Clinical significance of interleukin-23 and gene polymorphism in Behçets disease Tamer A Gheita, MD...

Clinical significance of interleukin-23 and gene

polymorphism in Behçets disease

Tamer A Gheita, MDProfessor of Rheumatology and Clinical Immunology,

Faculty of Medicine, Cairo University

Egypt

Faculty of Medicine, Cairo University

The following will be considered:

Behçet’s disease Interleukin-23 The Clinical Study

Behçet’s disease

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

Historical Background

Behçet’s disease

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]

Behçet’s disease: Historical Background

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].

Epidemiology

Behçet’s disease

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

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.

Global distribution of BD: Dot size reflects prevalence [6,7]


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].

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].


Etiopathogenesis

Behçet’s disease

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

Genetic

Infection

Autoimmunity

Endothelial and vascular dysfunction Apoptosis

Interesting immunological data promise a way out of the existing dilemma

Susceptibility is strongly associated with the presence of HLA-B51 allele [1]


Many factors play a role in the pathogenesis of BD:

HSV and StreptococciBacterial/viral antigens may cross react with human peptides

Etiopathogenesis of Behçet’s disease.

TNF, tumor necrosis factor; IL, interleukin; CTLA-4, cytotoyic T-lymphocyte antigen-4 [6,7].


Genetic factor:

The prevalence of the HLA-B51 allele is

high among BD patients (81% of Asians

and 13% in Western countries) [15].

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].

Computer illustration of HLA-B*5101 with HIV peptide in the binding pocket.


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].


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].


Diagnosis

Behçet’s disease

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]

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].


ISG Criteria for diagnosis of Behcet’s disease. Criterion Definition

Recurrent Oral ulcers

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 lesionsAnterior/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]

Aphthous ulcer of the labial mucosa [31]


Uveitis[ NHS Wales]


Erythema nodosum [Medical Point]

Papulo-pustules [Quizlet]

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].


Disease activity

Behçet’s disease

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

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 No symptoms 1 Symptoms for 1 week (1-7 days in total) 2 Symptoms for 2 weeks (8-14 days in total) 3 Symptoms for 3 weeks (15-21 days in total) 4 Symptoms for 4 weeks (22-28 days in total) (3) Eye involvement: Eye activity may be present if the following symptoms are present: Red eye Blurred vision Painful eyePlease 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?


Management

Behçets disease

Therapeutic approach to BD.

TNF: Tumor Necrosis Factor, IFN: Interferon. [6,7]

Behçet’s disease: Management

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 pro-

inflammatory 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.

Interleukin-23

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.

Ustekinumab mechanism of action.

Interleukin-23

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].

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].

Interleukin-23

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

1Rheumatology Department, Faculty of Medicine, Cairo University2Neuropsychiatry Department, Faculty of Medicine, Cairo University3internal Medicine Department, Faculty of Medicine, Cairo University4Oral and Maxillofacial Surgeon, Faculty of Oral & Dental Medicine, Cairo University5Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University6Clinical Pharmacology Department, Faculty of Pharmacy, Cairo University

Tamer A Gheita1, Sherif M Gamal1 , Ihab Shaker2, Hussein S El Fishawy3, Rehab El Sisi4, Olfat G Shaker5, Sanaa A Kenawy 6

The Clinical Study

Letter to the Editor Joint Bone Spine, 2015; 82:209–17

The Clinical Study

Background

The Clinical Study

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: Background

Aim of the work

The Clinical Study

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: Aim of the work

Patients and Methods

The Clinical Study

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: Patients and Methods

Results

The Clinical Study

Feature (mean±SD) BD patients (50)Age (years) 35.2 ±7.2Disease duration (years) 8.6 ±5.9BMI 26.7 ±4.2BDCAF 2.6 ±1.5Steroid dose (mg/d) 12.3 ±8.8Colchicine dose (mg/d) 0.97 ±0.5Hemoglobin (g/dl) 12.9 ±1.1TLC (x103/mm3) 7.8 ±2.3Platelets (x103/ mm3) 292.2 ±76.9ESR (mm/1st hr) 36.1 ±20.7Hs-CRP (mg/dl) 6.1 ±8.03

Interleukin-23 (pg/ml) 37.1 ± 12.2

IL23R (rs17375018) genotype n (%)AA 8 (16)AG 18 (36) GG 24 (48)

Table 1: Characteristics, serum IL-23 and IL-23R genotype in BD patients.

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

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

Clinical Characteristicn (%)

Serum IL-23 (pg/ml) in BD patients (n=50) Presence Absence p value

Oral ulcers 50 (100) - - -

Genital ulcers 41 (82) 36.6±12.03 39.5 ±14.6 0.61

Uveitis 24 (48) 42.6±12.9 32.04 ± 9.1 0.002

Skin lesions 37 (74) 38.6±12.4 32.9 ±11.2 0.13

Neuro-Behçets 19 (38) 42.6±14.4 33.7 ± 9.4 0.02

Pulmonary 11 (22) 38.2±12.8 36.8 ±12.2 0.75

Arthritis 19 (38) 37.6±12.5 36.8 ±12.3 0.84

DVT 17 (34) 41.3±10.3 34.9 ±12.7 0.06

FMS 12 (24) 43.7±12.9 35.04 ±11.4 0.054

+ve pathergy 14 (28) 41.5±12.1 35.4 ±12 0.13

Table 2: Serum IL-23 level according to the presence and absence of clinical characteristics in Behçet’s disease (BD) patients.

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).

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)


Conclusions

The Clinical Study

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 neuro-

Behçet'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.

The Clinical Study: Conclusions

Kasr Al-Ainy School of Medicine

Cairo University

Thank You

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Clinical significance of interleukin-23 and gene polymorphism in Behçets disease Tamer A Gheita, MD...

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