Faculty of Medicine,
Cairo University
Clinical significance of
interleukin-23 and gene
polymorphism in Behçets disease
Tamer A Gheita, MD
Professor of Rheumatology and Clinical Immunology,
Faculty of Medicine, Cairo University
Egypt
The following will be considered:
 Behçet’s disease
 Interleukin-23
 The Clinical Study
 Behçet’s disease
 Behçet’s disease: Historical Background
Behçet’s
disease (BD) is a multisystemic
vasculitis and chronic relapsing inflammatory
disease of unknown cause, characterized by
recurrent oral ulcers, genital ulcers, uveitis
and skin lesions [1]
 Behçet’s disease
Historical Background
 Behçet’s disease: Historical Background
Behçet's disease (BD) refers to Halusi Behçet
(1889-1948), a Turkish dermatologist who
recognized the triple-complex of recurrent
oral ulcers, genital ulcers and uveitis.
In
1936, he published it in Archives of
Dermatology and Venereal Disease
[2]
Halusi Behçet
(1889-1948)
An initial description was also made 1930 by Benedict
Adamantiades (1875-1962) the Greek ophthalmologist from
Prussia, Asia minor (nowadays Bursa, Turkey) who presented
‘A case of relapsing iritis with hypopyon’ [3].
 Behçet’s disease
Epidemiology
 Behçet’s disease: Epidemiology
Prevalence: The highest prevalence is reported along the
ancient Silk route extending from Eastern Asia to the
Mediterranean basin [4,5]
Ancient Silk route
 Behçet’s disease: Epidemiology
Global distribution of BD: Dot size reflects prevalence [6,7]
Turkey has the highest prevalence (80-370 cases/100.000). It is
lower in UK (0.64 cases) and about 0.2 cases/100.000 in USA.
 Behçet’s disease: Epidemiology
In Germany, the prevalence among citizens of Turkish origin is
21/100.000, which is lower than that in Turkey but far higher
than that among German natives [1,8].
Onset: is typically in the 3rd- 4th decade of life [6].
Gender preference: More common in males in the Middle East
while in Japan/Korea (Far East), females are more affected [4,8,9].
A more equal M:F ratio has been shown [10].
Frequency within families: is 2-5%, (10-15% in Middle East) [11].
Rate among twins: is unknown, however a pair of concordant
monozygotic twins and 2 discordant pairs were described [12,13].
 Behçet’s disease
Etiopathogenesis
 Behçet’s disease: Etiopathogenesis
The pathogenesis of BD is still a mystery.
There is consensus on the effect of possible environmental
factors as infectious agents being responsible for triggering
an immunological reaction and systemic features of BD in
genetically susceptible individuals [14].
 Behçet’s disease: Etiopathogenesis
Many factors play a role in the pathogenesis of BD:
 Genetic
Susceptibility is strongly associated with the presence of HLA-B51 allele [1]
Infection
HSV and Streptococci
Bacterial/viral antigens may cross react with human peptides
Autoimmunity
 Endothelial and vascular dysfunction
Apoptosis
Interesting immunological data promise a way out of the existing dilemma
 Behçet’s disease: Etiopathogenesis
Etiopathogenesis of Behçet’s disease.
TNF, tumor necrosis factor; IL, interleukin; CTLA-4, cytotoyic T-lymphocyte antigen-4
[6,7].
 Behçet’s disease: Etiopathogenesis
Genetic factor:
The prevalence of the HLA-B51 allele is
high among BD patients (81% of Asians
and 13% in Western countries) [15].
Computer illustration of HLA-B*5101
with HIV peptide in the binding pocket.
Identification of genes responsible for this susceptibility may
lead to more definitive diagnostic tests and new approaches
to the management of this potentially blinding condition [14].
