1. R heumatology R esearch C enter

2. CHARACTERISTICS Peripheral Arthritis: Asymmetric, Lower Limb Tendency to Sacroiliitis (X-Ray) Absence: RF, RA Nodes, Extra-articular Features Familial Aggregation HLA-B27 Peripheral Arthritis: Asymmetric, Lower Limb Tendency to Sacroiliitis (X-Ray) Absence: RF, RA Nodes, Extra-articular Features Familial Aggregation HLA-B27

3. CLASSIFICATION Ankylosing Spondylitis Reiter’s Syndrome Arthropathy of Inflammatory Bowel Dis. Psoriatic Arthritis Undifferentiated SPA Juvenile AS Ankylosing Spondylitis Reiter’s Syndrome Arthropathy of Inflammatory Bowel Dis. Psoriatic Arthritis Undifferentiated SPA Juvenile AS

4. R heumatology R esearch C enter

6. GENERAL PATTERN Young Male Articular Manifestations –SI Joints –Spine –Peripheral Joints: Rhyzomelic Extra-Articular Manifestations –Uveitis –Aortitis HLA-B27 Young Male Articular Manifestations –SI Joints –Spine –Peripheral Joints: Rhyzomelic Extra-Articular Manifestations –Uveitis –Aortitis HLA-B27

7. HISTORY Brodie1850 31 year old man, Ankylosed Spine, Uveitis Strumpell1884 2 patients, Ankylosed Spine, Hip Joints Pierre Marie1889 Von Bechterew1893 X-Ray: SI joints1930 Brodie1850 31 year old man, Ankylosed Spine, Uveitis Strumpell1884 2 patients, Ankylosed Spine, Hip Joints Pierre Marie1889 Von Bechterew1893 X-Ray: SI joints1930

8. EPIDEMIOLOGY 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 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

9. ETIOLOGY Unknown Strong Association with B27: Hypothesis –In Susceptible Individuals Immune Response Genetically Determined To Environmental Factors Unknown Strong Association with B27: Hypothesis –In Susceptible Individuals Immune Response Genetically Determined To Environmental Factors

10. HLA-B27 B*2705, B*2704, B*2702 Association B*2706, B*2709 Preventive HLA-B27 in General Population 2-10% HLA-B27 in AS 90% –Iran (RRC)55% - 60% AS in HLA-B27 1-2% AS in First Degree Relatives 10-30% B*2705, B*2704, B*2702 Association B*2706, B*2709 Preventive HLA-B27 in General Population 2-10% HLA-B27 in AS 90% –Iran (RRC)55% - 60% AS in HLA-B27 1-2% AS in First Degree Relatives 10-30%

11. FAMILIAL BACKGROUND Siblings 10% Twins –Monozygotic63% –Dizygotic12.5% – Dizygotic + B2723% Other Genetic Factors Siblings 10% Twins –Monozygotic63% –Dizygotic12.5% – Dizygotic + B2723% Other Genetic Factors

12. OTHER GENETIC FACTORS HLA-B60 3-6 fold increase Other Genetic Factors –Other HLA B7-Creg, B38, B39, DR1, DR8 –Non-HLA Chromosome 16 (Crohn), 17 (Psoriasis) HLA-B60 3-6 fold increase Other Genetic Factors –Other HLA B7-Creg, B38, B39, DR1, DR8 –Non-HLA Chromosome 16 (Crohn), 17 (Psoriasis)

13. ENVIRONMENTAL FACTORS Shigella Flexneri –Reactive to Anti-B27 Antibody Yersinia Enterocolittica –Reactive to Anti-B27 Antibody Escherishia Coli –IgA Antibody in AS Patients Klebsiella Pneumoniae Shigella Flexneri –Reactive to Anti-B27 Antibody Yersinia Enterocolittica –Reactive to Anti-B27 Antibody Escherishia Coli –IgA Antibody in AS Patients Klebsiella Pneumoniae

