                                                                                                                                                                                          To clarify the role of IL-18 and IL-1β in the pathogenesis of MAS, we developed a mouse model to evaluate the role of each cytokine with TLR9 stimulation after continuous infusion with IL-18, IL-1β, and a combination of both for 7 days.

                                                                                                                                                                                                                                                                  Clinical manifestations after CpG injection

                                                                                                                                                                                                                                                                  Body weight was significantly decreased in the IL-1β and the combination groups. Splenomegaly was observed in all groups, whereas hepatomegaly was noted in IL-18 group only.

                                                                                                                                                                                                                                                                          Laboratory findings after CpG injection

                                                                                                                                                                                                                                                                          Decreased T cell numbers, anemia, and thrombocytopenia were observed in the combination group.

                                                                                                                                                                                                                                                                                  Cytokine mRNA expression levels after CpG injection

                                                                                                                                                                                                                                                                                  IFN-γ, CXCL9, and IL-12A mRNA levels were upregulated and IL-10 mRNA levels in the spleen were downregulated in the IL-18 group.

                                                                                                                                                                                                                                                                                          Cytokine mRNA levels were regulated by IL-18 in a dose-dependent manner

                                                                                                                                                                                                                                                                                          Mizuta M, et al. J Allergy Clin Immunol. 2023;152:940-948

                                                                                                                                                                                                                                                                                          TNF-α, CXCL9, and IL-12A mRNA levels were upregulated, IL-10 mRNA was downregulated only in mice with extremely elevated plasma IL-18 levels.

                                                                                                                                                                                                                                                                                                  Distinct roles of IL-18 and IL-1β in murine model of MAS

                                                                                                                                                                                                                                                                                                  Distinct roles of IL-18 and IL-1ß in murine model of macrophage activation syndrome

                                                                                                                                                                                                                                                                                                  Mizuta M, et al. J Allergy Clin Immunol. 2023;152:940-948

                                                                                                                                                                                                                                                                                                  IL-18 and IL-1β have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1β might be necessary to treat MAS.

                                                                                                                                                                                                                                                                                                          Conclusions

                                                                                                                                                                                                                                                                                                          • · Serum IL-18 level is a useful biomarker for the diagnosis and monitoring of disease activity of s-JIA.
                                                                                                                                                                                                                                                                                                          • · There are 2 subsets of s-JIA patients with distinct clinical features based on their serum IL-6 and IL-18 levels.
                                                                                                                                                                                                                                                                                                          • · Serum IL-18 level is useful for the prediction of the development of MAS.
                                                                                                                                                                                                                                                                                                          • · Serum neopterin and CXCL9 levels are useful biomarkers for the diagnosis of MAS.
                                                                                                                                                                                                                                                                                                          • · Serum cytokine profile including IL-18 and CXCL9 is useful for understating the pathology in patients with s-JIA, in particular, in patients receiving biologics.
                                                                                                                                                                                                                                                                                                          • · IL-18 and IL-1β have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1β might be necessary to treat MAS.
                                                                                                                                                                                                                                                                                                                  • Thank you for your attentions.