 Behçet’s disease: Etiopathogenesis
Genes as:
 HLA-B51,
 MHC-class-I-Chain-related gene A (MICA) and
 Tumor necrosis factor (TNF)
are located on chromosome 6 of MHC and play a crucial role
Only HLA-B51 is directly related to the pathogenesis; Other
disease related genes have strong linkage disequilibrium with
HLA-B51 [10, 16-19].
The search for genes related to BD continues [20].
 Behçet’s disease: Etiopathogenesis
Role of Cytokines:
In BD, the overproduction of proinflammatory cytokines
constitutes an important aspect
[21].
and are considered
markers of disease activity [10, 17, 22,23].
A central pathogenetic role of TNF in the inflammatory process
of BD has been suggested and a therapeutic benefit of TNF-α
blockers has been reported
[24,25].
 Behçet’s disease
Diagnosis
 Behçet’s disease: Diagnosis
Behçet's disease
- can present in a myriad of ways
- can involve nearly every organ & system and
- has a tendency to recur.
 Behçet’s disease: Diagnosis
Manifestations of BD are extremely diverse:
Clinical spectrum ranges from mild mucocutaneous lesions
to severe ocular, vascular or neurological disability [24,26,27]
Mucocutaneous manifestations constitute the hallmark,
while uveitis, meningoencephalitis and large vessel disease
are the most serious [28].
Diagnosis is sometimes difficult to confirm as there are no
pathognomonic laboratory findings [10]
 Behçet’s disease: Diagnosis
Diagnostic criteria:
The most commonly used is the 1990 International Study
Group (ISG) Criteria (sensitivity =91% and specificity =96%)[29]
A major limitation of these criteria is the inability to diagnose
BD in the absence of recurrent oral ulceration [30].
 Behçet’s disease: Diagnosis
ISG Criteria for diagnosis of Behcet’s disease.
Criterion
Recurrent
Oral ulcers
Definition
Minor/major aphthous or herpetiform ulceration
(observed by physician/patient) which recurs at least 3 times/year
Plus two of the following criteria
Recurrent
Genital ulcers
Aphthous ulceration or scarring observed by physician or patient
Eye lesions
Anterior/posterior uveitis, or cells in vitreous on slit lamp examination;
or retinal vasculitis observed by ophthalmologist.
Skin lesions
Erythema nodosum observed by physician/patient, pseudofolliculitis,
papulopustular lesions; or acneform nodules observed by physician in
postadolescent patients not on corticosteroid treatment.
+ve pathergy test Read by physician at 24-48 hours.
Findings are applicable only in absence of other clinical explanations. Presence of recurrent oral
ulcers and any 2 of the remaining criteria yields a sensitivity of 91% and specificity of 96% [29]
 Behçet’s disease: Diagnosis
Aphthous ulcer of the labial mucosa [31]
Uveitis
[ NHS Wales]
 Behçet’s disease: Diagnosis
Papulo-pustules
[Quizlet]
Erythema nodosum
[Medical Point]
 Behçet’s disease: Diagnosis
The frequency of clinical manifestation of BD is:
Oral ulcers (100%), followed by
genital lesions (80-100%), then
ocular lesions (50-79%), and followed by
skin lesions (35-60%).
Arthritis comes 5th (30-50%), followed by
major vessel occlusion/aneurysm (10-37%), then
neurological involvement (10-30%) and finally
gastrointestinal involvement (0-25%) [32].
 Behçet’s disease
Disease activity
 Behçet’s disease: Disease activity
The Behçet’s Disease Current Activity Form (BDCAF)
scoring appears to be relatively simple to use, reliable
and free of bias [33].
 Behçet’s disease: Disease activity
 Behçet’s disease: Disease activity
Scoring system for Activity form:
Scoring depends on the symptoms present over the preceding 4 weeks prior to assessment. Only clinical features that the clinician feels are due to BD should be scored.
(1) To complete the self rating scale of overall wellbeing for the last 4 weeks, please ask the patient the following question:
“Here are some faces expressing various feelings, thinking about your Behçet’s disease only, which of these faces describe how you have been feeling over the last 4 weeks?”
