1. PARISA MOMEN ZADEH Supervisor: Dr. Mahdi Mahmoudi June 2013 1

2.  History  Introduction  Diagnosis  Epidemiology  Pathophysiology  Treatment 2

3.  Vladimir Bekhterev of Russia in 1893  Adolph Strumpell of Germany in 1897  Pierre Marie of France in 1898 3

4.  Spondylitis ankylosing is a chronic inflammatory disease of the sacroiliac joints and spine that may be associated with variety of extraspinal lesions. 4

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7. Skeletal Manifestations Central SI joint Spine Peripheral Enthesitis Exteraskeletal Manifestations Eye Cardiovascular Pulmonar Neurologic Renal 7

8. Ankylosing spondylitis affects the eyes > %40 of cases leading to episodes of eye inflammation called acute iritis. Acute iritis causes Eye pain Increased sensitivity to light

9.  MODIFIED NEW YORK CRITERIA FOR ANKYLOSING SPONDYLITIS.  Criteria 1.Low back pain of at least 3 months duration improved by exercise and not relieved by rest. 2.Limitation of lumbar spine in sagittal and frontal planes. 3.Chest expansion decreased relative to normal values for age and sex. 4a.Unilateral sacroilliatis grade 3 or 4 4b.Bilateral sacroillitis grade 2 to 4  Definite ankylosing spondylitis if(4a or 4b) and any clinical criteria(1-3) 9

10.  Prevalence ◦ 0.5 to 2 / 1000 ◦ 10 to 20 / 1000 of B27 ◦ 100 to 300 / 1000 of B27 + Family Background  Incidence ◦ 7.3 / 100,000 / Year  Racial Distribution ◦ B27 Related ◦ White, African American, African, Japanese 10

11.  The disease occurs in young adults (10–40 years old), especially in those aged 20 to 30 years. occurs with a frequency of 0.5-5/100,000 in males, being less common in females and blacks. 11

12.  Genetic 12 Immune Response Environmen tal Factors

13.  According to recent genome-wide association studies the MHC locus was the largest cause of susceptibility to AS and six non-MHC regions were related to AS.These regions were located on chromosomes 1p,2q,9q,10q,16q and 19q.IL-1 gene family is located in these regions. 13

14.  HLA-B27 in General Population 2-10%  HLA-B27 in AS 90%  Iran (RRC) 92%  AS in HLA-B27 1-2%  AS in First Degree Relatives 10- 30%  Twins  Monozygotic 63%  Dizygotic 12.5% 14

15.  B*2705, B*2704, B*2702 Causative  B*2706, B*2709 Preventive 15

16. .HLA-B27.ERAP( endoplasmic reticulum aminopeptidase ).IL-1R2( interleukin-1receptor type2 ).IL-23R.ANTXR2( anthrax toxin receptor 2 )..CARD9.SNAPC4,… 16

17. Linkage between HLA-B27 (HLA locus on the short arm of chromosome 6p21.31)and AS is the strongest known association between an HLA class I molecule and a disease. HLA class I molecules present peptides repertoires from the metabolic degradation of endogenous proteins to cytolytic T-lymphocytes (CTLs) and natural killer (NK) cells, evaluating for tolerance to self-antigens. Thus, peptide binding determines the properties of HLA class I molecules, and the study of the pathogenic role of HLA-B27 in AS has focused on their function as presenting antigenic peptides, although their involvement in disease has not yet been established. 17

18. MICRO-ORGANISM (Intra Cellular) MICRO-ORGANISM (Intra Cellular) 18 APC – B27 T-Cell (CD8+) IMMUNE RESPONSE

19.  ARTS 1 : ( encoded by three genes on chromosome 5 )  Endoplasmic reticulum aminopeptidase  ERAP is associated with HLA-B27 processing  Two known effects of ARTS 1 ◦ Cleavage of cytokine receptors(IL-1, IL-6, TNF) from the cell surface ◦ Cleavage of the N-terminus of peptide precursors in the reticulum  optimal length for the presentation by HLA class I molecules 19 ARTS1 is responsible for processing peptides to optimal length for the presentation by HLA class I molecules

20.  IL-23R encoded on chromosome 1p31.3, has been identified as having a major role in many human disease, including psoriasis and IBD.IL-23R is a key regulator of the inflammatory pathway.Blockade of the IL-23R pathway has been shown to suppress the development of IBD and psoriasis.Because of both IBD psoriasis occur in AS patients, IL- 23R is also associated with AS process. 20

21.  IL-1R2 synthesized and released against infection.According to the role of IL-1 as a pro-inflammatory cytokine and their role in autoimmune disease we investigated some SNPs in this gene in AS patient. 21

22.  ANTAXR2 encodes a receptor for anthrxtoxin.The protein binds to collagen IV and laminin.Mutation in this gene cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.Multiple transcript variant encoding different isoforms have been found for this gene. 22

23.  CARD9 encoded on chromosome 9q has a central role in the regulation of the innate immune system. It functions as a cytosolic signal transduction protein with several distinct roles. It acts downstream of the antifungal pattern recognition receptor (PRR), dectin 1 and splenic tyrosine kinase (SYK). Activation of SYK leads to signaling through CARD9 which acts with BCL10 (Bcell Lymphoma and MALT1 to induce pro-inflammatory signals via the canonical NF-κ B pathway and the stimulation of the p38 MAP kinase and JNK pathways. CARD9 also has a role in the detection of intracellular pathogens via cytoplasmic PRRs of the NOD family. For example, CARD9 has a critical function in NOD2-mediated activation of p38 and JNK in innate immune responses to intracellular pathogens. Stimulation of CARD9 induces the maturation of dendritic cells into antigen-presenting cells that can prime naïve T cells to become IFN-γ -producing Th1 cells and/or IL-17 producing Th17 cells. The latter have already been implicated in AS because of the association of IL23R with AS and its role in Th17 cell Propagation. Thus CARD9 has a role in coupling the innate and adaptive immune responses. 23

24.  SNAPC4 encoded on chromosome 9q is a subunit of the SNAP complex, a multi- subunit complex of proteins that required for the transcription of RNA polymerase II and III snRNAs. A role for this gene in susceptibility to AS seems relatively unlikely and it is more likely that the SNAPC4 SNP is in linkage disequilibrium (LD) with a CARD9 - associated SNP. 24

25. Chromosom al band SNPPositionCandidate gene Minor allele 9q34.3rs4077515139266496CARD9T 9q34.3rs3812571139275294SNAPC4C 2q11.2rs2310173102030060IL1R2A 4q21.21rs433313081168853ANTXR2G 25

26.  Mechanical stress at the entheses  Infection by specific pathogenes such as Klebsiella Pneumoniae 26

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28. 28 Shober Shober TestTest

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31.  Inflammatory ◦ ESR ◦ CRP  HLA-B27 ◦ 90%(Iran 55%, RRC Studies)  Urinalysis ◦ Proteinuria Hemar 31

32.  SI Joints  Spine  Peripheral Joints ◦ Hip ◦ Others 32

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34. Physical Therapy,Exercise and patient Education 34 Medical NSAIDs DMARDs TNF  blockers Surgical

35. 35 THANK YOU