                                                                                                                                                                                                                                                                                                                    Pediatric Rheumatology and Nephrology Team

                                                                                                                                                                                                                                                                                                                    in Kanazawa University and Institute of Science Tokyo

Clinical significance of serum IL-18 levels 
for the diagnosis and monitoring of disease activity …
1/40
Systemic juvenile idiopathic arthritis (s-JIA)
a systemic inflammatory disorder of unknown etiolog…
2/40
Role of cytokines in the pathogenesis of s-JIA
Mellins ED, et al. Nat Rev Rheumatol. 2011;7:416-26…
3/40
Macrophage activation syndrome (MAS)
s-JIA
Viral infections
Drugs
IFN-γ ↑↑
• Continuous fever
…
4/40
The hallmark of MAS is uncontrolled immune response involving continual activation and expansion of…
5/40
Fever
Rash
Cervical lymphadenopathy
Arthritis
Coronary artery dilation
CRP↑ GOT↑ Complication …
6/40
Kinjo N et al J Clin Apher. 2018;33:117-120
CRP 
(mg/dl)
Feve
rRas
h
IVI
G
IF
X
mPS
L
T…
7/40
CQ1. 
What is a useful biomarker for the diagnosis of s-JIA?
8/40
Serum cytokine levels in patients with s-JIA
Serum IL-6 and sTNF-RII levels were significantly ele…
9/40
Serum cytokine levels in patients with s-JIA
Mizuta M, et al. Rheumatology. 2021;60:231-238.
Mizu…
10/40
The patterns of serum cytokine profile are characteristic in each disease and are useful for the di…
11/40
Serum IL-18 level (pg/ml)
median / range Cutoff value AUC
s-JIA 34,750 (3,000-340,000)
KD 360 (6…
12/40
Serum IL-18 levels
as a biomarker for the diagnosis of s-JIA 
ILAR criteria PRINTO criteria
ILAR…
13/40
CQ2.
Is serum IL-18 level useful 
for the monitoring of disease activity in s-JIA?
14/40
Disease courses of s-JIA
Singh-Grewal D et al. Arthritis Rheum. 2006;54:1595–1601
Disease activit…
15/40
Serum IL-18 levels 
as an indicator of disease activity of s-JIA
MAS MAS MAS relapses relapse
Se…
16/40
106
105
104
103
102
Disease activity
polycyclic
(days)
106
105
104
103
102
Systemic sy…
17/40
0
0.
2
0.
4
0.
6
0.
8
1
0 5 1
0
1
5
persistent(n=18)
Monophasic and polycyclic
(n=4…
18/40
CQ3.
Are there different subtypes of s-JIA 
based on cytokine expression pattern?
19/40
● MAS
Distinct clinical features of the 2 s-JIA subsets 
based on their serum IL-6 and IL-18 leve…
20/40
CQ4.
Are Serum IL-18 levels useful 
for the prediction and diagnosis of MAS?
21/40
Interleukin-18 
for predicting the development of MAS
Cut off value 47750 pg/ml
Sensitivity 86.7…
22/40
Interleukin-18 
for predicting the development of MAS
P<0.0001
P<0.0001
MAS -
MAS +
MAS
phas…
23/40
CQ5.
What is a useful biomarker for the diagnosis of MAS?
24/40
Low middle high
MAS
Active
TCZ(+)
MAS
Active(MAS+)
Active(MAS-)
TCZ(-)
Extensive cytokine e…
25/40
Biomarkers Cut off values Area under the ROC curve values
Neopterin 19.5 0.9465
CXCL9 3130 0.9333…
26/40
Schulert GS et al. Arthritis Care Res 2018; 70: 409-419より引用一部改変
Biologics modify clinical and labo…
27/40
Shimizu M et al. Cytokine 2012; 58: 287-294 
The diagnostic significance of IL-18 
as a biomarker…
28/40
Is this episode MAS?
Patient 1: 8 years old boy with s-JIA receiving canakinumab and in remission …
29/40
Is this episode MAS?
Patient 2: 5 years old girl with s-JIA receiving tocilizumab and in remission…
30/40
Is this episode MAS?
Patient 1 Patient 2
IL6
IL-1
8
103
3x103
3x104
105
50
30
10
100
…
31/40
CQ5.
What is the role of IL-18 in the pathogenesis of MAS?
32/40
Day1 Day8 Day10
Pump insert    CpG injection
C57BL/6
Normal Sarine
IL-1β
IL-18
IL-1β+IL-18
M…
33/40
*** ***
IL-18+IL-1β+CpG
IL-1β+CpG
Body weight was significantly decreased in the IL-1β and the c…
34/40
Laboratory findings after CpG injection
WBC (x 10
2/μL)
RBC (x 10
4/μL)
*
ferritin (ng/mL)
N…
35/40
IL-18+IL-1β
IL-18
IL-1β
NS
Untreated
IFN-γ/GAPDH
*
***
*
**
*** ***
IL-18+IL-1β
IL-18
…
36/40
*
***
**
**
*
TNFα/GAPDH
* ***
IFN-γ/GAPDH
TNF-α/GAPDH
Cytokine mRNA levels were regulated…
37/40
Distinct roles of IL-18 and IL-1β 
in murine model of MAS
Mizuta M, et al. J Allergy Clin Immunol…
38/40
Conclusions
• Serum IL-18 level is a useful biomarker for the diagnosis and monitoring of disease …
39/40
Thank you for your attentions.
Pediatric Rheumatology and Nephrology Team
in Kanazawa University …
40/40


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