14. KLEBSIELLA Pneumoniae IgA & IgG Antibodies in AS –ELISA Antigen Resembling B27 –Nitrogenase Enzyme Cross-Reacting Antibodies –Anti-B27 Antibody Bind to B27 positive Cells Disease Manifestations IgA & IgG Antibodies in AS –ELISA Antigen Resembling B27 –Nitrogenase Enzyme Cross-Reacting Antibodies –Anti-B27 Antibody Bind to B27 positive Cells Disease Manifestations

15. SCENARIO

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

17. MOLECULAR MIMICRY ANTIBODY (anti B27) ANTIBODY (anti B27) B27 Cells T-Cell (CD8+) IMMUNE REACTION MICRO-ORGANISM (Peptide Mimicking B27) MICRO-ORGANISM (Peptide Mimicking B27) APC T-Cell (CD4+) B-Cell

18. AUTO-REACTIVE T CELLS HLA-B27 (Intra Thymus) HLA-B27 (Intra Thymus) Autoreactive CD8+ T-Cell MICRO-ORGANISM (Intra Cellular) MICRO-ORGANISM (Intra Cellular) APC – B27 T-Cell (CD8+) IMMUNE RESPONSE Periphery

20. GENERAL PATTERN Articular Manifestations –Central SI Joints Lumbar Spine Dorsal Spine Cervical Spine –Peripheral Extra-Articular Manifestations –Enthesitis –Eye –Aorta –Kidney Articular Manifestations –Central SI Joints Lumbar Spine Dorsal Spine Cervical Spine –Peripheral Extra-Articular Manifestations –Enthesitis –Eye –Aorta –Kidney

21. PAIN & STIFFNESS INFLAMMATORY –Morning –> 1 hour NOCTURNAL –Second half –Awaken –Walk INFLAMMATORY –Morning –> 1 hour NOCTURNAL –Second half –Awaken –Walk

22. SACROILIITIS Bilateral Pelvic Pain –Buttock –Referral Pain Physical Exam –Direct Pressure –Direct Mobilization –Indirect Mobilization Evolution –Bony Ankylosis Bilateral Pelvic Pain –Buttock –Referral Pain Physical Exam –Direct Pressure –Direct Mobilization –Indirect Mobilization Evolution –Bony Ankylosis

23. LUMBAR SPINE Low Back Pain –Referral Pain –Sciatica Irradiation Physical Exam –Limitation –Shober Test Progression –Loss of Lordosis –Ankylosis Low Back Pain –Referral Pain –Sciatica Irradiation Physical Exam –Limitation –Shober Test Progression –Loss of Lordosis –Ankylosis

24. DORSAL SPINE Back Pain –Chondro-costal Pain –Intercostal Irradiation Physical Exam –Limitation –Chest Expansion Progression –kyphosis –Ankylosis Back Pain –Chondro-costal Pain –Intercostal Irradiation Physical Exam –Limitation –Chest Expansion Progression –kyphosis –Ankylosis

25. CERVICAL SPINE Neck Pain –Referral Pain –Cervico-Brachial Irradiation Physical Exam –Limitation Progression –Loss of Lordosis, kyphosis –Ankylosis Neck Pain –Referral Pain –Cervico-Brachial Irradiation Physical Exam –Limitation Progression –Loss of Lordosis, kyphosis –Ankylosis

26. SPINE DEFORMITY

27. PERIPHERAL JOINTS Rhyzomelic Joints –Hip –Shoulder Talalgia Large and Medium Joints Small Joints –Sterno-Clavicular –Temporo-Mendibular Rhyzomelic Joints –Hip –Shoulder Talalgia Large and Medium Joints Small Joints –Sterno-Clavicular –Temporo-Mendibular

28. EXTRA-ARTICULAR Eye Involvement Cardiovascular Manifestations Pulmonary Disease Neurological Manifestations Renal Manifestations Bowel Disease Eye Involvement Cardiovascular Manifestations Pulmonary Disease Neurological Manifestations Renal Manifestations Bowel Disease