To complete the self rating scale of wellbeing Today, please ask the patient the following question:
“Here are some faces expressing various feelings, thinking about your Behçet’s disease only, which of these faces describe how you feel today?”
(2) Scoring for fatigue, headache, oral and genital ulceration, skin lesions, joint symptoms, and gastrointestinal symptoms is based on duration of symptoms
(round up to nearest week). Please ask “Over the last 4 weeks, for how many weeks in total have you had………?”
0
1
2
3
4
No symptoms
Symptoms for 1 week
Symptoms for 2 weeks
Symptoms for 3 weeks
Symptoms for 4 weeks
(1-7 days in total)
(8-14 days in total)
(15-21 days in total)
(22-28 days in total)
(3) Eye involvement: Eye activity may be present if the following symptoms are present:
Red eye
Blurred vision
Painful eye
Please ask the following question (Tick if symptom is present): “Over the last 4 weeks have you had a red eye_, a painful eye_ or a blurred or reduced vision_?”
If any of these symptoms are present or if you feel there may be eye activity refer patient to ophthalmologist who will determine the eye score (Behçet’s Oculopathy Index)
Nervous system:
Please ask the following question (Tick if symptom is present):
“Over the last 4 wks have you had any blackouts_, difficulty of speech or hearing, double vision, weakness or loss of feeling in the face, arm or leg_, memory loss_ or loss of balance_?”
If the answer to all these is ‘no’ then answers to Q1-5 are deemed negative; otherwise determine the following:
Q1. Are there new symptoms or signs consistent with meningeal involvement?
Q2. Are there new symptoms or signs consistent with isolated cranial nerve involvement?
Q3. Are there new symptoms or signs consistent with brainstem or cerebellar involvement?
Q4. Are there new symptoms or signs consistent with cerebral hemisphere involvement?
Q5. Are there new symptoms or signs consistent with spinal cord involvement?
Major vessel involvement (exclude neurological involvement):
Please ask the following question (Tick if symptom is present):
“Over the last 4 weeks have you had chest pain_, breathlessness_,coughed up blood_,or had any pain, swelling or discoloration of either the face_, arm_or leg_?”
If the answer to all these is ‘no’ then answers to Q1-4 are deemed negative; otherwise determine the following:
Q1. Are there new symptoms or signs consistent with peripheral deep venous thrombosis?
Q2. Are there new symptoms or signs consistent with central deep venous thrombosis?
Q3. Are there new symptoms or signs consistent with peripheral arterial thrombosis/aneurysm?
Q4. Are there new symptoms or signs consistent with pulmonary arterial thrombosis/aneurysm?
 Behçets disease
Management
 Behçet’s disease: Management
Therapeutic approach to BD.
.
TNF: Tumor Necrosis Factor, IFN: Interferon [6,7]
 Interleukin-23
 Interleukin-23
Over the last decade our knowledge of the role of IL-23 and
IL-17 cytokine pathways in immunity and immune-mediated
inflammatory diseases, has grown exponentially [34].
 Interleukin-23
IL-23 is a member of the IL-12 family of cytokines with proinflammatory properties.
Its ability to potently enhance the expansion of T helper 17
(Th17) cells indicates the responsibility for many of the
inflammatory autoimmune responses.
It is a key participant in central regulation of the cellular
mechanisms involved in inflammation. Both IL-23 and IL-17
form a new axis through Th17 cells
 Interleukin-23
Function of interleukin (IL)-12 and IL-23 on effector cells.
IL-12-specific effects are designated red; IL-23-specific effects are designated green; Properties of both in blue.
CXCL, chemokine (C-X-C) motif; IFNγ, interferon gamma; GMCSF, granulocyte macrophage colony stimulating factor;
NKT, natural killer cells; TNFα, tumor necrosis factor.
 Interleukin-23
Ustekinumab mechanism of action.
