SERONEGATIVE SPONDYLARTHROPATHY

Rheumatology Research CenterRheumatology Research Center

CHARACTERISTICSCHARACTERISTICS

• 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

CLASSIFICATIONCLASSIFICATION

• 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

Rheumatology Research CenterRheumatology Research Center

GENERAL PATTERNGENERAL 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

HISTORYHISTORY

• Brodie 1850• 31 year old man, Ankylosed Spine, Uveitis

• Strumpell 1884• 2 patients, Ankylosed Spine, Hip Joints

• Pierre Marie 1889

• Von Bechterew 1893

• X-Ray: SI joints 1930

• Brodie 1850• 31 year old man, Ankylosed Spine, Uveitis

• Strumpell 1884• 2 patients, Ankylosed Spine, Hip Joints

• Pierre Marie 1889

• Von Bechterew 1893

• X-Ray: SI joints 1930

EPIDEMIOLOGYEPIDEMIOLOGY• 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

ETIOLOGYETIOLOGY• 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

HLA-B27HLA-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%

FAMILIAL BACKGROUNDFAMILIAL BACKGROUND

• Siblings 10%

• Twins

– Monozygotic 63%

– Dizygotic 12.5%

– Dizygotic + B27 23%

• Other Genetic Factors

• Siblings 10%

• Twins

– Monozygotic 63%

– Dizygotic 12.5%

– Dizygotic + B27 23%

• Other Genetic Factors

OTHER GENETIC FACTORSOTHER 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)

ENVIRONMENTAL FACTORSENVIRONMENTAL 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

KLEBSIELLA PneumoniaeKLEBSIELLA 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

SCENARIOSCENARIO

INFECTIOUS DISSEMINATIONINFECTIOUS DISSEMINATIONMICRO-ORGANISM

(Intra Cellular)MICRO-ORGANISM

(Intra Cellular)

APC – B27APC – B27

T-Cell (CD8+)T-Cell (CD8+)

IMMUNE RESPONSEIMMUNE RESPONSE

MOLECULAR MIMICRYMOLECULAR MIMICRY

ANTIBODY(anti B27)

ANTIBODY(anti B27)

B27 CellsB27 Cells

T-Cell (CD8+)T-Cell (CD8+)

IMMUNE REACTIONIMMUNE REACTION

MICRO-ORGANISM(Peptide Mimicking B27)MICRO-ORGANISM(Peptide Mimicking B27)

APC APC

T-Cell (CD4+)T-Cell (CD4+)

B-CellB-Cell

AUTO-REACTIVE T CELLSAUTO-REACTIVE T CELLS

HLA-B27(Intra Thymus)

HLA-B27(Intra Thymus)

Autoreactive CD8+ T-CellAutoreactive CD8+ T-Cell

MICRO-ORGANISM(Intra Cellular)

MICRO-ORGANISM(Intra Cellular)

APC – B27APC – B27

T-Cell (CD8+)T-Cell (CD8+)

IMMUNE RESPONSEIMMUNE RESPONSE

Periphery

GENERAL PATTERNGENERAL 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

PAIN & STIFFNESSPAIN & STIFFNESS

• INFLAMMATORY

– Morning

– > 1 hour

• NOCTURNAL

– Second half

– Awaken

– Walk

• INFLAMMATORY

– Morning

– > 1 hour

• NOCTURNAL

– Second half

– Awaken

– Walk

SACROILIITISSACROILIITIS• 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

LUMBAR SPINELUMBAR 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

DORSAL SPINEDORSAL 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

CERVICAL SPINECERVICAL 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

SPINE DEFORMITYSPINE DEFORMITY

PERIPHERAL JOINTSPERIPHERAL 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

EXTRA-ARTICULAREXTRA-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

EYE LESIONS (Ant. Uveitis)EYE LESIONS (Ant. Uveitis)