29. EYE LESIONS (Ant. Uveitis) 25%, Unilateral, Acute Onset, B27 Related Clinical Manifestations –Pain –Increased Lacrymation –Photophobia –Blurred Vision Exam –Discolored Iris –Small Pupil ProgressionSelf Subsiding 25%, Unilateral, Acute Onset, B27 Related Clinical Manifestations –Pain –Increased Lacrymation –Photophobia –Blurred Vision Exam –Discolored Iris –Small Pupil ProgressionSelf Subsiding

30. CARDIAC MANIFESTATIONS Aortic Valve Incompetence Ascending Aortitis Cardiac Conduction Abnormality Cardiomegaly Pericarditis Aortic Valve Incompetence Ascending Aortitis Cardiac Conduction Abnormality Cardiomegaly Pericarditis

31. PULMONARY Rare, very late onset (20 y) Fibrosis of Upper lobes –Cough –Dyspnea –Hemoptysis X-ray Linear or Patchy Opacities Rare, very late onset (20 y) Fibrosis of Upper lobes –Cough –Dyspnea –Hemoptysis X-ray Linear or Patchy Opacities

32. NEUROLOGICAL Quadriplegia –Atlantoaxial Subluxation –Cervical Fracture  Dislocation Paraplegia –Cervical or Dorsal Fracture Coda Equina –Spontaneous –Fracture Quadriplegia –Atlantoaxial Subluxation –Cervical Fracture  Dislocation Paraplegia –Cervical or Dorsal Fracture Coda Equina –Spontaneous –Fracture

33. RENAL INVOLVEMENY IgA Nephropathy Amyloidosis IgA Nephropathy Amyloidosis

34. BOWEL DISEASE Enteric Mucosal Inflammation –Terminal Ileum –Colon –Asymptomatic Enteric Mucosal Inflammation –Terminal Ileum –Colon –Asymptomatic

36. LAB TESTS Inflammatory –ESR –CRP HLA-B27 –90%(Iran 55%, RRC Studies) Urinalysis –Proteinuria Inflammatory –ESR –CRP HLA-B27 –90%(Iran 55%, RRC Studies) Urinalysis –Proteinuria

37. X-RAY SI Joints Spine Peripheral Joints –Hip –Others SI Joints Spine Peripheral Joints –Hip –Others

38. SACROILIAC JOINT Pseudo-Widening Blurred Borders Irregularity (Post Stamp Serration) Bony Sclerosis Progression –Bony Ankylosis Pseudo-Widening Blurred Borders Irregularity (Post Stamp Serration) Bony Sclerosis Progression –Bony Ankylosis

39. SACROILIITIS

47. SPINE Syndesmophyte Squaring (Romanus) Ligament Ossification Spondylodiscitis Syndesmophyte Squaring (Romanus) Ligament Ossification Spondylodiscitis

48. SYNDESMOPHYTE

51. BAMBOO SPINE

52. PATHOPHYSIOLOGY

53. DISCAL OSSIFICATION

54. ROMANUS

56. SPONDYLO-DISCITIS

57. LIGAMENT OSSIFICATION

58. PERIPHERAL JOINTS Hip –Erosive Arthritis –Non Erosive Bony Ankylosis Others Hip –Erosive Arthritis –Non Erosive Bony Ankylosis Others

59. COXITIS

64. SHOULDER

65. CALCANEITIS

69. NSAID Full Dose –COX1: Indomethacin150 mg/24h –COX2: Celecoxib (Cobix*)600 mg/24h Adjust To Need Full Dose –COX1: Indomethacin150 mg/24h –COX2: Celecoxib (Cobix*)600 mg/24h Adjust To Need

70. DMARD Sulphasalazine2 to 3 g/24 h Methotrexate7.5 to 15 mg/week Prednisolone5-10 mg/daily Anti TNF –Etanercept25mg2/weekly SC –Infliximab5mg/kgweek 0-2-6-12-18 IV Sulphasalazine2 to 3 g/24 h Methotrexate7.5 to 15 mg/week Prednisolone5-10 mg/daily Anti TNF –Etanercept25mg2/weekly SC –Infliximab5mg/kgweek 0-2-6-12-18 IV