Ustekinumab binds to the p40 subunit of interleukin (IL)-12 and IL-23 and prevents their interaction with the
cell surface IL-12Rβ1 receptor, subsequently inhibiting IL-12- and IL-23-mediated cell signaling, activation and
cytokine production (image not drawn to scale). NK, natural killer. [35].
 Interleukin-23
Targeting of IL-23, its receptor or axis is a potential
therapeutic
approach
for
autoimmune
diseases
including psoriasis, inflammatory bowel disease (IBD),
rheumatoid arthritis (RA) and multiple sclerosis (MS)
[36].
 The Clinical Study
 The Clinical Study
Clinical significance of serum interleukin-23 and A/G gene
(rs17375018) polymorphism in Behçet’s disease:
relation to neuro-Behçet, uveitis and disease activity
Tamer A Gheita1, Sherif M Gamal1 , Ihab Shaker2, Hussein S El Fishawy3, Rehab El Sisi4, Olfat G Shaker5, Sanaa A Kenawy 6
1Rheumatology Department,
Faculty of Medicine, Cairo University
2Neuropsychiatry Department, Faculty of Medicine, Cairo University
3internal Medicine Department, Faculty of Medicine, Cairo University
4Oral and Maxillofacial Surgeon, Faculty of Oral & Dental Medicine, Cairo University
5Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University
6Clinical Pharmacology Department, Faculty of Pharmacy, Cairo University
 The Clinical Study
Letter to the Editor
Joint Bone Spine, 2015; 82:209–17
 The Clinical Study
Background
 The Clinical Study: Background
A substantial body of knowledge has accumulated supporting
a strong genetic underpinning in BD of the MHC-related
allele HLA-B51 1.
Identification of additional genetic susceptibility loci has
clearly caught up 1.
IL-23 is involved in the pathogenesis of BD. A strong
association of IL-23R single nucleoprotein (rs17375018) was
found with BD in a Chinese population 2.
Rs (Ref SNP): Reference single-nucleotide polymorphisms
 The Clinical Study
Aim of the work
 The Clinical Study: Aim of the work
The aim of this work was to measure the level of serum
IL-23 and assess IL-23R (rs17375018) genotypes in
Behçet’s disease (BD) patients and to study the clinical
significance and relation to disease activity.
Rs (Ref SNP): Reference single-nucleotide polymorphisms
 The Clinical Study
Patients and Methods
 The Clinical Study: Patients and Methods
50 BD patients 3 (M:F 41:9) were recruited from Cairo University
Hospitals. Disease activity was assessed using BDCAF 4.
The study conforms to the 1995 Helsinki declaration.
All patients gave their informed consent prior to their inclusion.
30 age and sex matched control were also included.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Serum IL-23 was quantified by ELISA
(Hu IL-23 Heterodimer kit, BioSource immunoassay, Europe S.A. Nivelles, Belgium).
IL-23R (rs17375018) was genotyped by Real-time PCR-based
allelic discrimination (QIA- Amp DNA-Minikit, Qiagen, Germany).
 The Clinical Study
Results
 The Clinical Study: Results
Table 1: Characteristics, serum IL-23 and IL-23R genotype in BD patients.
Feature (mean±SD)
Age (years)
Disease duration (years)
BMI
BDCAF
Steroid dose
(mg/d)
Colchicine dose (mg/d)
Hemoglobin
(g/dl)
3
TLC
(x10 /mm3)
Platelets (x103/ mm3)
ESR (mm/1st hr)
Hs-CRP (mg/dl)
BD patients (50)
35.2 ±7.2
8.6 ±5.9
26.7 ±4.2
2.6 ±1.5
12.3 ±8.8
0.97 ±0.5
12.9 ±1.1
7.8 ±2.3
292.2 ±76.9
36.1 ±20.7
6.1 ±8.03
Interleukin-23 (pg/ml)
37.1 ± 12.2
IL23R (rs17375018) genotype
AA
AG
GG
n (%)
8 (16)
18 (36)
24 (48)
BMI: Body mass index , BDCAF: Behcets disease current activity form, TLC: Total leucocytic
count, ESR: Erythrocyte sedimentation rate, hs-CRP: Highly sensitive-C-reactive protein
Serum IL-23 was significantly higher in patients compared to control (21.9±6.3 pg/ml; p<0.0001)
and in females (47.3±13.6 pg/ml) compared to males (34.9±10.8pg/ml; p=0.03).