• 25%, Unilateral, Acute Onset, B27 Related

• Clinical Manifestations– Pain

– Increased Lacrymation

– Photophobia

– Blurred Vision

• Exam– Discolored Iris

– Small Pupil

• Progression Self Subsiding

• 25%, Unilateral, Acute Onset, B27 Related

• Clinical Manifestations– Pain

– Increased Lacrymation

– Photophobia

– Blurred Vision

• Exam– Discolored Iris

– Small Pupil

• Progression Self Subsiding

CARDIAC MANIFESTATIONSCARDIAC MANIFESTATIONS

• Aortic Valve Incompetence

• Ascending Aortitis

• Cardiac Conduction Abnormality

• Cardiomegaly

• Pericarditis

• Aortic Valve Incompetence

• Ascending Aortitis

• Cardiac Conduction Abnormality

• Cardiomegaly

• Pericarditis

PULMONARYPULMONARY

• 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

NEUROLOGICALNEUROLOGICAL

• 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

RENAL INVOLVEMENYRENAL INVOLVEMENY

• IgA Nephropathy

• Amyloidosis

• IgA Nephropathy

• Amyloidosis

BOWEL DISEASEBOWEL DISEASE

• Enteric Mucosal Inflammation

– Terminal Ileum

– Colon

– Asymptomatic

• Enteric Mucosal Inflammation

– Terminal Ileum

– Colon

– Asymptomatic

LAB TESTSLAB 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

X-RAYX-RAY

• SI Joints

• Spine

• Peripheral Joints

– Hip

– Others

• SI Joints

• Spine

• Peripheral Joints

– Hip

– Others

SACROILIAC JOINTSACROILIAC 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

SACROILIITISSACROILIITIS

SACROILIITISSACROILIITIS

SACROILIITISSACROILIITIS

SACROILIITISSACROILIITIS

SACROILIITISSACROILIITIS

SACROILIITISSACROILIITIS

SACROILIITISSACROILIITIS

SACROILIITISSACROILIITIS

SPINESPINE

• Syndesmophyte

• Squaring (Romanus)

• Ligament Ossification

• Spondylodiscitis

• Syndesmophyte

• Squaring (Romanus)

• Ligament Ossification

• Spondylodiscitis

SYNDESMOPHYTESYNDESMOPHYTE

SYNDESMOPHYTESYNDESMOPHYTE

SYNDESMOPHYTESYNDESMOPHYTE

BAMBOO SPINEBAMBOO SPINE

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

DISCAL OSSIFICATIONDISCAL OSSIFICATION

ROMANUSROMANUS

ROMANUSROMANUS

SPONDYLO-DISCITISSPONDYLO-DISCITIS

LIGAMENT OSSIFICATIONLIGAMENT OSSIFICATION

PERIPHERAL JOINTSPERIPHERAL JOINTS

• Hip

– Erosive Arthritis

– Non Erosive Bony Ankylosis

• Others

• Hip

– Erosive Arthritis

– Non Erosive Bony Ankylosis

• Others

COXITISCOXITIS

COXITISCOXITIS

COXITISCOXITIS

COXITISCOXITIS

COXITISCOXITIS

SHOULDERSHOULDER

CALCANEITISCALCANEITIS

CALCANEITISCALCANEITIS

CALCANEITISCALCANEITIS

NSAIDNSAID

• Full Dose

– COX1: Indomethacin 150 mg/24h

– COX2: Celecoxib (Cobix*) 600 mg/24h

• Adjust To Need

• Full Dose

– COX1: Indomethacin 150 mg/24h

– COX2: Celecoxib (Cobix*) 600 mg/24h

• Adjust To Need

DMARDDMARD

• Sulphasalazine 2 to 3 g/24 h

• Methotrexate 7.5 to 15 mg/week

• Prednisolone 5-10 mg/daily

• Anti TNF

– Etanercept 25mg 2/weekly SC

– Infliximab 5mg/kg week 0-2-6-12-18 IV

• Sulphasalazine 2 to 3 g/24 h

• Methotrexate 7.5 to 15 mg/week

• Prednisolone 5-10 mg/daily

• Anti TNF

– Etanercept 25mg 2/weekly SC

– Infliximab 5mg/kg week 0-2-6-12-18 IV