 The Clinical Study: Results
Table 2: Serum IL-23 level according to the presence and absence of
clinical characteristics in Behçet’s disease (BD) patients.
Clinical Characteristic
n (%)
Oral ulcers
50 (100)
Genital ulcers
41 (82)
Uveitis
24 (48)
Skin lesions
37 (74)
Neuro-Behçets 19 (38)
Pulmonary
11 (22)
Arthritis
19 (38)
DVT
17 (34)
FMS
12 (24)
+ve pathergy
14 (28)
Serum IL-23 (pg/ml) in BD patients (n=50)
Presence
Absence
p value
36.6±12.03 39.5 ±14.6
0.61
42.6±12.9
32.04 ± 9.1
0.002
38.6±12.4
32.9 ±11.2
0.13
42.6±14.4
33.7 ± 9.4
0.02
38.2±12.8
36.8 ±12.2
0.75
37.6±12.5
36.8 ±12.3
0.84
41.3±10.3
34.9 ±12.7
0.06
43.7±12.9
35.04 ±11.4
0.054
41.5±12.1
35.4 ±12
0.13
DVT: deep venous thrombosis, FMS: fibromyalgia syndrome.
Only nine of those with uveitis had concomitant neuro-Behçet.
IL23 level significantly correlated with BDCAF (r=0.62,p<0.0001) and
disease duration (r=0.42,p=0.002).
 The Clinical Study: Results
IL23R genotypes
were comparable between patients and control
AA 8/50(16%) vs 6/30(20%), AG 18/50(36%) vs 10/30(33.3%), GG 24/50(48%) vs 14/30(46.7%) (p>0.05)
were similar according to gender.
in neurobehçets was AA(5.3%), AG(36.8%), GG(57.9%)
and those without: AA(22.6%),AG(35.5%),GG(41.9%)
in those with uveitis had AA(8.3%), AG(33.3%), GG(58.3%)
while those without had AA(23.1%),AG(38.5%), GG(38.5%).
BDCAF was significantly lower in AA genotype (1.88±1.13)
compared to AG (2.06±1.39) and GG (3.17±1.49) patients (p=0.02)
 The Clinical Study
Conclusions
 The Clinical Study: Conclusions
 Serum IL-23 level was significantly increased in BD patients.
Serum IL-23 level was significantly higher in BD patients with
 uveitis. This confirms the findings of others 5.
neuro-Behçet's.
A crucial role for IL-6/IL-15 in the pathogenesis of neuro-Behçet‘s was found.
The precise role of IL-23 remains elusive. IL-23R is upregulated by IL-6 6-8.
Serum IL-23 level significantly correlated with BD activity.
This is in accordance to the result of Na et al.9.
There was a tendency to elevated IL23 in BD patients with FMS.
Cytokine involvement in FMS was favored 10.
 GG-genotype was higher with neuro-Behçet's and uveitis
GG-genotype was reported to be of higher prevalence in BD patients 2.
 The Clinical Study: Conclusions
This is the first study to report the possible role played
by IL-23 and IL-23R gene polymorphism in neuroBehçet's (and not only uveitis) with a significant relation
to disease activity making both potential markers.
Larger scale longitudinal studies are required to confirm
the role of IL-23 and IL-23R gene polymorphism in
neuro-Behҫet and to study their impact on the response
to therapy.
Cairo University
Kasr Al-Ainy
School of Medicine
Thank You
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